PCOM Library / Hot Topics in Research / Archive for "Internal Medicine"

Category: Internal Medicine

Hot Topics: New Therapy Enhances Peanut Allergy Tolerance

Jackie Werner Hot Topics in Research, Internal Medicine

AR101 Oral Immunotherapy for Peanut Allergy

PALISADE Group of Clinical Investigators, Vickery BP, Vereda A, et al. AR101 oral immunotherapy for peanut allergy. N Engl J Med. 2018;379(21):1991-2001. http://dx.doi.org/10.1056/NEJMoa1812856

BACKGROUND
Peanut allergy, for which there are no approved treatment options, affects patients who are at risk for unpredictable and occasionally life-threatening allergic reactions.

METHODS
In a phase 3 trial, we screened participants 4 to 55 years of age with peanut allergy for allergic dose-limiting symptoms at a challenge dose of 100 mg or less of peanut protein (approximately one third of a peanut kernel) in a double-blind, placebo-controlled food challenge. Participants with an allergic response were randomly assigned, in a 3:1 ratio, to receive AR101 (a peanut-derived investigational biologic oral immunotherapy drug) or placebo in an escalating-dose program. Participants who completed the regimen (i.e., received 300 mg per day of the maintenance regimen for approximately 24 weeks) underwent a double-blind, placebo-controlled food challenge at trial exit. The primary efficacy end point was the proportion of participants 4 to 17 years of age who could ingest a challenge dose of 600 mg or more, without dose-limiting symptoms.

RESULTS
Of the 551 participants who received AR101 or placebo, 496 were 4 to 17 years of age; of these, 250 of 372 participants (67.2%) who received active treatment, as compared with 5 of 124 participants (4.0%) who received placebo, were able to ingest a dose of 600 mg or more of peanut protein, without dose-limiting symptoms, at the exit food challenge (difference, 63.2 percentage points; 95% confidence interval, 53.0 to 73.3; P<0.001). During the exit food challenge, the maximum severity of symptoms was moderate in 25% of the participants in the active-drug group and 59% of those in the placebo group and severe in 5% and 11%, respectively. Adverse events during the intervention period affected more than 95% of the participants 4 to 17 years of age. A total of 34.7% of the participants in the active-drug group had mild events, as compared with 50.0% of those in the placebo group; 59.7% and 44.4% of the participants, respectively, had events that were graded as moderate, and 4.3% and 0.8%, respectively, had events that were graded as severe. Efficacy was not shown in the participants 18 years of age or older.

CONCLUSIONS
In this phase 3 trial of oral immunotherapy in children and adolescents who were highly allergic to peanut, treatment with AR101 resulted in higher doses of peanut protein that could be ingested without dose-limiting symptoms and in lower symptom severity during peanut exposure at the exit food challenge than placebo.

Hot Topics: YouTube Misinforms About Prostate Cancer

Jackie Werner Hot Topics in Research, Oncology

Dissemination of Misinformative and Biased Information about Prostate Cancer on YouTube

Loeb S, Sengupta S, Butaney M, et al. Dissemination of misinformative and biased information about prostate cancer on YouTube. Eur Urolhttps://doi.org/10.1016/j.eururo.2018.10.056.

YouTube is a social media platform with more than 1 billion users and >600 000 videos about prostate cancer. Two small studies examined the quality of prostate cancer videos on YouTube, but did not use validated instruments, examine user interactions, or characterize the spread of misinformation. We performed the largest, most comprehensive examination of prostate cancer information on YouTube to date, including the first 150 videos on screening and treatment. We used the validated DISCERN quality criteria for consumer health information and the Patient Education Materials Assessment Tool, and compared results for user engagement. The videos in our sample had up to 1.3 million views (average 45 223) and the overall quality of information was moderate. More videos described benefits (75%) than harms (53%), and only 50% promoted shared decision-making as recommended in current guidelines. Only 54% of the videos defined medical terms and few provided summaries or references. There was a significant negative correlation between scientific quality and viewer engagement (views/month p = 0.004; thumbs up/views p = 0.015). The comments section underneath some videos contained advertising and peer-to-peer medical advice. A total of 115 videos (77%) contained potentially misinformative and/or biased content within the video or comments section, with a total reach of >6 million viewers.

Patient summary
Many popular YouTube videos about prostate cancer contained biased or poor-quality information. A greater number of views and thumbs up on YouTube does not mean that the information is trustworthy.

