Cancer microRNA May Play a Role in Regulating Events in the Nucleus

microRNAs (miRNA), non-coding RNA molecules, are widely known for regulating mRNA stability and translation. miR-10b has been increasingly implicated in the pathogenesis of gliomas, cancers of the brain. Given the therapeutic potential of targeting miR-10b, researchers at the Brigham sought to understand the mechanism behind the glioma dependence, often referred to as addiction, on miR-10b. Using Covalent Ligation of Endogenous Argonaute-bound RNAs and subsequent RNA sequencing (CLEAR-CLIP), which enables an unbiased identification of miRNA targets, researchers discovered a new and unconventional nuclear function for miR-10b. They found that it interacts with U6 snRNA, a core component of nuclear spliceosomal machinery, resulting in global splicing alterations within glioma cells and tumors. The work contributes to a growing body of evidence supporting miRNA nuclear localization and subsequent cancer-associated aberrations in gene expression.

“Although our data reveals the mechanistic relationships between miR-10b binding to U6, and miR-10b effects on U6 modifications and structure, the molecular mechanisms underlying downstream splicing alterations need to be further investigated,” said corresponding author Anna M. Krichevsky, PhD, of the Department of Neurology. “Through this paper, we show an unexpected intersection of the miRNA and splicing machineries and consider this to be an important step toward miRNA-based treatment of cancers.”

Read more in Molecular Cancer.

Researchers Use Endotyping to Explore Underlying Biology of Asthma

Asthma affects 26 million people in the U.S. It has been hypothesized that there are multiple asthma endotypes — subtypes defined by a distinct pathophysiological mechanism. Researchers at the Brigham have identified five different metabolomic-driven endotypes, or “metabo-endotypes,” of asthma and interrogated their underlying biology. Using data from the Genetics of Asthma in Costa Rica Study (GACRS) and the Childhood Asthma Management Program (CAMP), the research team found the five metabo-endotypes show major differences in asthma-relevant phenotypes, specifically relating to lung obstruction. They determined that cholesterol esters, triglycerides and fatty acids were the major drivers of these metabo-endotypes. The goal of this study is to further clinicians’ understandings of asthma endotypes so that treatment can be optimized to that endotype.

“With our findings, a clinician can more appropriately treat an individual’s disease because they can target its particular mechanisms,” said Rachel Kelly, PhD, of the Brigham’s Channing Division of Network Medicine. “I believe endotyping will become a critical focus for many complex diseases as we move toward precision medicine, and as such, they will become a critical part of the patient experience.”

Read more in the American Journal of Respiratory and Critical Care Medicine.

Female Primary Care Physicians Face A Higher Electronic Health Record Workload Than Male Counterparts

Previous studies have shown that female physicians spend more time working in the electronic health record (EHR) than do male physicians. A new study from the Brigham examines the reasons for this difference. The retrospective study included a sample of 125 primary care physicians (PCPs) at the Brigham and measured the time spent in the EHR, as well as the volume of messages that PCPs received from both staff and patients. The results show that female PCPs spend 20 percent more time working in the EHR inbasket than do male PCPs.  This difference was not explained by the higher percentage of female patients seen by female PCPs.  Instead, the increased time in the EHR inbasket was explained by the significantly higher volume of messages sent to female PCPs compared with their male counterparts: female PCPs received 24 percent more messages from staff, and 26 percent more messages from patients. The authors suggest that development of strategies to address the disproportionate EHR workload is needed in order to decrease the high rate of burnout among female PCPs.

“These differential EHR burdens may contribute to higher burnout rates in female PCPs,” said Eve Rittenberg, MD, of the Brigham’s Division of Women’s Health. “In particular, time spent in the EHR inbasket, within which physicians respond to messages from patients, staff, and colleagues, has been linked to burnout.”

Read more in the Journal of General Internal Medicine.

