A MicroRNA Approach to Evaluating Elevated Prostate Cancer Risk in Cancer-Free Men.

Objective criteria are required for prostate cancer (PCa) risk assessment, treatment decisions, evaluation of therapy, and initial indications of recurrence. Circulating microRNAs were utilized as biomarkers to distinguish PCa patients from cancer-free subjects or those encountering benign prostate hyperplasia. A panel of 60 microRNAs was developed with established roles in PCa initiation, progression, metastasis, and recurrence. Utilizing the FirePlex® platform for microRNA analysis, we demonstrated the efficacy and reproducibility of a rapid, high-throughput, serum-based assay for PCa biomarkers that circumvents the requirement for extraction and fractionation of patient specimens supporting feasibility for expanded clinical research and diagnostic applications.

Iatrogenic hyperchloremia: An overview in hospitalized patients for pharmacists.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: The purpose of this therapeutic update is to provide pharmacists with a general overview of the pathophysiology of hyperchloremia and describe strategies to help prevent development of this electrolyte abnormality in hospitalized patients. SUMMARY: Hyperchloremia is an electrolyte abnormality associated with an increased incidence of acute kidney injury and metabolic acidosis. Intravenous (IV) fluids utilized for volume resuscitation, medication diluents, and total parental nutrition all may contribute to the development of hyperchloremia. Current evidence suggests that administration of balanced crystalloids for either fluid resuscitation or maintenance fluids may impact serum chloride levels and patient outcomes. In multiple randomized controlled trials, administering balanced crystalloids for fluid resuscitation in critically ill patient populations did not decrease mortality. However, further analyses of subpopulations within these trials have demonstrated that patients with sepsis may benefit from receiving balanced crystalloids for initial fluid resuscitation. Results from several small studies suggest that altering the composition of these IV fluids may help prevent development of hyperchloremia. CONCLUSION: Management of hyperchloremia is preventative in nature and can be mitigated through management of resuscitation fluids, medication diluents, and total parenteral nutrition. Inpatient pharmacists should be aware of the potential risk of fluid-associated hyperchloremia and assist with optimal fluid management to prevent and manage hyperchloremia.

The association of glucose control on in-hospital mortality in the cardiac intensive care unit.

BACKGROUND: Current guidelines recommend maintaining serum blood glucose (BG) levels between 150 and 180 mg/dL for patients admitted to the intensive care unit (ICU); however, these recommendations are based on randomized controlled trials among general ICU patients and observational studies among specific subgroups. Little is known about the impact of glucose control among patients cared for in the cardiac intensive care unit (CICU). METHODS: This was a retrospective cohort analysis of patients >18 years of age admitted to the University of Michigan CICU from December 2016 through December 2020 with at least one BG measurement during CICU admission. The primary outcome was in-hospital mortality. The secondary outcome was CICU length of stay. RESULTS: A total of 3217 patients were included. When analyzed based on quartiles of mean CICU BG, there were significant differences in in-hospital mortality across BG quartiles for those with diabetes mellitus (DM) and those without DM. In multivariable logistic regression, age, Elixhauser comorbidity score, use of mechanical ventilation, any hypoglycemic event, and any BG value >180 mg/dL were significant predictors for in-hospital mortality in both patients with and without DM, yet average BG was only predictive of in-hospital mortality in patients without DM. CONCLUSIONS: This study highlights the importance of glucose control in critically ill adult patients admitted to the CICU. The trends in mortality based on quartiles and deciles of average BG suggest a difference in optimal blood glucose levels in those with and without DM. However, regardless of diabetes status, mortality increases with higher average BG.

Association Between Sedative Medication Administration and Delirium Development in a Medical Intensive Care Unit.

Background: Delirium develops frequently in intensive care unit (ICU) patients. Societal guidelines have suggested that benzodiazepines may cause delirium. This study investigates if a change in sedation administration use over time is associated with changes in delirium incidence. Methods: This was a retrospective cohort study conducted over a 4 year time period in a medical ICU. All data was abstracted from a local data warehouse. The primary outcome of the study was the association between annual cumulative benzodiazepine use and incidence of delirium during the study period. Data was analyzed using descriptive characteristics and Spearman's correlation coefficient. Additionally, multivariate logistic regression was performed to identify independent risk factors for delirium development. Results: From 2015 to 2018, annual total benzodiazepine administration decreased from 62,215 mg to 18,105 mg lorazepam equivalents (p = <.01). The cumulative dose of dexmedetomidine increased, with 657,262 mcg administered in 2015 and 1,476,951 mcg in 2018 (p < .01). No differences in annual delirium incidence were found. Risk factors that were significantly correlated with delirium following multivariate logistic regression included acute respiratory distress syndrome, renal failure, hepatic failure, septic shock, severe alcohol withdrawal, vasopressor use, corticosteroid use, benzodiazepine use, antipsychotic use, opiate use, and propofol use. Conclusions: A profound change in sedation medication paradigm did not influence delirium rates in a medical ICU.

