Cognitive effects of long-term androgen deprivation therapy in older men with prostate cancer.

OBJECTIVE: Androgen deprivation therapy (ADT) is a common treatment for prostate cancer (PCa), with increasing numbers of men on ADT for longer. Limited evidence suggests ADT impacts cognition. This study addressed gaps in the literature by focusing on older men with PCa and assessing ADT usage longer than 1 year. METHODS: This study of 133 men ≥65 years of age with PCa included two groups: (1) men on ADT for 1-3 years (ADT-exposed), and (2) a comparison group of men with PCa not on ADT (ADT-unexposed). Group comparisons on individual neuropsychological test scores are reported, as well as effect sizes (Cohen's d). RESULTS: Half (n = 67) of the sample was ADT-exposed and half (n = 66) were unexposed. The average age was 72 years, most were White, and over 50% had at least secondary education. There were no statistically significant differences between groups by age, race, or education. Unadjusted analyses showed the ADT-exposed group, compared with the ADT-unexposed group, performed significantly lower in domains of verbal learning (d = 0.45-0.52, p = 0.01 to <0.01), verbal recall (d = 0.33-0.54, p = 0.06 to <0.01), and possible effects in visuospatial construction (d = 0.33, p = 0.08 to 0.06). When controlling for age and education, similar patterns emerged. The ADT exposed-group performed significantly lower in domains of verbal learning (d = 0.45-0.52, p = 0.06 to 0.03) and verbal recall (d = 0.33-0.54, p = 0.11 to 0.03), and possible effects in visuospatial construction d = 0.33, p = 0.18 to 0.13. CONCLUSIONS: This study suggests long-term ADT exposure impacts verbal learning, verbal recall, and possibly visuospatial abilities in older men (≥65) with PCa. The potential cognitive effects of ADT should be discussed with older patients considering long-term use of ADT.

A sepsis trigger tool reduces time to antibiotic administration in the NICU.

OBJECTIVE: Prolonged time to antibiotic administration is associated with increased morbidity and mortality. Interventions to decrease the time to antibiotic administration may improve mortality and morbidity. STUDY DESIGN: We identified possible change concepts for reducing time to antibiotic usage in the NICU. For the initial intervention, we developed a sepsis screening tool based on NICU-specific parameters. The main goal of the project was to reduce time to antibiotic administration by 10%. RESULTS: The project was conducted from April 2017 until April 2019. There were no missed cases of sepsis in the project period. Time to antibiotic administration for patients who were started on antibiotics decreased during the project, with the mean shifting from 126 to 102 min, a reduction of 19%. CONCLUSIONS: We successfully reduced time to antibiotic delivery in our NICU using a trigger tool to identifying potential cases of sepsis in the NICU environment. The trigger tool requires broader validation.

Exercise Associated with Cognitive Function in Older Men with Prostate Cancer Undergoing Androgen Deprivation Therapy.

BACKGROUND: To examine associations between exercise and cognitive function in older men undergoing hormone therapy for prostate cancer. METHOD: Men ≥ 65 years old with prostate cancer, currently undergoing androgen deprivation therapy for ≥ 6 months (n = 50), completed the Godin-Shephard Leisure-Time Physical Activity Questionnaire, and standard neuropsychological tests. Pearson's correlations and linear regressions were used to examine associations between exercise and cognitive performance. RESULTS: Exercise was significantly positively correlated with performance on tests of memory, attention, and executive function. Linear regressions showed that when controlling for age and education, exercise remained a significant predictor of attention and executive function performance (p < 0.05), and showed moderate, but statistically non-significant effects on memory performance (p < 0.10). CONCLUSION: Greater exercise is associated with better functioning in multiple cognitive domains in men with prostate cancer undergoing hormone therapy, providing proof-of-concept evidence that exercise may be a feasible intervention to limit cognitive dysfunction in prostate cancer patients.

shox2 is required for vestibular statoacoustic neuron development.

