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

Category: Internal Medicine

Hot Topics: New Factors Could Reverse Arterial Plaque Buildup

Jackie Werner Cardiology, Hot Topics in Research

Endothelial TGF-β signalling drives vascular inflammation and atherosclerosis

Chen, P., Qin, L., Li, G., Wang, Z., Dahlman, J. E., Malagon-Lopez, J., . . . Simons, M. (2019). Endothelial TGF-β signalling drives vascular inflammation and atherosclerosis. Nature Metabolism, http://doi.org/10.1038/s42255-019-0102-3

Atherosclerosis is a progressive vascular disease triggered by interplay between abnormal shear stress and endothelial lipid retention. A combination of these and, potentially, other factors leads to a chronic inflammatory response in the vessel wall, which is thought to be responsible for disease progression characterized by a buildup of atherosclerotic plaques. Yet molecular events responsible for maintenance of plaque inflammation and plaque growth have not been fully defined. Here we show that endothelial transforming growh factor β (TGF-β) signalling is one of the primary drivers of atherosclerosis-associated vascular inflammation. Inhibition of endothelial TGF-β signalling in hyperlipidemic mice reduces vessel wall inflammation and vascular permeability and leads to arrest of disease progression and regression of established lesions. These proinflammatory effects of endothelial TGF-β signalling are in stark contrast with its effects in other cell types and identify it as an important driver of atherosclerotic plaque growth and show the potential of cell-type-specific therapeutic intervention aimed at control of this disease.

Hot Topics: Cannabis Use in Teen Cancer Patients Increasing

Jackie Werner Hot Topics in Research, Oncology

Cannabis Use in Young Adult Cancer Patients

Donovan, K. A., Oberoi-Jassal, R., Chang, Y. D., Rajasekhara, S., Haas, M. F., Randich, A. L., & Portman, D. G. (2019). Cannabis use in young adult cancer patients. Journal of Adolescent and Young Adult Oncologyhttp://doi.org/10.1089/jayao.2019.0039

Background: The use of cannabis by young adult (YA) cancer patients is likely to increase as medical cannabis becomes more available. Clinically relevant data on cannabis use are needed to establish benchmarks for use, to identify patients who are more likely to use cannabis, and to assess outcomes associated with use.

Objective: The current study sought to determine the rate of cannabis use in YA cancer patients ages 18 to 39, identify demographic and clinical correlates of use, and examine differences in moderate-to-severe symptoms between users and nonusers.

Methods: We conducted a retrospective review of objectively measured tetrahydrocannabinol (THC), self-reported cannabis use, and cancer-related symptomatology in YA cancer patients in active treatment referred for comprehensive supportive care.

Results: Approximately 30% of YA cancer patients tested positive for THC on urine drug testing. At the univariate level, cannabis users were more likely to be male, to have a lifetime history of smoking at least 100 cigarettes, and to be more recently diagnosed. Cannabis use was associated with moderate-to-severe symptomatology, including pain, nausea, lack of appetite, constipation, difficulty sleeping, and poorer overall well-being.

Conclusions: YAs referred for comprehensive supportive care may be managing their cancer-related symptoms with cannabis. Further research is needed to better understand patients’ perceptions of cannabis’s therapeutic and adverse effects, in patients who used cannabis before diagnosis, and in patients who commenced use in response to a cancer diagnosis.

Hot Topics: Liver Cell Could Regenerate Tissue

Jackie Werner Gastroenterology, Hot Topics in Research

Single cell analysis of human foetal liver captures the transcriptional profile of hepatobiliary hybrid progenitors

Segal JM, Kent D, Wesche DJ, et al. Single cell analysis of human foetal liver captures the transcriptional profile of hepatobiliary hybrid progenitors. Nature Communications. 2019;10(1):3350. https://doi.org/10.1038/s41467-019-11266-x.

The liver parenchyma is composed of hepatocytes and bile duct epithelial cells (BECs). Controversy exists regarding the cellular origin of human liver parenchymal tissue generation during embryonic development, homeostasis or repair. Here we report the existence of a hepatobiliary hybrid progenitor (HHyP) population in human foetal liver using single-cell RNA sequencing. HHyPs are anatomically restricted to the ductal plate of foetal liver and maintain a transcriptional profile distinct from foetal hepatocytes, mature hepatocytes and mature BECs. In addition, molecular heterogeneity within the EpCAM+ population of freshly isolated foetal and adult human liver identifies diverse gene expression signatures of hepatic and biliary lineage potential. Finally, we FACS isolate foetal HHyPs and confirm their hybrid progenitor phenotype in vivo. Our study suggests that hepatobiliary progenitor cells previously identified in mice also exist in humans, and can be distinguished from other parenchymal populations, including mature BECs, by distinct gene expression profiles.

