Search

Hunger is, by necessity, an ancient motivational drive, yet the molecular nature of homeostatic pressures of this sort and how they modulate health and physiology are largely unknown. Here we show that the molecular encoding of hunger slows aging in Drosophila. We identify the branched-chain amino acids (BCAAs) as dietary hunger signals that extend lifespan despite increasing food intake when reduced, and in parallel show that optogenetic activation of a subset of hunger-promoting neurons is sufficient to recapitulate these effects. We find that remodeling of the neuronal histone acetylome is associated with dietary BCAA reduction, and that this requires BCAA metabolism in specific subsets of neurons. Preventing the histone acetylome from being molded by dietary BCAAs abrogates both increased feeding and extended lifespan. However, the mechanisms that promote feeding and modulate aging downstream of alterations in histone acetylation occur through spatially and temporally distinct responses; differential usage of the histone variant H3.3A in the brain is an acute response to hunger that promotes increased feeding without modulating lifespan, while a prolonged experience of hunger may slow aging by promoting a beneficial decrease of a set-point around which hunger levels are regulated. Identification of a molecular basis for the encoding of hunger and demonstration of its sufficiency in extending lifespan reveals that motivational states alone are deterministic drivers of aging and behavior.

While a growing number of machine learning (ML) systems have been deployed in clinical settings with the promise of improving patient care, many have struggled to gain adoption and realize this promise. Based on a qualitative analysis of coded interviews with clinicians who use an ML-based system for sepsis, we found that, rather than viewing the system as a surrogate for their clinical judgment, clinicians perceived themselves as partnering with the technology. Our findings suggest that, even without a deep understanding of machine learning, clinicians can build trust with an ML system through experience, expert endorsement and validation, and systems designed to accommodate clinicians’ autonomy and support them across their entire workflow.

Classic psychiatry patients are rare; real-world patients tend to have overlapping features of multiple disorders. Striving for diagnostic certainty, and treatments aimed at tentative diagnoses, often fail these patients. In such cases, tolerating diagnostic ambiguity and "treating the symptoms" can sometimes be transformative. An important symptom, often undertreated in a diagnosis-based approach, is rumination. We present a case study of a woman who, after 20 years of treatment failure, achieved significant symptom relief when her primary complaint-"labored thinking"-was targeted specifically. However, because no seriously ill person has only 1 symptom, 6 clinicians from different subdisciplines will discuss the patient's other issues, ones that an overfocus on rumination might leave out.

Endometriosis is a chronic, inflammatory gynaecological disease that can have severe negative impacts on quality of life and fertility, placing burden on patients and the healthcare system. Due to the heterogeneous nature of endometriosis, and the lack of correlation between symptom and surgical disease severity, diagnosis and treatment remain a significant clinical challenge. Extracellular vesicles (EVs) are biologically active particles containing molecular cargo involved in intercellular communication, that can be exploited for diagnostic and therapeutic purposes.We systematically reviewed studies exploring EVs and their role in endometriosis, specifically addressing diagnostic and therapeutic potential and current understanding of pathophysiology. Five databases (Pubmed, Embase, Medline, Web of Science, Google Scholar) were searched for keywords ‘endometriosis’ and either ‘extracellular vesicles’ or ‘exosomes’.There were 28 studies included in the review. Endometrium derived EVs contribute to the development of endometriosis. EVs derived from endometriosis lesions contribute to angiogenesis, immunomodulation and fibrosis. Such EVs can be detected in blood, with early data demonstrating utility in diagnosis and recurrence detection. EV isolation techniques varied between studies and only eight of twenty-eight studies fully characterised EVs according to current recommended standards. Reporting/type of endometriosis was limited across studies. Varied patient population, type of sample and isolation techniques created bias and difficulty in comparing studies.EVs hold promise for improving care for symptomatic patients who have never had surgery, as well as those with recurrent symptoms after previous surgery. We encourage further EV research in endometriosis with the inclusion of rigorous reporting of both the patient population and technical methodology used, with the ultimate goal of achieving clinical utility for diagnosis, prognosis and eventually treatment.