Homeobox genes act at the top of genetic hierarchies to regulate cell specification and differentiation during embryonic development. We identified the short stature homeobox domain 2 (shox2) transcription factor that is required for vestibular neuron development. shox2 transcripts are initially localized to the otic placode of the developing inner ear where neurosensory progenitors reside. To study shox2 function, we generated CRISPR-mediated mutant shox2 fish. Mutant embryos display behaviors associated with vestibular deficits and showed reduced number of anterior statoacoustic ganglion neurons that innervate the utricle, the vestibular organ in zebrafish. Moreover, a shox2-reporter fish showed labeling of developing statoacoustic ganglion neurons in the anterior macula of the otic vesicle. Single cell RNA-sequencing of cells from the developing otic vesicle of shox2 mutants revealed altered otic progenitor profiles, while single molecule in situ assays showed deregulated levels of transcripts in developing neurons. This study implicates a role for shox2 in development of vestibular but not auditory statoacoustic ganglion neurons.

Diagnosing Transthyretin Cardiac Amyloidosis by Technetium Tc 99m Pyrophosphate: A Test in Evolution.

OBJECTIVES: This study aimed to characterize trends in technetium Tc 99m pyrophosphate (99mTc-PYP) scanning for amyloid transthyretin cardiac amyloidosis (ATTR-CA) diagnosis, to determine whether patients underwent appropriate assessment with monoclonal protein and genetic testing, to evaluate use of single-photon emission computed tomography (SPECT) in addition to planar imaging, and to identify predictive factors for ATTR-CA. BACKGROUND: 99mTc-PYP scintigraphy has been repurposed for noninvasive diagnosis of ATTR-CA. Increasing use of 99mTc-PYP can facilitate identification of ATTR-CA, but appropriate use is critical for accurate diagnosis in an era of high-cost targeted therapeutics. METHODS: Patients undergoing 99mTc-PYP scanning 1 h after injection at a quaternary care center from 2010 to 2019 were analyzed; clinical information was abstracted; and SPECT results were analyzed. RESULTS: Over the decade, endomyocardial biopsy rates remained stable with scanning rates peaking at 132 in 2019 (p < 0.001). Among 753 patients (516 men, mean age 77 years), 307 (41%) had a visual score of 0, 177 (23%) of 1, and 269 (36%) of 2 or 3. Of 751 patients with analyzable heart to contralateral chest ratios, 249 (33%) had a ratio ≥1.5. Monoclonal protein testing status was assessed in 550 patients, of these, 174 (32%) did not undergo both serum immunofixation and serum free light chain analysis tests, and 331 (60%) did not undergo all 3 tests-serum immunofixation, serum free light chain analysis, and urine protein electrophoresis. Of 196 patients with confirmed ATTR-CA, 143 (73%) had genetic testing for transthyretin mutations. In 103 patients undergoing cardiac biopsy, grades 2 and 3 99mTc-PYP had sensitivity of 94% and specificity of 89% for ATTR-CA with 100% specificity for grade 3 scans. With respect to SPECT as a reference standard, planar imaging had false positive results in 16 of 25 (64%) grade 2 scans. CONCLUSIONS: Use of noninvasive testing with 99mTc-PYP scanning for evaluation of ATTR-CA is increasing, and the inclusion of monoclonal protein testing and SPECT imaging is crucial to rule out amyloid light chain amyloidosis and distinguish myocardial retention from blood pooling.

Central venous catheter bundle adherence: Kamishibai card (K-card) rounding for central-line-associated bloodstream infection (CLABSI) prevention.

OBJECTIVE: To institute facility-wide Kamishibai card (K-card) rounding for central venous catheter (CVC) maintenance bundle education and adherence and to evaluate its impact on bundle reliability and central-line-associated bloodstream infection (CLABSI) rates. DESIGN: Quality improvement project. SETTING: Inpatient units at a large, academic freestanding children's hospital. PARTICIPANTS: Data for inpatients with a CVC in place for ≥1 day between November 1, 2017 and October 31, 2018 were included. INTERVENTION: A K-card was developed based on 7 core elements in our CVC maintenance bundle. During monthly audits, auditors used the K-cards to ask bedside nurses standardized questions and to conduct medical record documentation reviews in real time. Adherence to every bundle element was required for the audit to be considered "adherent." We recorded bundle reliability prospectively, and we compared reliability and CLABSI rates at baseline and 1 year after the intervention. RESULTS: During the study period, 2,321 K-card audits were performed for 1,051 unique patients. Overall maintenance bundle reliability increased significantly from 43% at baseline to 78% at 12 months after implementation (P < .001). The hospital-wide CLABSI rate decreased from 1.35 during the 12-month baseline period to 1.17 during the 12-month intervention period, but the change was not statistically significant (incidence rate ratio [IRR], 0.87; 95% confidence interval [CI], 0.60-1.24; P = .41). CONCLUSIONS: Hospital-wide CVC K-card rounding facilitated standardized data collection, discussion of reliability, and real-time feedback to nurses. Maintenance bundle reliability increased after implementation, accompanied by a nonsignificant decrease in the CLABSI rate.