Hot Topics: Neurotoxin Targets Malaria Mosquitos

Jackie Werner Hot Topics in Research, Infectious Disease

A neurotoxin that specifically targets Anopheles mosquitoes

Contreras E, Masuyer G, Qureshi N, et al. A neurotoxin that specifically targets anopheles mosquitoes. Nature Communications. 2019;10(1):2869. https://doi.org/10.1038/s41467-019-10732-w.

Clostridial neurotoxins, including tetanus and botulinum neurotoxins, generally target vertebrates. We show here that this family of toxins has a much broader host spectrum, by identifying PMP1, a clostridial-like neurotoxin that selectively targets anopheline mosquitoes. Isolation of PMP1 from Paraclostridium bifermentans strains collected in anopheline endemic areas on two continents indicates it is widely distributed. The toxin likely evolved from an ancestral form that targets the nervous system of similar organisms, using a common mechanism that disrupts SNARE-mediated exocytosis. It cleaves the mosquito syntaxin and employs a unique receptor recognition strategy. Our research has an important impact on the study of the evolution of clostridial neurotoxins and provides the basis for the use of P. bifermentans strains and PMP1 as innovative, environmentally friendly approaches to reduce malaria through anopheline control.

Hot Topics: EEG Analysis Detects Hidden Consciousness

Jackie Werner Critical Care, Hot Topics in Research

Detection of Brain Activation in Unresponsive Patients with Acute Brain Injury

Claassen J, Doyle K, Matory A, et al. Detection of brain activation in unresponsive patients with acute brain injury. New Engl Journal of Medicine. 2019;380(26):2497-2505. https://doi.org/10.1056/NEJMoa1812757.

BACKGROUND

Brain activation in response to spoken motor commands can be detected by electroencephalography (EEG) in clinically unresponsive patients. The prevalence and prognostic importance of a dissociation between commanded motor behavior and brain activation in the first few days after brain injury are not well understood.

METHODS

We studied a prospective, consecutive series of patients in a single intensive care unit who had acute brain injury from a variety of causes and who were unresponsive to spoken commands, including some patients with the ability to localize painful stimuli or to fixate on or track visual stimuli. Machine learning was applied to EEG recordings to detect brain activation in response to commands that patients move their hands. The functional outcome at 12 months was determined with the Glasgow Outcome Scale–Extended (GOS-E; levels range from 1 to 8, with higher levels indicating better outcomes).

RESULTS

A total of 16 of 104 unresponsive patients (15%) had brain activation detected by EEG at a median of 4 days after injury. The condition in 8 of these 16 patients (50%) and in 23 of 88 patients (26%) without brain activation improved such that they were able to follow commands before discharge. At 12 months, 7 of 16 patients (44%) with brain activation and 12 of 84 patients (14%) without brain activation had a GOS-E level of 4 or higher, denoting the ability to function independently for 8 hours (odds ratio, 4.6; 95% confidence interval, 1.2 to 17.1).

CONCLUSIONS

A dissociation between the absence of behavioral responses to motor commands and the evidence of brain activation in response to these commands in EEG recordings was found in 15% of patients in a consecutive series of patients with acute brain injury.

Hot Topics: Exercise in Older Adults Boosts Memory

Jackie Werner Geriatrics, Hot Topics in Research, Memory Impairment

Semantic Memory Activation After Acute Exercise in Healthy Older Adults

Won J, Alfini AJ, Weiss LR, et al. Semantic memory activation after acute exercise in healthy older adults. Journal of the International Neuropsychological Society: 1-12. https://doi.org/10.1017/S1355617719000171.

Objectives: A growing body of research suggests that regular participation in long-term exercise is associated with enhanced cognitive function. However, less is known about the beneficial effects of acute exercise on semantic memory. This study investigated brain activation during a semantic memory task after a single session of exercise in healthy older adults using functional magnetic resonance imaging (fMRI). Methods: Using a within-subjects counterbalanced design, 26 participants (ages, 55–85 years) underwent two experimental visits on separate days. During each visit, participants engaged in 30 min of rest or stationary cycling exercise immediately before performing a Famous and Non-Famous name discrimination task during fMRI scanning. Results: Acute exercise was associated with significantly greater semantic memory activation (Famous>Non-Famous) in the middle frontal, inferior temporal, middle temporal, and fusiform gyri. A planned comparison additionally showed significantly greater activation in the bilateral hippocampus after exercise compared to rest. These effects were confined to correct trials, and as expected, there were no differences between conditions in response time or accuracy. Conclusions: Greater brain activation following a single session of exercise suggests that exercise may increase neural processes underlying semantic memory activation in healthy older adults. These effects were localized to the known semantic memory network, and thus do not appear to reflect a general or widespread increase in brain blood flow. Coupled with our prior exercise training effects on semantic memory-related activation, these data suggest the acute increase in neural activation after exercise may provide a stimulus for adaptation over repeated exercise sessions.

