Combined mpMRI/US fusion targeted and concurrent standard biopsies in the detection of prostate cancer: a retrospective study.

In this retrospective study we compared the PCa detection rates between combined (combined MRI/US fusion targeted biopsy with concurrent standard biopsy) and standard systemic, combined and targeted (component), and targeted (component) and concurrent standard (component) biopsies. DESIGN: Two cohorts, totaling 735 cases, were selected from the University of Wisconsin Pathology archive. 390 cases (cohort 1) were combined biopsies from 2017-2020 and 345 cases (cohort 2) were part of the standard US-guided systematic biopsies from the same period. PCa was stratified into three categories: low, intermediate, and high risks. RESULTS: We found that combined biopsy was significantly better than the standard biopsy in detection of PCa (65.4% vs. 51.6%, P<0.01) and intermediate-risk PCa (18.7% vs. 10.4%, P=0.05) but only slightly better at detecting high-risk PCa (26.7% vs. 23.5%, P=0.32). Further examining the biopsy results in cohort 1, we found that combined biopsy was superior to targeted biopsy (65.4% vs. 56.9%, P=0.02) or concurrent standard biopsy (65.4% vs. 52.1%, P=0.0002) in PCa detection. Combined biopsy detected significantly more high-risk PCa than concurrent standard biopsy (26.7% vs. 17.4, P=0.002), but the difference in detecting high-risk PCa between combined and targeted biopsies was not significant (26.7% vs. 22.1%, P=0.133). Similarly, the differences in detecting PCa and high-risk PCa between targeted and concurrent standard biopsies were not significant (56.9% vs. 52.1%, P=0.172 and 22.1% vs. 17.4, P=0.133, respectively). Both targeted and concurrent standard biopsies missed PCa of each risk level. CONCLUSION: Combined MRI/US fusion targeted plus standard prostate biopsy is a superior technique for the detection of PCa and clinically significant PCa.

Seasonal and Regional Influences on Alcohol Consumption: An Analysis of Near-Real-Time Urine Drug Test Results in Those Seeking Health Care.

AIMS: To examine the probability of detecting alcohol via urine drug testing (UDT) as influenced by age, gender, seasonality, geography, COVID-19, and time in those seeking health care. METHODS: A cross-sectional study of UDT results from January 1, 2013, to December 31, 2020, was conducted using adult patient specimens submitted for testing by health care professionals as part of routine care. The UDT analysis used LC-MS/MS to detect two alcohol metabolites, ethyl glucuronide and ethyl sulfate. Seasonal adjustment of positivity rates was accomplished using the STL method; trend analysis was performed on seasonally adjusted rates. Logistic regression was used to associate demographic features, and an interaction term for collection year and U.S. census division was included to help understand the changing nature of alcohol use over time and across divisions. RESULTS: Alcohol positivity rate shows strong seasonal changes with an oscillating profile that peaks in the summer and is at a low point in winter. The highest predicted positivity rate for alcohol was in male patients, 45-64 years of age, and from a primary care setting. Alcohol positivity peaked in 2016 and declined the following year. While remaining relatively steady since 2017, a small but significant increase was noted after the COVID-19 emergency declaration on March 13, 2020. The probability of being alcohol-positive varies significantly by geographic region, and not all regions are changing at the same rate. CONCLUSIONS: Alcohol positivity in UDT in patients seeking health care is influenced by multiple factors and has increased during the COVID-19 pandemic.

Death Certification: Errors and Interventions.

OBJECTIVE: Death certificates are legal documents containing critical information. Despite the importance of accurate certification, errors remain common. Estimates of error prevalence vary between studies, and error classification systems are often unclear. Relatively few studies have assessed the frequency at which death certification errors occur in US hospitals, and even fewer have attempted a standardized classification of errors based on their severity. In the current study, our objective was to evaluate the frequency of death certification errors at an academic center, implement a standardized method of categorizing error severity, and analyze sources of error to better identify ways to improve death certification accuracy. DESIGN: We retrospectively reviewed the accuracy of cause and manner of death certification at our regional academic institution for 179 cases in which autopsy was performed between 2013-2016. We compared non-pathologist physician completed death certificates with the cause and manner of death ultimately determined at autopsy. METHODS: Errors were classified via a 5-point scale of increasing error severity. Grades I-IIc were considered minor errors, while III-V were considered severe. Sources of error were analyzed. RESULTS: In the majority of cases (85%), death certificates contained ≥ one error, with multiple errors (51%) being more common than single (33%). The most frequent error type was Grade 1 (53%), followed by Grade III (30%), and Grade IIb (18%). The more severe Grade IV errors were seen in 23% of cases; no Grade V errors were found. No amendments were made to any death certificates following finalization of autopsy results during the study period. CONCLUSION: This study reaffirms the importance of autopsy and autopsy pathologists in ensuring accurate and complete death certification. It also suggests that death certification errors may be more frequent than previously reported. We propose a method by which death certification errors can be classified in terms of increasing severity. By understanding the types of errors occurring on death certificates, academic institutions can work to improve certification accuracy. Better clinician education, coordination with autopsy pathologists, and implementation of a systematic approach to ensuring concordance of death certificates with autopsy results is recommended.