Sustained Morphine Delivery Suppresses Bone Formation and Alters Metabolic and Circulating miRNA Profiles in Male C57BL/6J Mice.

Opioid use is detrimental to bone health, causing both indirect and direct effects on bone turnover. Although the mechanisms of these effects are not entirely clear, recent studies have linked chronic opioid use to alterations in circulating miRNAs. Here, we developed a model of opioid-induced bone loss to understand bone turnover and identify candidate miRNA-mediated regulatory mechanisms. We evaluated the effects of sustained morphine treatment on male and female C57BL/6J mice by treating with vehicle (0.9% saline) or morphine (17 mg/kg) using subcutaneous osmotic minipumps for 25 days. Morphine-treated mice had higher energy expenditure and respiratory quotient, indicating a shift toward carbohydrate metabolism. Micro-computed tomography (µCT) analysis indicated a sex difference in the bone outcome, where male mice treated with morphine had reduced trabecular bone volume fraction (Tb.BV/TV) (15%) and trabecular bone mineral density (BMD) (14%) in the distal femur compared with vehicle. Conversely, bone microarchitecture was not changed in females after morphine treatment. Histomorphometric analysis demonstrated that in males, morphine reduced bone formation rate compared with vehicle, but osteoclast parameters were not different. Furthermore, morphine reduced bone formation marker gene expression in the tibia of males (Bglap and Dmp1). Circulating miRNA profile changes were evident in males, with 14 differentially expressed miRNAs associated with morphine treatment compared with two differentially expressed miRNAs in females. In males, target analysis indicated hypoxia-inducible factor (HIF) signaling pathway was targeted by miR-223-3p and fatty acid metabolism by miR-484, -223-3p, and -328-3p. Consequently, expression of miR-223-3p targets, including Igf1r and Stat3, was lower in morphine-treated bone. In summary, we have established a model where morphine leads to a lower trabecular bone formation in males and identified potential mediating miRNAs. Understanding the sex-specific mechanisms of bone loss from opioids will be important for improving management of the adverse effects of opioids on the skeleton. © 2022 American Society for Bone and Mineral Research (ASBMR).

Early Enteral Nutrition in Mechanically Ventilated Patients With COVID-19 Infection.

BACKGROUND: Nutrition therapy is essential in critically ill adults. Little is known about appropriate nutrition therapy in patients with severe coronavirus disease 2019 (COVID-19) infection. METHODS: This was a retrospective, observational study in adult patients with confirmed COVID-19 infection receiving mechanical ventilation. Data regarding patient demographics and nutrition therapy were collected. Patients that received enteral nutrition within 24 hours of starting mechanical ventilation were compared with patients starting enteral nutrition later. The primary outcome was inpatient length of stay. Propensity score matching was conducted to control for baseline differences in patient groups. RESULTS: One hundred fifty-five patients were included in final analysis. Patients who received enteral nutrition within 24 hours received a significantly greater daily amount of calories (17.5 vs 15.2 kcal/kg, P = .015) and protein (1.04 vs 0.85 g/kg, P = .003). There was no difference in length of stay (18.5 vs 23.5 days, P = .37). The propensity score analysis included 100 patients. Following propensity scoring, significant differences in daily calorie (17.7 [4.6] vs 15.1 [5.1] kcal/kg/d, P = .009) and protein (1.03 [0.35] vs 0.86 [0.38] g/kg/d, P = .014) provision remained. No differences in length of stay or other outcomes were noted in the propensity score analysis. CONCLUSION: Initiation of enteral nutrition within 24 hours was not associated with improved outcomes in mechanically ventilated adults with COVID-19. No harm was detected either. Future research should seek to clarify optimal timing of enteral nutrition initiation in patients with COVID-19 who require mechanical ventilation.

Lifestyle, Behavioral, and Dietary Risk Factors in Relation to Mammographic Breast Density in Women at High Risk for Breast Cancer.