Hot Topics: Steroid Implant Restores Sight

Jackie Werner Hot Topics in Research, Oncology, Surgery

Outcomes Associated With Sustained-Release Intraocular Fluocinolone Implants in a Case of Melanoma-Associated Retinopathy Treated Without Systemic Immunosuppression

Karatsai E, Robson AG, Taylor SRJ. Outcomes associated with sustained-release intraocular fluocinolone implants in a case of melanoma-associated retinopathy treated without systemic immunosuppression. 2019. https://doi.org/10.1001/jamaophthalmol.2019.0284.

Importance  Melanoma-associated retinopathy (MAR) is a paraneoplastic syndrome in which antiretinal antibodies crossreact with retinal ON-bipolar cells, resulting in night blindness and progressive visual field loss. Current therapeutic options include cytoreductive surgery in combination with immunoglobulin, corticosteroids, or plasmapheresis, but their effectiveness is limited and may be contraindicated, given the possible protective role of circulating autoantibodies against metastatic spread. We report 3-year follow-up of the first case (to our knowledge) of MAR treated with intravitreal long-acting steroid implants.

Objective  To report on a patient with MAR who was treated with intravitreal fluocinolone acetonide implants in the absence of systemic immunosuppression.

Design, Setting, and Participants  This is a 3-year follow-up of a 73-year-old woman with a history of surgical excision of a malignant melanoma of the left pinna who presented with visual symptoms of shimmering and nyctalopia. Fundus examination, fundus autofluorescence, and optical coherence tomography were normal, with no evidence of cystoid macular edema. Automated perimetry showed a reduction in visual field and full-field electroretinography (ERG) demonstrated findings consistent with generalized ON-bipolar cell dysfunction, typical of MAR. The patient was treated with bilateral fluocinolone acetonide intravitreal implants.

Main Outcomes and Measures  Visual acuity, visual field, and electroretinography testing for 3 years after treatment.

Results  Visual fields improved in this 73-year-old patient from 20/30 (Snellen measured as 6/9) OD and 20/16 (6/5) OS at baseline to 20/20 OU within 1 week of treatment. Detailed electroretinography monitoring indicated characteristic abnormalities that partly resolved after treatment, consistent with improved inner retinal ON-bipolar cell function. Bilateral cataracts developed approximately 2 years after injection; cataract surgery was performed uneventfully. At 3 years posttreatment, the patient remained visually stable and in systemic disease remission, with best-corrected visual acuity remaining at 20/20 OU.

Conclusions and Relevance  We report what is, to our knowledge, the first case of MAR treated with intravitreal slow-release corticosteroid implants, which shows improvements in visual symptoms, visual fields, and retinal function. Sustained-release intraocular steroid implants may offer an effective and safe alternative to systemic immunosuppression in MAR, although results from 1 case should be generalized with abundant caution.

Hot Topics: Algorithm Predicts Irregular Heartbeats

Jackie Werner Cardiology, Hot Topics in Research

A New Prediction Model for Ventricular Arrhythmias in Arrhythmogenic Right Ventricular Cardiomyopathy

Bhonsale A, Murray B, Tichnell C, et al. A new prediction model for ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy. . 2019. https://doi.org/10.1093/eurheartj/ehz103.

Aims: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is characterized by ventricular arrhythmias (VAs) and sudden cardiac death (SCD). We aimed to develop a model for individualized prediction of incident VA/SCD in ARVC patients.