Hot Topics: Botox May Help Aftermath of Cardiac Surgery

Jackie Werner Cardiology, Hot Topics in Research, Surgery

Long-term suppression of atrial fibrillation by botulinum toxin injection into epicardial fat pads in patients undergoing cardiac surgery: Three-year follow-up of a randomized study

Romanov A, Pokushalov E, Ponomarev D, et al. Long-term suppression of atrial fibrillation by botulinum toxin injection into epicardial fat pads in patients undergoing cardiac surgery: Three-year follow-up of a randomized study. Heart Rhythm. 2018. http://dx.doi.org/10.1016/j.hrthm.2018.08.019

Background
Botulinum toxin (BTX) injections into epicardial fat pads in patients undergoing coronary artery bypass grafting (CABG) has resulted in suppression of atrial fibrillation (AF) during the early postoperative period through 1-year of follow-up in a pilot program.

Objective
The purpose of this study was to report 3-year AF patterns by the use of implantable cardiac monitors (ICMs).

Methods
Sixty patients with a history of paroxysmal AF and indications for CABG were randomized 1:1 to either BTX or placebo injections into 4 posterior epicardial fat pads. All patients received an ICM with regular follow-up for 3 years after surgery. The primary end point of the extended follow-up period was incidence of any atrial tachyarrhythmia after 30 days of procedure until 36 months on no antiarrhythmic drugs. The secondary end points included clinical events and AF burden.

Results
At the end of 36 months, the incidence of any atrial tachyarrhythmia was 23.3% in the BTX group vs 50% in the placebo group (hazard ratio 0.36; 95% confidence interval 0.14–0.88; P = .02). AF burden at 12, 24, and 36 months was significantly lower in the BTX group than in the placebo group: 0.22% vs 1.88% ( P = .003), 1.6% vs 9.5% ( P < .001), and 1.3% vs 6.9% ( P = .007), respectively. In the BTX group, 2 patients (7%) were hospitalized during follow-up compared with 10 (33%) in the placebo group ( P = .02).

Conclusion
Injection of BTX into epicardial fat pads in patients undergoing CABG resulted in a sustained and substantial reduction in atrial tachyarrhythmia incidence and burden during 3-year follow-up, accompanied by reduction in hospitalizations.

Hot Topics: Reward Behavior Provides Insights into Depression

Jackie Werner Hot Topics in Research, Mood Disorders, Neurology

Reward behaviour is regulated by the strength of hippocampus–nucleus accumbens synapses

LeGates TA, Kvarta MD, Tooley JR, et al. Reward behaviour is regulated by the strength of hippocampus–nucleus accumbens synapses. Nature. 2018. https://doi.org/10.1038/s41586-018-0740-8.

Reward drives motivated behaviours and is essential for survival, and therefore there is strong evolutionary pressure to retain contextual information about rewarding stimuli. This drive may be abnormally strong, such as in addiction, or weak, such as in depression, in which anhedonia (loss of pleasure in response to rewarding stimuli) is a prominent symptom. Hippocampal input to the shell of the nucleus accumbens (NAc) is important for driving NAc activity1,2 and activity-dependent modulation of the strength of this input may contribute to the proper regulation of goal-directed behaviours. However, there have been few robust descriptions of the mechanisms that underlie the induction or expression of long-term potentiation (LTP) at these synapses, and there is, to our knowledge, no evidence about whether such plasticity contributes to reward-related behaviour. Here we show that high-frequency activity induces LTP at hippocampus–NAc synapses in mice via canonical, but dopamine-independent, mechanisms. The induction of LTP at this synapse in vivo drives conditioned place preference, and activity at this synapse is required for conditioned place preference in response to a natural reward. Conversely, chronic stress, which induces anhedonia, decreases the strength of this synapse and impairs LTP, whereas antidepressant treatment is accompanied by a reversal of these stress-induced changes. We conclude that hippocampus–NAc synapses show activity-dependent plasticity and suggest that their strength may be critical for contextual reward behaviour.

