Malignant teratoid intraocular ciliary body medulloepithelioma in a 5-year-old male with corresponding somatic copy number alteration profile of aqueous humor cell-free DNA.

BACKGROUND: Intraocular, ciliary body, medulloepithelioma (CBME) is a rare tumor of the nonpigmented ciliary body epithelium, typically presenting in childhood. We describe a case of CBME. MATERIALS AND METHODS: Ocular examination and imaging guided diagnostic and treatment decisions. Aqueous humor (AH) liquid biopsy was collected from the affected eye at eventual enucleation. Whole genome sequencing (WGS) was employed to determine somatic copy number alterations (SCNA) in AH cell-free DNA (cfDNA). Tumor sample was analyzed using various assays to evaluate for oncogenic mutations and SCNAs. Histopathology determined diagnosis. RESULTS: A 5-year-old male with glaucoma and cataract in the left eye (OS) experienced worsening left eye pain and redness. There was no light perception OS and the eye was hypotonus. Anterior segment exam showed complete cataract and rubeosis iridis. Ocular B-scan ultrasound OS revealed an intraocular lesion with calcifications and retinal detachment. Orbital MRI suggested left globe hypercellularity. An infiltrative lesion involving the ciliary body was seen in the left eye on examination under anesthesia. Left eye enucleation was performed in the setting of pain, blindness, and tumor, with anterior chamber paracentesis for AH liquid biopsy collection. SCNA profile of AH cfDNA demonstrated loss of copy of chromosomes 4, 6, and 9. Tumor was negative for clinically significant mutations or SCNAs. Histopathology diagnosed malignant teratoid CBME. CONCLUSIONS: We present a case of CBME and include the unique SCNA profile of AH cfDNA from the enucleated eye. This case suggests utility of AH liquid biopsy in distinguishing between differential diagnoses for intraocular mass lesions.

Do all cardiac surgery patients benefit from antifibrinolytic therapy?

BACKGROUND: In trauma patients, the recognition of fibrinolysis phenotypes has led to a re-evaluation of the risks and benefits of antifibrinolytic therapy (AF). Many cardiac patients also receive AF, but the distribution of fibrinolytic phenotypes in that population is unknown. The purpose of this hypothesis-generating study was to fill that gap. METHODS: Seventy-eight cardiac surgery patients were retrospectively reviewed. Phenotypes were defined as hypofibrinolytic (LY30 <0.8%), physiologic (0.8%-3.0%), and hyperfibrinolytic (>3%) based on thromboelastogram. RESULTS: The population was 65 ± 10-years old, 74% male, average body mass index of 29 ± 5 kg/m2 . Fibrinolytic phenotypes were distributed as physiologic = 45% (35 of 78), hypo = 32% (25 of 78), and hyper = 23% (18 of 78). There was no obvious effect of age, gender, race, or ethnicity on this distribution; 47% received AF. For AF versus no AF, the time with chest tube was longer (4 [1] vs. 3 [1] days, p = .037), and all-cause morbidity was more prevalent (51% vs. 25%, p = .017). However, when these two groups were further stratified by phenotypes, there were within-group differences in the percentage of patients with congestive heart failure (p = .022), valve disease (p = .024), on-pump surgery (p < .0001), estimated blood loss during surgery (p = .015), transfusion requirement (p = .015), and chest tube output (p = .008), which highlight other factors along with AF that might have affected all-cause morbidity. CONCLUSION: This is the first description of the prevalence of three different fibrinolytic phenotypes and their potential influence on cardiac surgery patients. The use of AF was associated with increased morbidity, but because of the small sample size and treatment allocation bias, additional confirmatory studies are necessary. We hope these present findings open the dialog on whether it is safe to administer AFs to cardiac surgery patients who are normo- or hypofibrinolytic.

Gene therapy for neurological disorders: challenges and recent advancements.

Major advancements in targeted gene therapy have opened up avenues for the treatment of major neurological disorders through a range of versatile modalities varying from expression of exogenous to suppression of endogenous genes. Recent technological innovations for improved gene sequence delivery have focussed on highly specific viral vector designs, plasmid transfection, nanoparticles, polymer-mediated gene delivery, engineered microRNA and in vivo clustered regulatory interspaced short palindromic repeats (CRISPR)-based therapeutics. These advanced techniques have profound applications in treating highly prevalent neurological diseases and neurodevelopmental disorders including Parkinson's disease, Alzheimer's disease and autism spectrum disorder, as well as rarer diseases such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, lysosomal storage diseases, X-linked adrenoleukodystrophy and oncological diseases. In this article, we present an overview of the latest advances in targeted gene delivery and discuss the challenges and future direction of gene therapy in the treatment of neurological disorders.

Continuous Indirect Calorimetry in Critically Injured Patients Reveals Significant Daily Variability and Delayed, Sustained Hypermetabolism.