Methods and Results: Five hundred and twenty-eight patients with a definite diagnosis and no history of sustained VAs/SCD at baseline, aged 38.2 ± 15.5 years, 44.7% male, were enrolled from five registries in North America and Europe. Over 4.83 (interquartile range 2.44–9.33) years of follow-up, 146 (27.7%) experienced sustained VA, defined as SCD, aborted SCD, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator (ICD) therapy. A prediction model estimating annual VA risk was developed using Cox regression with internal validation. Eight potential predictors were pre-specified: age, sex, cardiac syncope in the prior 6 months, non-sustained ventricular tachycardia, number of premature ventricular complexes in 24 h, number of leads with T-wave inversion, and right and left ventricular ejection fractions (LVEFs). All except LVEF were retained in the final model. The model accurately distinguished patients with and without events, with an optimism-corrected C-index of 0.77 [95% confidence interval (CI) 0.73–0.81] and minimal over-optimism [calibration slope of 0.93 (95% CI 0.92–0.95)]. By decision curve analysis, the clinical benefit of the model was superior to a current consensus-based ICD placement algorithm with a 20.6% reduction of ICD placements with the same proportion of protected patients (P < 0.001).

Conclusion: Using the largest cohort of patients with ARVC and no prior VA, a prediction model using readily available clinical parameters was devised to estimate VA risk and guide decisions regarding primary prevention ICDs (www.arvcrisk.com).

Hot Topics: Online Intervention May Decrease HIV Risk

Jackie Werner Hot Topics in Research, Infectious Disease, Psychology and Psychiatry

Acceptability and Preliminary Efficacy of an Online HIV Prevention Intervention for Single Young Men Who Have Sex with Men Seeking Partners Online: The myDEx Project

Bauermeister JA, Tingler RC, Demers M, et al. Acceptability and preliminary efficacy of an online HIV prevention intervention for single young men who have sex with men seeking partners online: The myDEx project. AIDS and Behavior. 2019. https://doi.org/10.1007/s10461-019-02426-7.

Prevention of new cases of HIV among young gay, bisexual and other men who have sex with men (YGBMSM; ages 18–24) remains a priority. We developed and pilot tested an online intervention (myDEx) using a pilot randomized trial design with 180 online-recruited single YGBMSM who reported recent unprotected anal intercourse, self-reporting as HIV negative or status-unaware, and who met sexual partners through online dating applications. myDEx participants reported higher overall satisfaction (d = 0.46) and willingness to recommend the intervention to friends (d = 0.48) than controls. myDEx participants were less likely to report foregoing condoms to achieve an emotional connection with a partner (d =0 .43), and more likely to report greater emotional regulation during their partner-seeking behaviors (d = 0.44). myDEx participants reported fewer partners with whom they had condomless receptive anal sex (d = 0.48). Our pilot results demonstrate the potential of the myDEx intervention, suggesting that a larger efficacy trial may be warranted in the future.

Hot Topics: Routine Data Can Quickly Detect Sepsis in Newborns

Jackie Werner Critical Care, Hot Topics in Research, Pediatrics

Machine learning models for early sepsis recognition in the neonatal intensive care unit using readily available electronic health record data

Masino AJ, Harris MC, Forsyth D, et al. Machine learning models for early sepsis recognition in the neonatal intensive care unit using readily available electronic health record data. PLOS ONE. 2019;14(2):e0212665. https://doi.org/10.1371/journal.pone.0212665.

Background

Rapid antibiotic administration is known to improve sepsis outcomes, however early diagnosis remains challenging due to complex presentation. Our objective was to develop a model using readily available electronic health record (EHR) data capable of recognizing infant sepsis at least 4 hours prior to clinical recognition.

Methods and findings

We performed a retrospective case control study of infants hospitalized ≥48 hours in the Neonatal Intensive Care Unit (NICU) at the Children’s Hospital of Philadelphia between September 2014 and November 2017 who received at least one sepsis evaluation before 12 months of age. We considered two evaluation outcomes as cases: culture positive–positive blood culture for a known pathogen (110 evaluations); and clinically positive–negative cultures but antibiotics administered for ≥120 hours (265 evaluations). Case data was taken from the 44-hour window ending 4 hours prior to evaluation. We randomly sampled 1,100 44-hour windows of control data from all times ≥10 days removed from any evaluation. Model inputs consisted of up to 36 features derived from routine EHR data. Using 10-fold nested cross-validation, 8 machine learning models were trained to classify inputs as sepsis positive or negative. When tasked with discriminating culture positive cases from controls, 6 models achieved a mean area under the receiver operating characteristic (AUC) between 0.80–0.82 with no significant differences between them. Including both culture and clinically positive cases, the same 6 models achieved an AUC between 0.85–0.87, again with no significant differences.

Conclusions

Machine learning models can identify infants with sepsis in the NICU hours prior to clinical recognition. Learning curves indicate model improvement may be achieved with additional training examples. Additional input features may also improve performance. Further research is warranted to assess potential performance improvements and clinical efficacy in a prospective trial.