Hot Topics: Chronic Pain Lessened by Stimulating the Brain

Jackie Werner Hot Topics in Research, Neurology, Substance Use Disorders

Patients’ Experience With Opioid Tapering: A Conceptual Model With Recommendations for Clinicians

Ahn S, Prim JH, Alexander ML, McCulloch KL, Fröhlich F. Identifying and engaging neuronal oscillations by transcranial alternating current stimulation in patients with chronic low back pain: A randomized, crossover, double-blind, sham-controlled pilot study. The Journal of Pain. . https://doi.org/10.1016/j.jpain.2018.09.004

Clinical guidelines discourage prescribing opioids for chronic pain, but give minimal advice about how to discuss opioid tapering with patients. We conducted focus groups and interviews involving 21 adults with chronic back or neck pain in different stages of opioid tapering. Transcripts were qualitatively analyzed to characterize patients’ tapering experiences, build a conceptual model of these experiences, and identify strategies for promoting productive discussions of opioid tapering. Analyses revealed 3 major themes. First, owing to dynamic changes in patients’ social relationships, emotional state, and health status, patients’ pain and their perceived need for opioids fluctuate daily; this finding may conflict with recommendations to taper by a certain amount each month. Second, tapering requires substantial patient effort across multiple domains of patients’ everyday lives; patients discuss this effort superficially, if at all, with clinicians. Third, patients use a variety of strategies to manage the tapering process (eg, keeping an opioid stash, timing opioid consumption based on planned activities). Recommendations for promoting productive tapering discussions include understanding the social and emotional dynamics likely to impact patients’ tapering, addressing patient fears, focusing on patients’ best interests, providing anticipatory guidance about tapering, and developing an individualized tapering plan that can be adjusted based on patient response.

Perspective: This study used interview and focus group data to characterize patients’ experiences with opioid tapering and identify communication strategies that are likely to foster productive, patient-centered discussions of opioid tapering. Findings will inform further research on tapering and help primary care clinicians to address this important, often challenging topic.

Hot Topics: Some Seizures Start After Brain Inhibition

Jackie Werner Biomedical Sciences, Hot Topics in Research, Neurology

Low‐Voltage Fast Seizures in Humans Begin with Increased Interneuron Firing

Elahian B, Lado NE, Mankin E, et al. Low-voltage fast seizures in humans begin with increased interneuron firing. Annals of Neurology. 2018. https://doi.org/10.1002/ana.25325

Objective
Intracellular recordings from cells in entorhinal cortex tissue slices show that low‐voltage fast (LVF) onset seizures are generated by inhibitory events. Here, we determined whether increased firing of interneurons occurs at the onset of spontaneous mesial–temporal LVF seizures recorded in patients.

Methods
The seizure onset zone (SOZ) was identified using visual inspection of the intracranial electroencephalogram. We used wavelet clustering and temporal autocorrelations to characterize changes in single‐unit activity during the onset of LVF seizures recorded from microelectrodes in mesial–temporal structures. Action potentials generated by principal neurons and interneurons (ie, putative excitatory and inhibitory neurons) were distinguished using waveform morphology and K‐means clustering.

Results
From a total of 200 implanted microelectrodes in 9 patients during 13 seizures, we isolated 202 single units; 140 (69.3%) of these units were located in the SOZ, and 40 (28.57%) of them were classified as inhibitory. The waveforms of both excitatory and inhibitory units remained stable during the LVF epoch (p > > 0.05). In the mesial–temporal SOZ, inhibitory interneurons increased their firing rate during LVF seizure onset (p < 0.01). Excitatory neuron firing rates peaked 10 seconds after the inhibitory neurons (p < 0.01). During LVF spread to the contralateral mesial temporal lobe, an increase in inhibitory neuron firing rate was also observed (p < 0.01).

Interpretation
Our results suggest that seizure generation and spread during spontaneous mesial–temporal LVF onset events in humans may result from increased inhibitory neuron firing that spawns a subsequent increase in excitatory neuron firing and seizure evolution.

Hot Topics: New Drug Found Effective for Influenza

Jackie Werner Hot Topics in Research, Infectious Disease, Pharmaceutical Sciences

Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents

Hayden FG, Sugaya N, Hirotsu N, et al. Baloxavir marboxil for uncomplicated influenza in adults and adolescents. N Engl J Med. 2018;379(10):913-923. https://doi.org/10.1056/NEJMoa1716197.

BACKGROUND

Baloxavir marboxil is a selective inhibitor of influenza cap-dependent endonuclease. It has shown therapeutic activity in preclinical models of influenza A and B virus infections, including strains resistant to current antiviral agents.

METHODS

We conducted two randomized, double-blind, controlled trials involving otherwise healthy outpatients with acute uncomplicated influenza. After a dose-ranging (10 to 40 mg) placebo-controlled trial, we undertook a placebo- and oseltamivir-controlled trial of single, weight-based doses of baloxavir (40 or 80 mg) in patients 12 to 64 years of age during the 2016–2017 season. The dose of oseltamivir was 75 mg twice daily for 5 days. The primary efficacy end point was the time to alleviation of influenza symptoms in the intention-to-treat infected population.