BACKGROUND: Women at high risk for breast cancer due to genetics or risk factor profiles are counseled to adopt lifestyle, behavioral, and dietary changes to help reduce their risk. These recommendations are based on studies of women at average risk, so their effectiveness in high-risk women is unclear. METHODS: We evaluated the impact of physical activity, smoking, alcohol consumption, and intake of folate and carotenoids on mammographic breast density-a proxy for breast cancer risk-among 387 high-risk women. Exposures were self-reported on questionnaires. Breast dense area, nondense area, and percent dense area were measured from screening mammograms with Library for Breast Radiodensity Assessment software. Cross-sectional associations were estimated with multivariable quantile regression models. RESULTS: After adjusting for age, adiposity, reproductive history, and use of postmenopausal hormones, no breast density measure was associated with physical activity level, smoking status, alcohol consumption, or estimated intake of folate, alpha-carotene, beta-carotene, lutein/zeaxanthin, and beta-cryptoxanthin. Lycopene intake was associated with lower dense area when comparing the highest and lowest intake categories (adjusted difference in median = -14 cm2, 95% confidence interval: -29 to 1.3 cm2). This association may be explained by incomplete adjustment for adiposity. CONCLUSIONS: Recommended lifestyle, behavioral, and dietary changes to mitigate personal risk of breast cancer do not substantially impact mammographic breast density measures. IMPACT: Alternative strategies, such as increased uptake of chemoprevention, may better serve risk reduction efforts in women at high risk for breast cancer.

Safety of dexmedetomidine in the cardiac intensive care unit.

AIMS: Dexmedetomidine is one of the sedative agents recommended by the Society of Critical Care Medicine as a preferred option over benzodiazepines in critically ill, mechanically ventilated patients. Little data exists describing sedation in the cardiac intensive care unit (CICU). The purpose of this study was to determine the prevalence of adverse events in CICU patients treated with dexmedetomidine. METHODS AND RESULTS: This was a retrospective cohort analysis of patients >18 years old admitted to the University of Michigan CICU from June 2014 to October 2019 who received dexmedetomidine therapy. The primary outcome was the composite of adverse events including bradycardia, hypotension, increasing vasopressor/inotrope requirements, and asystole. Secondary outcomes included individual components of the primary outcome. Patients that experienced adverse events were compared to those that did not experience adverse events to identify risk factors for adverse events. A total of 197 patients were included. There were 116 adverse events in 106 patients. Hypotension was the most common adverse event, making up 60.3% of adverse events reported. Increased vasopressor requirement and bradycardia both occurred in 22 patients (18.9%). Asystole occurred in two patients. B-type natriuretic peptide (BNP) levels were significantly higher in those experiencing an adverse event (848 pg/mL vs. 431 pg/mL; P = 0.03). CONCLUSIONS: Patients admitted to the CICU experienced a high rate of adverse events with dexmedetomidine use. Those experiencing adverse events were more likely to have a higher BNP. Future studies should explore the safety of alternative sedative agents to ascertain safe pharmacological options for patients admitted to the CICU.

Impact of Obesity on Tranexamic Acid Efficacy in Adult Patients With Major Bleeding.

BACKGROUND: Tranexamic acid (TXA) is an antifibrinolytic used for prophylaxis and treatment of acute bleeding. Although fixed dosing is often used in practice, weight-based dosing is sometimes used in the operating room (OR). The efficacy and safety of fixed-dose TXA is not well established in patients with above average weight or body mass index. OBJECTIVE: To characterize the efficacy and safety of intravenous TXA in obese patients with major bleeding. METHODS: This was a retrospective review of 165 patients receiving fixed-dose TXA for acute bleeding outside the OR. Blood product administration (BPA) before and after TXA was collected, along with demographic and bleed-related information. Thrombotic events were the major safety end point. A prespecified subgroup analysis was conducted in patients weighing at least 100 kg compared with a lower weight. Logistic regression was performed to determine whether an association exists between body weight and blood product requirement after TXA administration. RESULTS: In the 24 hours after TXA, patients received an average of 4.17 units of blood product. Patients weighing at least 100 kg averaged 4.04 total units, compared with 4.19 units in the lower weight group (P = 0.603). Administration of individual blood products did not differ between groups, and thrombotic events were similar. Regression analysis did not associate weight with total BPA. CONCLUSION AND RELEVANCE: In patients receiving fixed-dose TXA, weight does not appear to alter blood product requirements or rates of adverse thrombotic events. These data support continued use of fixed-dose TXA for treatment of acute major bleeding in obese patients.