Anterior cruciate ligament reconstruction (ACLR) is one of the most commonly performed outpatient orthopaedic procedures, yet there is little data about perioperative opioid prescribing practices. The purposes of this study were to quantify the perioperative opioid prescriptions filled by patients who underwent ACLR and to identify factors associated with greater postoperative opioid use. Patients who underwent ACLR at a single institution between June 2015 and May 2017 were studied using a regional prescription monitoring database to identify all preoperative and postoperative outpatient opioid prescriptions up to 2 years postoperatively. The number of morphine milligram equivalents of each opioid was calculated to determine total morphine milligram equivalents (TMEs) filled preoperatively, at discharge, and refilled postoperatively. Patients who refilled an opioid prescription postoperatively were compared with those who did not. Ninety-nine of 269 (36.8%) total patients refilled an opioid prescription postoperatively. Thirty-three patients (12.3%) required a refill after 2 weeks postoperatively, and no patients refilled after 21 months postoperatively. Fifty-seven patients (21%) received an opioid prescription in the 2 years following surgery that was unrelated to their ACL reconstruction. Increased age, higher body mass index (BMI), government insurance, current or prior tobacco use history, preoperative opioid use, and greater number of medical comorbidities were significantly associated with refilling a prescription opioid. Higher BMI and government insurance were independent predictors of refilling. Higher preoperative TMEs and surgeon were independent predictor of greater refill TMEs. In the opioid-naïve subgroup of 177 patients, only higher BMI was a predictor of refilling, and only greater comorbidities was a predictor of greater refill TMEs. The results demonstrate that preoperative opioid use was associated with postoperative opioid refills and higher refill TMEs in a dose-dependent fashion. A higher percentage of patients received an opioid prescription for reasons unrelated to the ACL reconstruction than refilled a prescription after the first 2 weeks postoperatively.

Introduction The purpose of this study is to determine which patient factors predict two-year postoperative met expectations in a cohort of patients undergoing knee surgery. Additionally, this study aims to measure the association between met expectations and postoperative outcomes. Methods 319 patients undergoing knee surgery at one institution were studied. Patients completed patient-reported outcome questionnaires prior to surgery and again two years postoperatively. Preoperative Expectations and postoperative Met Expectations were measured using the Musculoskeletal Outcomes and Data Evaluation Management System (MODEMS) Expectations domain. Results The mean Met Expectations score was significantly lower than the preoperative Expectations Score. Worse two-year Met Expectations were associated with older age, higher BMI, greater comorbidities, more previous surgeries, black race, unemployment, lower income, government insurance, Worker's Compensation, smoking, and no injury prior to surgery. Greater Met Expectations were correlated with better scores on all two-year outcome measures as well as greater improvement on most outcome measures. Race, insurance status, function, mental health, and knee pain were found to be independent predictors of Met Expectations. Conclusion This study identified multiple patient factors and outcome measures that were associated with Met Expectations two years after knee surgery.

Recent events in America in 2020 have stimulated a worldwide movement to dismantle anti-Black racism in all facets of our lives. Anti-Black racism is, as defined by the Movement for Black Lives, a "term used to specifically describe the unique discrimination, violence, and harm imposed on and impacting Black people specifically." In science, technology, engineering, and mathematics (STEM), we have yet to achieve the goal and responsibility to ensure that the field reflects the diversity of our lived experiences. Members of the Women in Molecular Imaging Network (WIMIN) have come together to take a stand on diversity, equity, and inclusion in the field of molecular imaging. We strongly condemn oppression in all its forms and strive to identify and dismantle barriers that lead to inequities in the molecular imaging community and STEM as a whole. In this series coined "Visions" (Antiracism and Allyship in Action), we identify and discuss specific actionable items for improving diversity and representation in molecular imaging and ensuring inclusion of all members of the community, inclusive of race, disability, ethnicity, religion, or LGBTQ+ identity. Although the issues highlighted here extend to other under-recruited and equity-seeking groups, for this first article, we are focusing on one egregious and persistent form of discrimination: anti-Black racism. In this special article, Black women residing in America present their lived experiences in the molecular imaging field and give candid insights into the challenges, frustrations, and hopes of our Black friends and colleagues. While this special article focuses on the experiences of Black women, we would like the readers to reflect on their anti-Blackness toward men, transgender, nonbinary, and gender non-conforming people. From the vulnerability we have asked of all our participants, these stories are meant to inspire and invoke active antiracist work among the readership. We present strategies for dismantling systemic racism that research centers and universities can implement in the recruitment, retention, mentorship, and development of Black trainees and professionals. We would like to specifically acknowledge the Black women who took the time to be interviewed, write perspectives, and share their lived experiences in hopes that it will inspire genuine and lasting change.