BACKGROUND: Previous studies have used using Indirect Calorimetry (IC) with solitary or sparse measurements of resting energy expenditure (REE). This "snapshot" may not capture the dynamic nature of metabolic requirements. Using continuous IC, we describe the variation of REE during the first days in the intensive care unit. METHODS: Injured adults (≥18 years) requiring mechanical ventilation from March 2018 to September 2018 were enrolled. IC was initiated within 4 days of admission and continuous REE recorded until 14 days, extubation, or death. Multiple 10-minute periods collected during steady state were used to calculate daily REE maximum, minimum, average, and variability [(REEmax - REEmin/2)/average REE]. RESULTS: We included 55 patients. Median age was 38 [27-58] years, 38 (69%) were male, body mass index was 28 [25-33] kg/m2 , and Acute Physiology and Chronic Health Evaluation II was 17 [14-24]. Mechanism of injury was: blunt (n = 38, 69%), penetrating (n = 9, 16%), and burn (n = 8, 15%). Average REE increased gradually from 1,663 kcal [1,435-2,143] to a maximum of 2,080 [1,701-2,336] on day 7, a relative 25% increase, which was sustained through day 14. REE variability ranged 8%-13% and was not reliably predicted by fever, tachycardia, elevated intracranial pressures, hypertension, or hypotension. CONCLUSION: In critically injured patients, steady-state REE measurements display fluctuations over a 24-hour period and demonstrate a gradual rise over the first few days after injury. Continuous REE, if available, is recommended for more precise matching of energy delivery to metabolic requirements.

The Effect of Financial Incentives on Patient Decisions to Undergo Low-value Head Computed Tomography Scans.

BACKGROUND: Excessive diagnostic testing and defensive medicine contribute to billions of dollars in avoidable costs in the United States annually. Our objective was to determine the influence of financial incentives, accompanied with information regarding test risk and benefit, on patient preference for diagnostic testing. METHODS: We conducted a cross-sectional survey of patients at the University of Michigan emergency department (ED). Each participant was presented with a hypothetical scenario involving an ED visit following minor traumatic brain injury. Participants were given information regarding potential benefit (detecting brain hemorrhage) and risk (developing cancer) of head computed tomography scan, as well as an incentive of $0 or $100 to forego testing. We used 0.1 and 1% for test benefit and risk, and values for risk, benefit, and financial incentive varied across participants. Our primary outcome was patient preference to undergo testing. We also collected demographic and numeracy information. We then used logistic regression to estimate odds ratios (ORs), which were adjusted for multiple potential confounders. Our sample size was designed to find at least 300 events (preference for testing) to allow for inclusion of up to 30 covariates in fully adjusted models. We had 85% to 90% power to detect a 10% absolute difference in testing rate across groups, assuming a 95% significance level. RESULTS: We surveyed 913 patients. Increasing test benefit from 0.1% to 1% significantly increased test acceptance (adjusted OR [AOR] = 1.6, 95% confidence interval [CI] = 1.2 to 2.1) and increasing test risk from 0.1% to 1% significantly decreased test acceptance (AOR = 0.70, 95% CI = 0.52 to 0.93). Finally, a $100 incentive to forego low-value testing significantly reduced test acceptance (AOR = 0.6; 95% CI = 0.4 to 0.8). CONCLUSIONS: Providing financial incentives to forego testing significantly decreased patient preference for testing, even when accounting for test benefit and risk. This work is preliminary and hypothetical and requires confirmation in larger patient cohorts facing these actual decisions.

Effect of patient-reported smoking status on short-term bariatric surgery outcomes.

INTRODUCTION: Preoperative patient screening is a major contributor to the remarkable safety of bariatric surgery. Smoking status is a modifiable patient risk factor, and smoking cessation is associated with improved outcomes in surgical patients. However, the length of smoking cessation necessary to optimize bariatric surgery patient outcomes is not yet defined. We sought to explore the relationship between patient-reported smoking status and short-term bariatric surgery outcomes. METHODS: Using prospectively collected data from the MBSC registry, we evaluated the effects of patient-reported length of tobacco abstinence on 30-day surgical outcomes. Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) patients (n = 49,772) were divided into three categories based on smoking status: never smoker, former smoker, and recent smoker. We compared risk-adjusted complication rates using multivariable logistic regression models and compared excess body weight loss using a one-way ANOVA test. RESULTS: The risk-adjusted rate of severe complications among RYGB patients in the recent smoker group was significantly increased relative to patients who had never smoked (OR 1.34; 95% CI, 1.01-1.77), but not among SG patients (OR 1.18; 95% CI 0.87-1.62). In the same populations, differences in overall complication rate were not significant for either RYGB (OR, 1.11; 95% CI 0.94-1.31) or LSG (OR 1.04; 95% CI 0.86-1.25). CONCLUSIONS: Recent smokers suffer detrimental effects of smoking on serious postoperative complications following RYGB surgery, but may not suffer an elevated risk of complications attributable to smoking for sleeve gastrectomy. An evaluation of the effect on long-term outcomes is necessary to further define the risks of smoking on bariatric surgery outcomes.

NanoLuc reporter for dual luciferase imaging in living animals.

Bioluminescence imaging is widely used for cell-based assays and animal imaging studies in biomedical research and drug development, capitalizing on the high signal to background of this technique. A relatively small number of luciferases are available for imaging studies, substantially limiting the ability to image multiple molecular and cellular events, as done commonly with fluorescence imaging. To advance dual reporter bioluminescence molecular imaging, we tested a recently developed, adenosine triphosphate­independent luciferase enzyme from Oplophorus gracilirostris (NanoLuc [NL]) as a reporter for animal imaging. We demonstrated that NL could be imaged in superficial and deep tissues in living mice, although the detection of NL in deep tissues was limited by emission of predominantly blue light by this enzyme. Changes in bioluminescence from NL over time could be used to quantify tumor growth, and secreted NL was detectable in small volumes of serum. We combined NL and firefly luciferase reporters to quantify two key steps in transforming growth factor ß signaling in intact cells and living mice, establishing a novel dual luciferase imaging strategy for quantifying signal transduction and drug targeting. Our results establish NL as a new reporter for bioluminescence imaging studies in intact cells and living mice that will expand imaging of signal transduction in normal physiology, disease, and drug development.