Identification of tRNA-derived small RNA (tsRNA) responsive to the tumor suppressor, RUNX1, in breast cancer.

Despite recent advances in targeted therapies, the molecular mechanisms driving breast cancer initiation, progression, and metastasis are minimally understood. Growing evidence indicate that transfer RNA (tRNA)-derived small RNAs (tsRNA) contribute to biological control and aberrations associated with cancer development and progression. The runt-related transcription factor 1 (RUNX1) transcription factor is a tumor suppressor in the mammary epithelium whereas RUNX1 downregulation is functionally associated with breast cancer initiation and progression. We identified four tsRNA (ts-19, ts-29, ts-46, and ts-112) that are selectively responsive to expression of the RUNX1 tumor suppressor. Our finding that ts-112 and RUNX1 anticorrelate in normal-like mammary epithelial and breast cancer lines is consistent with tumor-related activity of ts-112 and tumor suppressor activity of RUNX1. Inhibition of ts-112 in MCF10CA1a aggressive breast cancer cells significantly reduced proliferation. Ectopic expression of a ts-112 mimic in normal-like mammary epithelial MCF10A cells significantly increased proliferation. These findings support an oncogenic potential for ts-112. Moreover, RUNX1 may repress ts-112 to prevent overactive proliferation in breast epithelial cells to augment its established roles in maintaining the mammary epithelium.

Reconsidering Dexmedetomidine for Sedation in the Critically Ill: Implications of the SPICE III Trial.

Dexmedetomidine is a sedative agent that has gained popularity for use in the intensive care unit over the past 20 years. Guidelines recommend dexmedetomidine as a first-line agent to achieve light sedation in mechanically ventilated adults. Recently, the SPICE III (Sedation Practice in Intensive Care Evaluation III) trial was published. This was a randomized controlled trial comparing initial sedation with dexmedetomidine with usual care sedation in adult patients receiving mechanical ventilation. The results of this trial have both validated and contradicted previous findings about dexmedetomidine. This editorial examines the merits of the SPICE III trial and the role of dexmedetomidine in practice following its publication.

Exosomal miR-16-5p as a target for malignant mesothelioma.

Malignant mesothelioma (MM) is an asbestos-induced cancer arising on the mesothelial surface of organ cavities. MM is essentially incurable without a means of early diagnosis and no successful standard of care. These facts indicate a deep chasm of knowledge that needs to be filled. Our group recently delved into MM tumor biology from the perspective of exosome-contained microRNAs (miRNAs). We discovered that the most abundant miRNAs in MM cancer exosomes were tumor suppressors, particularly miR-16-5p. This observation lead us to hypothesize that MM cells preferentially secreted tumor-suppressor miRNAs via exosomes. Through separate avenues of potential therapeutic advance, we embarked on an innovative strategy to kill MM tumor cells. We employed small molecule inhibitors to block exosome secretion, thereby reducing miR-16-5p exosome loss and replenishing cellular miR-16-5p leading to reduced tumorigenic capacity and miR-16-5p target oncoproteins CCND1 and BCL2. Additionally, we force-fed MM tumor exosomes back to MM tumor cells, which led to cell death, and a reduction in the same oncoproteins. We recapitulated these results with direct transfection of miR-16-5p, confirmed that this is a cancer-cell specific effect, and elucidated a part of the miR-16-5p mechanism of exosome loading.

Towards a more precise and individualized assessment of breast cancer risk.

Many clinically based models are available for breast cancer risk assessment; however, these models are not particularly useful at the individual level, despite being designed with that intent. There is, therefore, a significant need for improved, precise individualized risk assessment. In this Research Perspective, we highlight commonly used clinical risk assessment models and recent scientific advances to individualize risk assessment using precision biomarkers. Genome-wide association studies have identified >100 single nucleotide polymorphisms (SNPs) associated with breast cancer risk, and polygenic risk scores (PRS) have been developed by several groups using this information. The ability of a PRS to improve risk assessment is promising; however, validation in both genetically and ethnically diverse populations is needed. Additionally, novel classes of biomarkers, such as microRNAs, may capture clinically relevant information based on epigenetic regulation of gene expression. Our group has recently identified a circulating-microRNA signature predictive of long-term breast cancer in a prospective cohort of high-risk women. While progress has been made, the importance of accurate risk assessment cannot be understated. Precision risk assessment will identify those women at greatest risk of developing breast cancer, thus avoiding overtreatment of women at average risk and identifying the most appropriate candidates for chemoprevention or surgical prevention.

