Primer Part 1 - Preparing a laboratory quality improvement project.

Quality in laboratory medicine encompasses multiple components related to total quality management, including quality control (QC), quality assurance (QA), quality indicators, and quality improvement (QI). Together, they contribute to minimizing errors (pre-analytical, analytical, or post-analytical) in clinical service delivery and improving process appropriateness and efficiency. In contrast to static quality benchmarks (QC, QA, quality indicators), the QI paradigm is a continuous approach to systemic process improvement for optimizing patient safety, timeliness, effectiveness, and efficiency. Healthcare institutions have placed emphasis on applying the QI framework to identify and improve healthcare delivery. Despite QI's increasing importance, there is a lack of guidance on preparing, executing, and sustaining QI initiatives in the field of laboratory medicine. This has presented a significant barrier for clinical laboratorians to participate in and lead QI initiatives. This three-part primer series will bridge this knowledge gap by providing a guide for clinical laboratories to implement a QI project that issuccessful and sustainable. In the first article, we introduce the steps needed to prepare a QI project with focus on relevant methodology and tools related to problem identification, stakeholder engagement, root cause analysis (e.g., fishbone diagrams, Pareto charts and process mapping), and SMART aim establishment. Throughout, we describe a clinical vignette of a real QI project completed at our institution focused on serum protein electrophoresis (SPEP) utilization. This primer series is the first of its kind in laboratory medicine and will serve as a useful resource for future engagement of clinical laboratory leaders in QI initiatives.

Uric Acid Nephropathy Secondary to Generalized Tonic-Clonic Seizures.

INTRODUCTION: Acute kidney injury is a well-known complication of generalized tonic-clonic seizures, most commonly due to rhabdomyolysis. Elevated serum uric acid resulting in uric acid nephropathy is an overlooked cause of acute kidney injury in these patients, with only a few published case reports. CASE REPORT: In the first case, a 23-year-old male was admitted with status epilepticus. His kidney function worsened and he developed anuria. He had a serum uric acid level of 20.7 mg/dL and required multiple sessions of hemodialysis. In the second case, a 32-year-old male was admitted with acute kidney injury after experiencing a breakthrough seizure. He had a serum uric acid level of 20.4 mg/dL and was treated with rasburicase with recovery of renal function. In the third case, a 29-year-old male was admitted with status epilepticus. His renal function deteriorated. His serum uric acid level was 19.5 mg/dL. He required hemodialysis and rasburicase. CONCLUSION: Uric acid nephropathy is a rare complication of generalized tonic-clonic seizures, which is poorly recognized by healthcare providers. We advocate for Nephrology consultation early in a patient's hospitalization to discuss the use of rasburicase to avoid the associated morbidity of renal replacement therapies.

Histone 3 Methyltransferases Alter Melanoma Initiation and Progression Through Discrete Mechanisms.

Perturbations to the epigenome are known drivers of tumorigenesis. In melanoma, alterations in histone methyltransferases that catalyze methylation at histone 3 lysine 9 and histone 3 lysine 27-two sites of critical post-translational modification-have been reported. To study the function of these methyltransferases in melanoma, we engineered melanocytes to express histone 3 lysine-to-methionine mutations at lysine 9 and lysine 27, which are known to inhibit the activity of histone methyltransferases, in a zebrafish melanoma model. Using this system, we found that loss of histone 3 lysine 9 methylation dramatically suppressed melanoma formation and that inhibition of histone 3 lysine 9 methyltransferases in human melanoma cells increased innate immune response signatures. In contrast, loss of histone 3 lysine 27 methylation significantly accelerated melanoma formation. We identified FOXD1 as a top target of PRC2 that is silenced in melanocytes and found that aberrant overexpression of FOXD1 accelerated melanoma onset. Collectively, these data demonstrate how histone 3 lysine-to-methionine mutations can be used to uncover critical roles for methyltransferases.

Age-Friendly University environmental scan: Exploring "age-friendliness" with stakeholders at one regional comprehensive university.

Internationally, universities are recognizing the importance of understanding and enhancing age as a component of diversity and inclusion efforts through the Age-Friendly University (AFU) initiative. Eastern Michigan University (EMU) joined the AFU Network in 2018 and has been conducting an environmental scan of supports, weaknesses, and opportunities for age inclusiveness since this time. This article describes a qualitative exploratory study undertaken as part of the Environmental Scan that aimed to understand the perspectives of university stakeholders on supports, barriers, and opportunties to age-friendliness. Twenty-eight participant stakeholders from divisions across the university campus were purposefully sampled to engage in in-depth interviews that were recorded and transcribed. Qualitative thematic findings generated through constant comparative method of analysis include: Experience Sharing, Need for Intentionality in Age-Friendly Efforts, and Existence of Age-Inclusivity Barriers and Opportunities for Change.

Corticostriatal Oscillations Predict High vs. Low Drinkers in a Rat Model of Limited Access Alcohol Consumption.