Developmental constraints on fin diversity.

The fish fin is a breathtaking repository full of evolutionary diversity, novelty, and convergence. Over 500 million years, the adaptation to novel habitats has provided landscapes of fin diversity. Although comparative anatomy of evolutionarily divergent patterns over centuries has highlighted the fundamental architectures and evolutionary trends of fins, including convergent evolution, the developmental constraints on fin evolution, which bias the evolutionary trajectories of fin morphology, largely remain elusive. Here, we review the evolutionary history, developmental mechanisms, and evolutionary underpinnings of paired fins, illuminating possible developmental constraints on fin evolution. Our compilation of anatomical and genetic knowledge of fin development sheds light on the canalized and the unpredictable aspects of fin shape in evolution. Leveraged by an arsenal of genomic and genetic tools within the working arena of spectacular fin diversity, evolutionary developmental biology embarks on the establishment of conceptual framework for developmental constraints, previously enigmatic properties of evolution.

99mTechnetium pyrophosphate scintigraphy with cadmium zinc telluride cameras is a highly sensitive and specific imaging modality to diagnose transthyretin cardiac amyloidosis.

BACKGROUND: Transthyretin cardiac amyloidosis (ATTR) is a rare, but underdiagnosed, cardiomyopathy. Traditionally diagnosed invasively, ATTR can be diagnosed with non-invasive 99mTechnetium pyrophosphate (99mTc-PYP) planar scintigraphy. Non-planar imaging has not been validated for ATTR diagnosis. Here, we develop and validate a Cadmium Zinc Telluride (CZT) protocol for diagnosing ATTR. METHODS: Forty-three subjects (24 ATTR, 19 non-ATTR) were imaged with Philips Dual-Head Anger (planar) and General Electric CZT cameras. Myocardial uptake was quantified by heart-to-contralateral (H/CL) ratios. CZT scans were quantified by two readers blinded to planar H/CL, with one repeating blinded quantification. Using the previously validated diagnostic threshold (H/CL ≥ 1.5), sensitivity and specificity of CZT scintigraphy was measured. McNemar's test and Pearson's correlation coefficient were calculated. RESULTS: Among subjects (76.7% male, age 77 ± 9), there was no significant difference in proportion of ATTR-positive identification between modalities. There was high correlation between CZT and planar H/CL ratios (r = 0.92, P < 0.0001), with low intra- [ICC = 0.89 (0.80-0.94)] and inter-observer [ICC = 0.80 (0.65-0.89)] variability. CZT scintigraphy had 100% sensitivity and specificity for diagnosing ATTR. CONCLUSION: 99mTc-PYP CZT imaging is as highly sensitive and specific diagnosing ATTR as planar imaging. These findings are clinically salient given the emergence of disease-modifying ATTR therapies, as it could expand diagnostic capability.

The evolutionary origins and diversity of the neuromuscular system of paired appendages in batoids.