Angiotensin II Brings More Questions Than Answers.

The approval of synthetic human angiotensin II (Giapreza, LaJolla Pharmaceuticals) by the FDA in December 2017 provides clinicians with a new tool in the treatment of distributive shock. Angiotensin II (ATII) was approved based on the results of the ATHOS-3 trial. In this trial, patients who received angiotensin II were more likely to achieve a mean arterial pressure of 75 mmHg or an increase in mean arterial pressure of 10 mmHg above that seen in patients who received a placebo. However, the results of ATHOS-3 also highlighted important concerns about thrombotic and infectious complications associated with ATII. Given that the cost of medication acquisition is approximately $1,500 per vial, practitioners must also decide how to implement ATII into practice in the most cost-effective manner. This commentary examines the current controversies surrounding both the safety and efficacy of ATII.

Impact of dextrose dose on hypoglycemia development following treatment of hyperkalemia.

BACKGROUND: Hyperkalemia is an electrolyte abnormality that may cause ventricular dysrhythmias and cardiac arrest. The presence of hyperkalemia may necessitate prompt treatment via intravenous insulin and dextrose. One notable complication of this therapy is the development of hypoglycemia. Previous trials have examined the impact of altering the insulin dose administered on hypoglycemia development; no trials to date however, have examined the impact of altering the dextrose dose. METHODS: This was a multicenter, retrospective, matched cohort study of patients who received intravenous insulin and dextrose for reversal of hyperkalemia. Patients received either 25 g or 50 g of dextrose in addition to 10 units of insulin. Study populations were matched based on preexisting rates of acute kidney injury, end-stage renal disease, and diabetes mellitus. Blood glucose levels were measured at 60 and 240 min following treatment. RESULTS: A total of 240 patients were included in the analysis. At 60 min following treatment, 15.8% of patients who received 25 g of dextrose developed hypoglycemia, as opposed to 8.3% of patients who received 50 g of dextrose (p = 0.11). Hyperglycemia was more common in patients who received 50 g of dextrose at 60 min posttreatment; however, this difference did not persist at 240 min. Potassium reduction at 60 min did not differ between groups. In patients with a pretreatment blood glucose <110 mg/dl or without diabetes, rates of hypoglycemia were significantly lower when 50 g of dextrose was administered. CONCLUSION: In the overall patient population, use of 50 g of dextrose instead of 25 g does not reduce hypoglycemia incidence. However, it may be beneficial is select patient populations, such as patients without type 2 diabetes or patients with a baseline blood glucose <110 mg/dl. Administration of 50 g of dextrose did not appear to place patients at significant risk for hyperglycemia however and could be considered during treatment of hyperkalemia.

Nanoparticle-based targeted cancer strategies for non-invasive prostate cancer intervention.

Prostate cancer is screened by testing circulating levels of the prostate-specific antigen (PSA) biomarker, monitoring changes over time, or a digital rectal exam. Abnormal results often lead to prostate biopsy. Prostate cancer positive patients are stratified into very low-risk, low-risk, intermediate-risk, and high-risk, based on clinical classification parameters, to assess therapy options. However, there remains a gap in our knowledge and a compelling need for improved risk stratification to inform clinical decisions and reduce both over-diagnosis and over-treatment. Further, current strategies for clinical intervention do not distinguish clinically aggressive prostate cancer from indolent disease. This mini-review takes advantage of a large number of functionally characterized microRNAs (miRNA), epigenetic regulators of prostate cancer, that define prostate cancer cell activity, tumor stage, and circulate as biomarkers to monitor disease progression. Nanoparticles provide an effective platform for targeted delivery of miRNA inhibitors or mimics specifically to prostate tumor cells to inhibit cancer progression. Several prostate-specific transmembrane proteins expressed at elevated levels in prostate tumors are under investigation for targeting therapeutic agents to prostate cancer cells. Given that prostate cancer progresses slowly, circulating miRNAs can be monitored to identify tumor progression in indolent disease, allowing identification of miRNAs for nanoparticle intervention before the crucial point of transition to aggressive disease. Here, we describe clinically significant and non-invasive intervention nanoparticle strategies being used in clinical trials for drug and nucleic acid delivery. The advantages of mesoporous silica-based nanoparticles and a number of candidate miRNAs for inhibition of prostate cancer are discussed.