Health promotion: healing through loss.

For many women, miscarriage constitutes an often sudden, unexpected physically as well as psychologically traumatic event. A large percentage of women having miscarriage must present to an outpatient setting, primarily the emergency department, for care during this time. Studies indicate that health care professionals are failing to meet the needs of women and their families during and after miscarriage and that greater emphasis should be placed on psychosocial and interpersonal skills. The problem has been identified as how to assist or prepare emergency nurses to better care for the physical and psychological needs of women having early, unanticipated loss of pregnancy. At 1 rural Midwest medical center, it was the women's health staff who took the initiative to address this problem. They recognized the need for a holistic approach to care for women experiencing pregnancy loss. This would be accomplished through bridging the gap between outpatient services and primary care. This resulted in creating a support group called Ended Beginnings, which was organized to help women convalesce through the physical, emotional, and spiritual hardships associated with pregnancy and infant loss. Positive feedback has been received from both patients and staff with regard to the extent to which collaborative services provide a positive impact for both the patient and staff assisting the patient during a time of sudden, unanticipated loss.

Evaluation of a novel ELISA for serotonin: urinary serotonin as a potential biomarker for depression.

Depression is a common disorder with physical and psychological manifestations often associated with low serotonin. Since noninvasive diagnostic tools for depression are sparse, we evaluated the clinical utility of a novel ELISA for the measurement of serotonin in urine from depressed subjects and from subjects under antidepressant therapy. We developed a competitive ELISA for direct measurement of serotonin in derivatized urine samples. Assay performance was evaluated and applied to clinical samples. The analytical range of the assay was from 6.7 to 425 µg serotonin/g creatinine (Cr). The limit of quantification was 4.7 µg/g Cr. The average recovery for spiked urine samples was 104.4%. Average intra-assay variation was 4.4%, and inter-assay variation was <20%. The serotonin analysis was very specific. No significant interferences were observed for 44 structurally and nonstructurally related urinary substances. Very good correlation was observed between urinary serotonin levels measured by ELISA and liquid chromatography tandem mass spectrometry (LC-MS/MS; ELISA = 1.16 × LC-MS/MS - 53.8; r = 0.965; mean % bias = 11%; n = 18). Serotonin was stable in acidified urine for 30 days at room temperature and at -20 °C. The established reference range for serotonin was 54-366 µg/g Cr (n = 64). Serotonin levels detected in depressed patients (87.53 ± 4.89 µg/g Cr; n = 60) were significantly lower (p < 0.001) than in nondepressed subjects (153.38 ± 7.99 µg/g Cr). Urinary excretion of serotonin in depressed individuals significantly increased after antidepressant treatment by 5-hydroxy-tryptophane and/or selective serotonin re-uptake inhibitor (p < 0.01). The present ELISA provides a convenient and robust method for monitoring urinary serotonin. It is suitable to monitor serotonin imbalances and may be particularly helpful in evaluating antidepressant therapies.

Neurotransmitters excreted in the urine as biomarkers of nervous system activity: validity and clinical applicability.

Strategies for managing the nervous system are numerous while methods of evaluating the nervous system are limited. Given the physiological importance of neurotransmitters as signaling molecules in the nervous system, the measurement of neurotransmitters has significant potential as a clinical tool. Of all the biological fluids that can be utilized, urinary neurotransmitter testing, due to its stability, sensitivity, and non-invasiveness, is the desired method to analyze nervous system function. Increasing use of this technology in a clinical setting demands a review of its feasibility, utility, and clinical value. We review the current body of literature pertaining to the mechanism of neurotransmitter transport across the blood-brain barrier as well as neurotransmitter filtration and excretion by the kidneys. In addition, this review summarizes the historical use of urinary neurotransmitter assessment to diagnose pheochromocytoma. Early research also correlated urinary assessment of neurotransmitters to various clinical symptoms and treatments of which we present research only for depression, ADHD, and inflammation because of the abundant amount of research in these areas. Finally, we review the limitations and challenges of urinary neurotransmitter testing. Taken together, evidence suggests that neurotransmitters excreted in the urine may have a place in clinical practice as a biomarker of nervous system function to effectively assess disturbances and monitor treatment efficacy.

TGF-beta1 is increased in a transgenic mouse model of familial Alzheimer's disease and causes neuronal apoptosis.