Appendage patterning and evolution have been active areas of inquiry for the past two centuries. While most work has centred on the skeleton, particularly that of amniotes, the evolutionary origins and molecular underpinnings of the neuromuscular diversity of fish appendages have remained enigmatic. The fundamental pattern of segmentation in amniotes, for example, is that all muscle precursors and spinal nerves enter either the paired appendages or body wall at the same spinal level. The condition in finned vertebrates is not understood. To address this gap in knowledge, we investigated the development of muscles and nerves in unpaired and paired fins of skates and compared them to those of chain catsharks. During skate and shark embryogenesis, cell populations of muscle precursors and associated spinal nerves at the same axial level contribute to both appendages and body wall, perhaps representing an ancestral condition of gnathostome appendicular neuromuscular systems. Remarkably in skates, this neuromuscular bifurcation as well as colinear Hox expression extend posteriorly to pattern a broad paired fin domain. In addition, we identified migratory muscle precursors (MMPs), which are known to develop into paired appendage muscles with Pax3 and Lbx1 gene expression, in the dorsal fins of skates. Our results suggest that muscles of paired fins have evolved via redeployment of the genetic programme of MMPs that were already involved in dorsal fin development. Appendicular neuromuscular systems most likely have emerged as side branches of body wall neuromusculature and have been modified to adapt to distinct aquatic and terrestrial habitats.

The use of serial cardiac 18F-fluorodeoxyglucose- positron emission tomography imaging to diagnose, monitor, and tailor treatment of cardiac sarcoidosis patients with arrhythmias: a case series and review.

BACKGROUND: Clinically evident cardiac involvement has been documented in 5% of sarcoidosis patients, primarily manifesting as heart block, ventricular arrhythmias, and heart failure. Heart Rhythm Society consensus guidelines recommend advanced cardiac imaging with fluorodeoxyglucose-positron emission tomography (FDG-PET) scan for diagnosis of cardiac sarcoidosis, given endomyocardial biopsy's low sensitivity. CASE SUMMARY: We describe four patients with cardiac sarcoidosis diagnosed with FDG-PET scan performed using a standardized imaging protocol for cardiac sarcoidosis. Serial FDG-PET scans were performed to monitor disease progression and response to therapy. Patients 1 and 2 presented with heart block, Patient 3 with heart failure and ventricular tachycardia (VT), and Patient 4 with VT. Patient 1 showed an initial decrease in standard uptake value (SUV) on immunosuppression, followed by an increase in SUV, necessitating steroid therapy. Patient 2's SUV decreased on immunosuppression. Patient 3 required 3.5 years of immunosuppression for the SUV to decrease to inactive disease levels, with SUV increasing and decreasing at different times during treatment, and subsequently developed VT. For Patient 4, areas of inflammation on the initial scan matched low voltage areas on the patient's EP study, confirming the arrhythmia's pathophysiological basis. DISCUSSION: Cardiac sarcoidosis progression and response to therapy are heterogeneous. Serial FDG-PET scans are useful to diagnose disease, tailor therapy, and monitor the clinical course of disease, allowing treatment decisions to be based on the quantitative level of inflammation seen on FDG-PET.

It's in Your Hands: An Educational Initiative to Improve Parent/Family Hand Hygiene Compliance.

BACKGROUND: Health care-associated infections contribute to increased morbidity and mortality, increased resource use, higher costs, and extended hospitalizations. Proper hand hygiene (HH) is essential to health care-associated infection prevention. Low compliance among parents in our neonatal intensive care unit (NICU) was identified and prompted development of an HH initiative. OBJECTIVE: The objective of this quality improvement project was to improve parent HH practices with the ultimate goal of achieving 100% compliance with parent HH. METHODS: Between December 2011 and November 2014, our NICU Infection Prevention Committee developed and implemented the parent/family HH initiative entitled "It's in Your Hands" and created learning materials based on the World Health Organization and Centers for Disease Control and Prevention recommendations. Materials included information sheets, posters, stickers, and checklists. Audits, based on the World Health Organization's Five Moments for Hand Hygiene, were performed several times per week to monitor compliance. RESULTS: Before the intervention, only 71% (n = 1143) of all observed parents and family members performed proper HH. After the intervention, proper HH increased to 89% (n = 939). An average compliance of 89% was maintained throughout the intervention phase. DISCUSSION: This initiative led to sustained improvements in HH compliance among NICU parents. It has empowered parents to speak up and request proper HH from health care providers when interacting with their child. This initiative has been adopted as a hospital-wide standard of care.