Individuals differ in their vulnerability to develop alcohol dependence, which is determined by innate and environmental factors. The corticostriatal circuit is heavily involved in the development of alcohol dependence and may contain neural information regarding vulnerability to drink excessively. In the current experiment, we hypothesized that we could characterize high and low alcohol-drinking rats (HD and LD, respectively) based on corticostriatal oscillations and that these subgroups would differentially respond to corticostriatal brain stimulation. Male Sprague-Dawley rats (n = 13) were trained to drink 10% alcohol in a limited access paradigm. In separate sessions, local field potentials (LFPs) were recorded from the nucleus accumbens shell (NAcSh) and medial prefrontal cortex (mPFC). Based on training alcohol consumption levels, we classified rats using a median split as HD or LD. Then, using machine-learning, we built predictive models to classify rats as HD or LD by corticostriatal LFPs and compared the model performance from real data to the performance of models built on data permutations. Additionally, we explored the impact of NAcSh or mPFC stimulation on alcohol consumption in HD vs. LD. Corticostriatal LFPs were able to predict HD vs. LD group classification with greater accuracy than expected by chance (>80% accuracy). Moreover, NAcSh stimulation significantly reduced alcohol consumption in HD, but not LD (p < 0.05), while mPFC stimulation did not alter drinking behavior in either HD or LD (p > 0.05). These data collectively show that the corticostriatal circuit is differentially involved in regulating alcohol intake in HD vs. LD rats, and suggests that corticostriatal activity may have the potential to predict a vulnerability to develop alcohol dependence in a clinical population.

Mammalian pigmentation is regulated by a distinct cAMP-dependent mechanism that controls melanosome pH.

The production of melanin increases skin pigmentation and reduces the risk of skin cancer. Melanin production depends on the pH of melanosomes, which are more acidic in lighter-skinned than in darker-skinned people. We showed that inhibition of soluble adenylyl cyclase (sAC) controlled pigmentation by increasing the pH of melanosomes both in cells and in vivo. Distinct from the canonical melanocortin 1 receptor (MC1R)-dependent cAMP pathway that controls pigmentation by altering gene expression, we found that inhibition of sAC increased pigmentation by increasing the activity of tyrosinase, the rate-limiting enzyme in melanin synthesis, which is more active at basic pH. We demonstrated that the effect of sAC activity on pH and melanin production in human melanocytes depended on the skin color of the donor. Last, we identified sAC inhibitors as a new class of drugs that increase melanosome pH and pigmentation in vivo, suggesting that pharmacologic inhibition of this pathway may affect skin cancer risk or pigmentation conditions.

Machine Learning Based Classification of Deep Brain Stimulation Outcomes in a Rat Model of Binge Eating Using Ventral Striatal Oscillations.

Neuromodulation-based interventions continue to be evaluated across an array of appetitive disorders but broader implementation of these approaches remains limited due to variable treatment outcomes. We hypothesize that individual variation in treatment outcomes may be linked to differences in the networks underlying these disorders. Here, Sprague-Dawley rats received deep brain stimulation separately within each nucleus accumbens (NAc) sub-region (core and shell) using a within-animal crossover design in a rat model of binge eating. Significant reductions in binge size were observed with stimulation of either target but with significant variation in effectiveness across individuals. When features of local field potentials (LFPs) recorded from the NAc were used to classify the pre-defined stimulation outcomes (response or non-response) from each rat using a machine-learning approach (lasso), stimulation outcomes could be classified with greater accuracy than expected by chance (effect sizes: core = 1.13, shell = 1.05). Further, these LFP features could be used to identify the best stimulation target for each animal (core vs. shell) with an effect size = 0.96. These data suggest that individual differences in underlying network activity may relate to the variable outcomes of circuit based interventions, and measures of network activity could have the potential to individually guide the selection of an optimal stimulation target to improve overall treatment response rates.

Tempo and mode of gene duplication in mammalian ribosomal protein evolution.

Gene duplication has been widely recognized as a major driver of evolutionary change and organismal complexity through the generation of multi-gene families. Therefore, understanding the forces that govern the evolution of gene families through the retention or loss of duplicated genes is fundamentally important in our efforts to study genome evolution. Previous work from our lab has shown that ribosomal protein (RP) genes constitute one of the largest classes of conserved duplicated genes in mammals. This result was surprising due to the fact that ribosomal protein genes evolve slowly and transcript levels are very tightly regulated. In our present study, we identified and characterized all RP duplicates in eight mammalian genomes in order to investigate the tempo and mode of ribosomal protein family evolution. We show that a sizable number of duplicates are transcriptionally active and are very highly conserved. Furthermore, we conclude that existing gene duplication models do not readily account for the preservation of a very large number of intact retroduplicated ribosomal protein (RT-RP) genes observed in mammalian genomes. We suggest that selection against dominant-negative mutations may underlie the unexpected retention and conservation of duplicated RP genes, and may shape the fate of newly duplicated genes, regardless of duplication mechanism.