RESULTS

In the phase 2 trial, the median time to alleviation of influenza symptoms was 23.4 to 28.2 hours shorter in the baloxavir groups than in the placebo group (P<0.05). In the phase 3 trial, the intention-to-treat infected population included 1064 patients; 84.8 to 88.1% of patients in each group had influenza A(H3N2) infection. The median time to alleviation of symptoms was 53.7 hours (95% confidence interval [CI], 49.5 to 58.5) with baloxavir, as compared with 80.2 hours (95% CI, 72.6 to 87.1) with placebo (P<0.001). The time to alleviation of symptoms was similar with baloxavir and oseltamivir. Baloxavir was associated with greater reductions in viral load 1 day after initiation of the regimen than placebo or oseltamivir. Adverse events were reported in 20.7% of baloxavir recipients, 24.6% of placebo recipients, and 24.8% of oseltamivir recipients. The emergence of polymerase acidic protein variants with I38T/M/F substitutions conferring reduced susceptibility to baloxavir occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 trial and phase 3 trial, respectively.

CONCLUSIONS

Single-dose baloxavir was without evident safety concerns, was superior to placebo in alleviating influenza symptoms, and was superior to both oseltamivir and placebo in reducing the viral load 1 day after initiation of the trial regimen in patients with uncomplicated influenza. Evidence for the development of decreased susceptibility to baloxavir after treatment was also observed.

Hot Topics: Anesthesiology Should Look to Neuroscience and Nociception

Jackie Werner Hot Topics in Research, Neurology, Surgery

Multimodal General Anesthesia: Theory and Practice

Brown EN, Pavone KJ, Naranjo M. Multimodal general anesthesia: Theory and practice. Anesthesia & Analgesia. http://dx.doi.org/10.1213/ANE.0000000000003668

Balanced general anesthesia, the most common management strategy used in anesthesia care, entails the administration of different drugs together to create the anesthetic state. Anesthesiologists developed this approach to avoid sole reliance on ether for general anesthesia maintenance. Balanced general anesthesia uses less of each drug than if the drug were administered alone, thereby increasing the likelihood of its desired effects and reducing the likelihood of its side effects. To manage nociception intraoperatively and pain postoperatively, the current practice of balanced general anesthesia relies almost exclusively on opioids. While opioids are the most effective antinociceptive agents, they have undesirable side effects. Moreover, overreliance on opioids has contributed to the opioid epidemic in the United States. Spurred by concern of opioid overuse, balanced general anesthesia strategies are now using more agents to create the anesthetic state. Under these approaches, called “multimodal general anesthesia,” the additional drugs may include agents with specific central nervous system targets such as dexmedetomidine and ones with less specific targets, such as magnesium. It is postulated that use of more agents at smaller doses further maximizes desired effects while minimizing side effects. Although this approach appears to maximize the benefit-to-side effect ratio, no rational strategy has been provided for choosing the drug combinations. Nociception induced by surgery is the primary reason for placing a patient in a state of general anesthesia. Hence, any rational strategy should focus on nociception control intraoperatively and pain control postoperatively. In this Special Article, we review the anatomy and physiology of the nociceptive and arousal circuits, and the mechanisms through which commonly used anesthetics and anesthetic adjuncts act in these systems. We propose a rational strategy for multimodal general anesthesia predicated on choosing a combination of agents that act at different targets in the nociceptive system to control nociception intraoperatively and pain postoperatively. Because these agents also decrease arousal, the doses of hypnotics and/or inhaled ethers needed to control unconsciousness are reduced. Effective use of this strategy requires simultaneous monitoring of antinociception and level of unconsciousness. We illustrate the application of this strategy by summarizing anesthetic management for 4 representative surgeries.

Hot Topics: Health-Related Quality of Life Not Sufficiently Measured in Oncology Studies

Jackie Werner Hot Topics in Research, Oncology, Research and Scholarly Communication

Evaluating Progression-Free Survival as a Surrogate Outcome for Health-Related Quality of Life in Oncology: A Systematic Review and Quantitative Analysis

Kovic B, Jin X, Kennedy S, et al. Evaluating progression-free survival as a surrogate outcome for health-related quality of life in oncology: A systematic review and quantitative analysis. JAMA Internal Medicine. 2018. http://doi.org/10.1001/jamainternmed.2018.4710.