Alzheimer's disease (AD) is a neurodegenerative disorder, due to excess amyloid-beta peptide (Abeta). TGF-beta1 and beta-catenin signaling pathways have been separately implicated in modulating Abeta-neurotoxicity. However, the underlying mechanisms remain unclear. Here, we report that TGF-beta1 and nuclear Smad7 and beta-catenin levels were markedly upregulated in cortical brain regions of the TgCRND8 mice, a mouse model of familial Alzheimer's disease. Coimmunoprecipitation of cortical brain tissue lysates revealed an interaction between Smad7 and beta-catenin. This interaction which was significantly enhanced in the TgCRND8 mice was also associated with an increase in TCF/LEF DNA-shift binding activity. TCF/LEF reporter gene activity was significantly increased in mouse primary cortical neuronal cultures (MCN) from the TgCRND8 mice, compared to controls. Interestingly, exposure of MCN to Abeta(1-42) led to an increase in TGF-beta1 and nuclear levels of both beta-catenin and Smad7. Furthermore, addition of TGF-beta1 to the MCN caused an increase in apoptosis and Smad7 levels. When Smad7 or beta-catenin levels were reduced by siRNA, TGF-beta1-induced apoptosis was suppressed, indicating that both Smad7 and beta-catenin are required for TGF-beta1-induced neurotoxicity. Since Abeta(1-42)-induced TGF-beta1, we suggest that TGF-beta1 may amplify Abeta(1-42)-mediated neurodegeneration in AD via Smad7 and beta-catenin interaction and nuclear localization.

NF-kappaB activated by ER calcium release inhibits Abeta-mediated expression of CHOP protein: enhancement by AD-linked mutant presenilin 1.

Mutations in presenilin which result in early-onset Alzheimer disease (AD) cause both increased calcium release from intracellular stores, primarily endoplasmic reticulum (ER), and changes in NF-kappaB activation. Some studies have also reported that neurons containing AD-linked mutant presenilins (mPS1) show increased vulnerability to various stresses, while others report no differences in neuronal death. The majority of these reports center on potential changes in ER stress, because of the enhanced ER calcium release seen in mPS1 neurons. One of the primary death effectors of ER stress is CHOP, also termed GADD153, which acts to transcriptionally inhibit protective cellular molecules such as Bcl-2 and glutathione. Because both CHOP and NF-kappaB are activated by increased intracellular calcium and stress, yet have diametrically opposite effects on neuronal vulnerability, we sought to examine this interaction in greater detail. We observed that IP3-mediated calcium release from ER, stimulated by Abeta exposure, mediated both CHOP expression and NF-kappaB DNA binding activity. Further, specific inhibition of NF-kappaB resulted in greater expression of CHOP, while activation of NF-kappaB inhibited CHOP expression. The enhanced release of calcium from IP3-mediated ER stores in mPS1 neurons stimulated increased NF-kappaB compared to normal neurons, which inhibited CHOP expression. Upon blockage of NF-kappaB, exposure to Abeta caused significantly greater Abeta-mediated CHOP expression and death in mPS1 neurons compared to normal neurons. Thus, AD-linked PS1 mutations disrupt the balance between stress-induced NF-kappaB and CHOP, resulting in greater dependence on stress-induced NF-kappaB activation in mPS1 neurons.

Measurement decisions for clinical assessment of limb volume changes in patients with bilateral and unilateral limb edema.

BACKGROUND AND PURPOSE: Therapy-related changes in limb volumes often are estimated using summated segmental volumes based on adjacent circumference measurements. The purposes of this study were: (1) to determine the effect of different segment lengths on calculated volume reductions after complete decongestive therapy and (2) to determine the effect of excluding posttherapy control limb volumes on calculated reductions in edema volume in patients with unilateral limb lymphedema. SUBJECTS: This two-part retrospective study was conducted using data from patients with bilateral leg lymphedema (n=70) and data from patients with unilateral arm lymphedema (n=75) and patients with unilateral leg lymphedema (n=45). METHODS: For the bilateral leg lymphedema group, pretreatment to posttreatment changes in limb volume were determined using segment lengths of 4, 8, and 12 cm. For the unilateral lymphedema group, pretreatment to posttreatment changes in edema volume were determined and compared using or not using posttreatment control limb volumes. RESULTS: Bilateral leg volume changes were similar for all segment lengths but not significantly different from each other. Unilateral edema volume changes were significantly overestimated in both arms and legs when posttherapy control limb volumes were not used. DISCUSSION AND CONCLUSION: The results indicate that segment lengths of 4 cm generally are not needed to obtain adequate estimates of leg volume changes. Both limb volumes should be measured to properly assess therapeutic outcomes in patients with unilateral limb lymphedema.