Synthesis and Characterization of Novel BMI1 Inhibitors Targeting Cellular Self-Renewal in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) represents one of the most lethal cancers worldwide due to therapy resistance and disease recurrence. Tumor relapse following treatment could be driven by the persistence of liver cancer stem-like cells (CSCs). The protein BMI1 is a member of the polycomb epigenetic factors governing cellular self-renewal, proliferation, and stemness maintenance. BMI1 expression also correlates with poor patient survival in various cancer types. OBJECTIVE: We aimed to elucidate the extent to which BMI1 can be used as a potential therapeutic target for CSC eradication in HCC. METHODS: We have recently participated in characterizing the first known pharmacological small molecule inhibitor of BMI1. Here, we synthesized a panel of novel BMI1 inhibitors and examined their ability to alter cellular growth and eliminate cancer progenitor/stem-like cells in HCC with different p53 backgrounds. RESULTS: Among various molecules examined, RU-A1 particularly downregulated BMI1 expression, impaired cell viability, reduced cell migration, and sensitized HCC cells to 5-fluorouracil (5-FU) in vitro. Notably, long-term analysis of HCC survival showed that, unlike chemotherapy, RU-A1 effectively reduced CSC content, even as monotherapy. BMI1 inhibition with RU-A1 diminished the number of stem-like cells in vitro more efficiently than the model compound C-209, as demonstrated by clonogenic assays and impairment of CSC marker expression. Furthermore, xenograft assays in zebrafish showed that RU-A1 abrogated tumor growth in vivo. CONCLUSIONS: This study demonstrates the ability to identify agents with the propensity for targeting CSCs in HCC that could be explored as novel treatments in the clinical setting.

Association Between Storage Interval and Contamination of Reprocessed Flexible Endoscopes in a Pediatric Gastrointestinal Procedural Unit.

OBJECTIVE The maximum safe storage interval after endoscope reprocessing remains unknown. We assessed the association between storage interval and endoscope contamination to evaluate the need for scope reprocessing prior to use. METHODS We conducted a study in 2 phases. In phase 1, we cultured 9 gastrointestinal (GI) endoscopes that had been stored for at least 7 days since reprocessing. Each scope was cultured in 3 places: external surfaces of hand piece, insertion tube, and internal channels. In phase 2, after reprocessing these scopes, we hung and cultured them prospectively in a similar fashion at 1-, 2-, 4-, 6-, and 8-week intervals without patient use. We defined clinically relevant contamination as >100 colony-forming units per milliliter (CFU/mL). RESULTS In phase 1, median hang time was 69 days (range, 8-555 days). Considering the 27 total cultures, 3 of 27 GI endoscopes (11.1%) had positive cultures, all with nonpathogenic skin flora at ≤100 CFU/mL. Median hang time was not statistically different between scopes with positive and negative cultures (P=.82). In phase 2, 7 of 131 prospective cultures (5.3%) from 6 of 9 GI endoscopes at varying storage intervals were positive, all at ≤100 CFU/mL. At 56 days after reprocessing (the longest storage interval studied), 1 of 24 cultures (4.2%) was positive (100 CFU/mL of Bacillus species from external biopsy/suction ports). CONCLUSIONS No endoscopes demonstrated clinically relevant contamination at hang times ranging from 7 to 555 days, and most scopes remained uncontaminated up to 56 days after reprocessing. Our data suggest that properly cleaned and disinfected GI endoscopes could be stored safely for longer intervals than currently recommended. Infect. Control Hosp. Epidemiol. 2017;38:131-135.

BMI-1 Targeting Interferes with Patient-Derived Tumor-Initiating Cell Survival and Tumor Growth in Prostate Cancer.