Importance  Progression-free survival (PFS) has become a commonly used outcome to assess the efficacy of new cancer drugs. However, it is not clear if delay in progression leads to improved quality of life with or without overall survival benefit.

Objective  To evaluate the association between PFS and health-related quality of life (HRQoL) in oncology through a systematic review and quantitative analysis of published randomized clinical trials. Eligible trials addressed oral, intravenous, intraperitoneal, or intrapleural chemotherapy or biological treatments, and reported PFS or health-related quality of life.

Data Sources  For this systematic review and quantitative analysis of randomized clinical trials of patients with cancer, we searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from January 1, 2000, through May 4, 2016.

Study Selection  Paired reviewers independently screened citations, extracted data, and assessed risk of bias of included studies.

Data Extraction and Synthesis  We examined the association of difference in median PFS duration (in months) between treatment groups with difference in global, physical, and emotional HRQoL scores between groups (standardized to a range of 0-100, with higher scores representing better HRQoL) using weighted simple regressions.

Main Outcome and Measure  The association between PFS duration and HRQoL.

Results  Of 35 960 records screened, 52 articles reporting on 38 randomized clinical trials involving 13 979 patients across 12 cancer types using 6 different HRQoL instruments were included. The mean (SD) difference in median PFS between the intervention and the control arms was 1.91 (3.35) months. The mean (SD) differences in change of HRQoL adjusted to per-month values were −0.39 (3.59) for the global domain, 0.26 (5.56) for the physical domain, and 1.08 (3.49) for the emotional domain. The slope of the association between the difference in median PFS and the difference in change for global HRQoL (n = 30 trials) was 0.12 (95% CI, −0.27 to 0.52); for physical HRQoL (n = 20 trials) it was −0.20 (95% CI, −0.62 to 0.23); and for emotional HRQoL (n = 13 trials) it was 0.78 (95% CI, −0.05 to 1.60).

Conclusions and Relevance  We failed to find a significant association between PFS and HRQoL in cancer clinical trials. These findings raise questions regarding the assumption that interventions prolonging PFS also improve HRQoL in patients with cancer. Therefore, to ensure that patients are truly obtaining important benefit from cancer therapies, clinical trial investigators should measure HRQoL directly and accurately, ensuring adequate duration and follow-up.

Hot Topics: Assessment Identifies Patients At Risk for Cardiac-Induced PTSD

Jackie Werner Cardiology, Hot Topics in Research, Psychology and Psychiatry

Development and Validation of a Measure to Assess Patients’ Threat Perceptions in the Emergency Department

Cornelius T, Agarwal S, Garcia O, Chaplin W, Edmondson D, Chang BP. Development and validation of a measure to assess patients’ threat perceptions in the emergency department. Acad Emerg Med. 2018;0. https://doi.org/10.1111/acem.13513.

Objective

Threat perceptions in the Emergency Department (ED) (e.g., patients’ subjective feelings of helplessness or lack of control) during evaluation for an acute coronary syndrome (ACS) are associated with the development of posttraumatic stress disorder (PTSD), and PTSD has been associated with medication nonadherence, cardiac event recurrence, and mortality. This study reports the development and validation of a 7‐item measure of ED Threat Perceptions in English‐ and Spanish‐speaking patients evaluated for ACS.

Methods

Participants were drawn from an observational cohort study of 1,000 patients evaluated for ACS between 2013‐2016 in a large, New York City hospital. Participants reported on threat perceptions in the ED and during inpatient stay (using 12 items previously identified as predictive of PTSD) and reported on cardiac‐induced PTSD one month post‐discharge. Exploratory and confirmatory factor analyses were used to establish the factor structure and test measurement invariance. Validity and reliability were examined, as was the association of ED Threat Perceptions with cardiac‐induced PTSD.

Results

Factor analyses identified a 7‐item measure of ED Threat Perceptions (e.g., “I feel helpless,” “I am worried that I am going to die”) for both English‐ and Spanish‐speaking patients. ED Threat Perceptions demonstrated convergent validity, correlating with ED stress and ED crowdedness (rs = .29, .14), good internal consistency (α = .82), and stability (r = .61). Threat Perceptions were associated with cardiac‐induced acute stress at inpatient and PTSD symptoms at one month (rs = .43, .39).

Conclusions

This brief tool assessing ED Threat Perceptions has clinical utility for providers to identify patients at risk for developing cardiac‐induced PTSD and is critical to inform research on whether threat may be modified in‐ED to reduce PTSD incidence.