Preserved Ratio Impaired Spirometry Associated with Increased Risk of Adverse Clinical Outcomes and Mortality

Patients with chronic lung diseases are often at a higher risk for morbidity and mortality than the average patient. While much is known about chronic obstructive pulmonary disease, clinical outcomes for patients with preserved ratio impaired spirometry (PRISm) are less understood. PRISm refers to a reduction in two key parameters that measure how much air a person can expel from their lungs both in the first second and during a full exhalation. Researchers at the Brigham sought to understand the prevalence, correlates, and clinical outcomes associated with PRISm in U.S. adults. The team conducted a retrospective cohort study with pooled, harmonized data from nine population-based cohorts (53,701 participants). The authors found a statistically significant increased risk for adverse respiratory and cardiovascular outcomes as well as mortality, among patients with PRISm compared to those with normal spirometry. However, additional research is needed to determine if this association is in fact causal.

“Though there are high prevalence rates of PRISm globally, there are currently no guidelines for how to evaluate and manage PRISm,” said lead author Emily S. Wan, MD, MPH of the Channing Division of Network Medicine. “Through this paper, we wanted to understand if PRISm is associated with adverse clinical outcomes relative to normal spirometry in a population-based sample of U.S. adults. Now that we have established that there is in fact a positive, significant correlation, the next steps will be to determine whether PRISm is a cause or consequence of disease processes which contribute to the increased rates of hospitalizations and death observed. Understanding this relationship will ultimately allow us to develop evidence-based guidelines to improve the care we deliver to our patients.”

Read more in JAMA.


Investigation Identifies Recurring Diagnostic Pitfalls and Points to Ways That Uncovering Pitfalls Can Help Improve Medical Diagnosis

When it comes to medical errors, diagnostic errors are the most common type of error reported by patients and the leading cause of malpractice claims. Brigham investigators complied and analyzed data from a diverse group of sources looking at data from 2004 to 2016 to identify patterns of diagnostic pitfalls. Data collected from 4,352 patient safety incident reports, 403 closed primary care diagnostic error malpractice claims, 24 ambulatory morbidity and mortality rounds, and 355 focus group responses found a total of 836 diagnostic errors, which the researchers use to characterize patterns of what went wrong. The findings were then used to compile a list of disease-specific diagnostic pitfalls and create a taxonomy of the generic types of errors occurring in primary care.

“Progress in understanding and preventing diagnostic errors has been modest, and clinicians could benefit from the knowledge of both disease-specific and generic cross-cutting pitfalls,” said Gordon D. Schiff, MD, of the Brigham’s Center for Patient Safety Research and Practice. “Our findings can help inform educational and quality improvement efforts to anticipate and prevent future errors.”

Read more in JAMA Network Open.

Artificial Intelligence May Reduce Frequency of Adverse Drug Events

Adverse drug events (ADEs), injuries related to drug-related medical interventions, are considered some of the most prevalent types of health-care-related harm. Given that these events are costly and often morbid, artificial intelligence (AI) is considered a promising tool in helping researchers and clinicians understand preventable and novel ADEs as well as a patient’s likelihood of having ADEs before receiving prescription medications. Researchers at the Brigham conducted a scoping review of 78 articles to identify the key use cases in which AI could be harnessed to prevent or mitigate the effects of ADEs. The review’s authors describe the use of AI to reduce the frequency of ADEs as an emerging area of study and identify several use cases in which AI could contribute to reducing or preventing ADEs. Furthermore, genetic information is thought to be critical in improving the performance of AI algorithms. With the prevalence of genotyping, researchers are confident that this type of data can be more accessible over time and ultimately used to improve AI algorithm functioning and patient health.

“One of our challenges is how to identify and select the most relevant genetic variables among large amounts of genetic profile information,” said lead author Ania Syrowatka, PhD, of the Division of General Internal Medicine and Primary Care. “Through this paper, we wanted to present a review of how AI could be used to prevent ADEs, and in the process, learned that we are still in the early stages of development and implementation. Systematic and comprehensive evaluations of these types of tools in prospective trials are necessary to generate the evidence to advance this field in a transparent, safe, and effective way.”

Read more in The Lancet Digital Health.


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