PURPOSE: Current prostate cancer management calls for identifying novel and more effective therapies. Self-renewing tumor-initiating cells (TICs) hold intrinsic therapy resistance and account for tumor relapse and progression. As BMI-1 regulates stem cell self-renewal, impairing BMI-1 function for TIC-tailored therapies appears to be a promising approach. EXPERIMENTAL DESIGN: We have previously developed a combined immunophenotypic and time-of-adherence assay to identify CD49bhiCD29hiCD44hi cells as human prostate TICs. We utilized this assay with patient-derived prostate cancer cells and xenograft models to characterize the effects of pharmacologic inhibitors of BMI-1. RESULTS: We demonstrate that in cell lines and patient-derived TICs, BMI-1 expression is upregulated and associated with stem cell-like traits. From a screened library, we identified a number of post-transcriptional small molecules that target BMI-1 in prostate TICs. Pharmacologic inhibition of BMI-1 in patient-derived cells significantly decreased colony formation in vitro and attenuated tumor initiation in vivo, thereby functionally diminishing the frequency of TICs, particularly in cells resistant to proliferation- and androgen receptor-directed therapies, without toxic effects on normal tissues. CONCLUSIONS: Our data offer a paradigm for targeting TICs and support the development of BMI-1-targeting therapy for a more effective prostate cancer treatment. Clin Cancer Res; 22(24); 6176-91. ©2016 AACR.

Barriers to the use of face protection for standard precautions by health care providers.

Health care providers sometimes choose not to use face protection even when indicated as part of standard precautions. We performed a survey of pediatric health care providers to determine barriers to the routine use of face protection. Lack of availability at the point of care and a perceived lack of need were the most commonly cited issues. Continuing education is needed regarding situations in which face protection is indicated for standard precautions.

Health care failure mode and effect analysis to reduce NICU line-associated bloodstream infections.

OBJECTIVE: Central line-associated bloodstream infections (CLABSIs) in NICU result in increased mortality, morbidity, and length of stay. Our NICU experienced an increase in the number of CLABSIs over a 2-year period. We sought to reduce risks for CLABSIs using health care failure mode and effect analysis (HFMEA) by analyzing central line insertion, maintenance, and removal practices. METHODS: A multidisciplinary team was assembled that included clinicians from nursing, neonatology, surgery, infection prevention, pharmacy, and quality management. Between March and October 2011, the team completed the HFMEA process and implemented action plans that included reeducation, practice changes, auditing, and outcome measures. RESULTS: The HFMEA identified 5 common failure modes that contribute to the development of CLABSIs. These included contamination, suboptimal environment of care, improper documentation and evaluation of central venous catheter dressing integrity, issues with equipment and suppliers, and lack of knowledge. Since implementing the appropriate action plans, the NICU has experienced a significant decrease in CLABSIs from 2.6 to 0.8 CLABSIs per 1000 line days. CONCLUSIONS: The process of HFMEA helped reduce the CLABSI rate and reinforce the culture of continuous quality improvement and safety in the NICU.

Partnering with family members to improve the intensive care unit experience.

Family members play an important and varied role in a patient's health care experience, ranging from emotional support to surrogate health care decision making. The family role can be substantial in the intensive care unit setting, as the patients rely upon family members to make health care decisions for them. The core components of patient- and family-centered care include information sharing, a welcoming environment, respect for individual values and needs, comfort and support, and providing a helpful framework for developing a productive partnership with family members. Involving family members in daily operations and providing services that make it easier for family members to participate in the care process result in the best possible care for their loved one. Including the family perspective in quality improvement initiatives better ensures that any changes made will result in better care for future patients and family members.

Semaphorin-PlexinD1 signaling limits angiogenic potential via the VEGF decoy receptor sFlt1.

Sprouting angiogenesis expands the embryonic vasculature enabling survival and homeostasis. Yet how the angiogenic capacity to form sprouts is allocated among endothelial cells (ECs) to guarantee the reproducible anatomy of stereotypical vascular beds remains unclear. Here we show that Sema-PlxnD1 signaling, previously implicated in sprout guidance, represses angiogenic potential to ensure the proper abundance and stereotypical distribution of the trunk's segmental arteries (SeAs). We find that Sema-PlxnD1 signaling exerts this effect by antagonizing the proangiogenic activity of vascular endothelial growth factor (VEGF). Specifically, Sema-PlxnD1 signaling ensures the proper endothelial abundance of soluble flt1 (sflt1), an alternatively spliced form of the VEGF receptor Flt1 encoding a potent secreted decoy. Hence, Sema-PlxnD1 signaling regulates distinct but related aspects of angiogenesis: the spatial allocation of angiogenic capacity within a primary vessel and sprout guidance.