Pancreatic cancer (PC) remains the fourth leading cause of cancer death; therefore, there is a clinically unmet need for novel therapeutics and diagnostic markers to treat this devastating disease. Physicians often rely on biopsy or CT for diagnosis, but more specific protein biomarkers are highly desired to assess the stage and severity of PC in a noninvasive manner. Serum biomarkers such as carbohydrate antigen 19-9 are of particular interest as they are commonly elevated in PC but have exhibited suboptimal performance in the clinic. MUC5AC has emerged as a useful serum biomarker that is specific for PC versus inflammation. We developed RA96, an anti-MUC5AC antibody, to gauge its utility in PC diagnosis through immunohistochemical analysis and whole-body PET in PC. Methods: In this study, extensive biochemical characterization determined MUC5AC as the antigen for RA96. We then determined the utility of RA96 for MUC5AC immunohistochemistry on clinical PC and preclinical PC. Finally, we radiolabeled RA96 with (89)Zr to assess its application as a whole-body PET radiotracer for MUC5AC quantification in PC. Results: Immunohistochemical staining with RA96 distinguished chronic pancreatitis, pancreatic intraepithelial neoplasia, and varying grades of pancreatic ductal adenocarcinoma in clinical samples. (89)Zr-desferrioxamine-RA96 was able to detect MUC5AC with high specificity in mice bearing capan-2 xenografts. Conclusion: Our study demonstrated that RA96 can differentiate between inflammation and PC, improving the fidelity of PC diagnosis. Our immuno-PET tracer (89)Zr-desferrioxamine-RA96 shows specific detection of MUC5AC-positive tumors in vivo, highlighting the utility of MUC5AC targeting for diagnosis of PC.

Emerald is the most well-recognized beryl (Be3Al2Si6O18) variety, and although it has been extensively studied, a satisfactory method for quantifying the water content within the structural channels of the crystal lattice has yet to be proposed. Water is frequently present in the structural channels of beryl and can occur in two orientations (Type I and Type II). While spectroscopic methods are ideal for determining the orientation of the water molecules, measuring the overall water content often requires expensive or destructive analytical techniques. Sodium is necessary to charge-balance divalent cation substitutions at the Al site of beryl; it is also correlated with H2O in the structural channels, which typically occurs as Type II water. In this study, we present equations that can be used to easily calculate the H2O content of an emerald beryl with significant Na+ content based on either Na+apfu or Na2O weight percent. Unlike previous work, these equations are derived from single-crystal X-ray diffraction data which can be used to accurately measure both the Na+ and H2O contents. We checked the validity of the data using electron probe microanalyses for elements heavier than O. We compared the results with hypothetical scenarios in which different cation substitutions are prevalent, as weight percentages are variable based on the elemental contents. Our results indicate that Na+ or Na2O weight percent can be used to calculate H2O content in emerald beryl with reasonable accuracy, which will allow future researchers to use a simple calculation instead of expensive or destructive techniques when determining H2O content in emeralds.

Background: Understanding how hereditary, lifestyle and demographic risk factors influence the development of breast cancer is critical for its prevention and treatment. For this purpose, the Susan G. Komen Tissue Bank at the IU Simon Comprehensive Cancer Center (KTB) serves as the world’s primary repository for normal breast tissue and blood samples from healthy women (~5,500 tissue + blood donors and ~4,500 blood-only donors). In addition, KTB has received mammograms, H&E images and additional longitudinal health and wellness data from its donors via ongoing annual surveys. Whole genome sequencing has also recently been completed on a subset of 500 donors, including ~125 initially healthy donors who later went on to develop breast cancer. To make these disparate, multi-modal data accessible to the larger research community and add advanced precision health analytics capabilities to the KTB database, LifeOmic's Precision Health Cloud (PHC), a secure healthcare-compliant cloud platform, was chosen to host the KTB data moving forward. The PHC provides browsing and querying capabilities across all data including genomic, demographic, histology, donor surveys, and scanned images. Data from donors can be viewed individually as well as analyzed across cohorts of interest. Computation resources, such as informatics workflows and machine learning infrastructure, are available on the same secure environment to leverage the power of cloud computing without having to download large files. This is in addition to visual and custom analytics using Jupyter Notebooks accessible to collaborators. Methods: We loaded all available KTB data from ~10,000 donors into the PHC. Donor-reported data collected at the time of donation and subsequent follow-up questionnaire responses were loaded as FHIR Observations and Medications in the PHC. Additional imaging and genomic data loaded into the PHC include approximately 12,000 mammogram images, 5,000 H&E images, 5,000 ancestry-informative genotypes and 500 VCF and BAM files from whole genome sequencing. A timeline view of each donor shows data collected from each donation and follow-up surveys. All genetic variants were annotated upon ingestion into the PHC with functional effect on genes, population allele frequency, ClinVar clinical significance and in silico predictions for functional impact. Results: To demonstrate the utility of KTB data hosted in the PHC, we will show how the PHC can be used to directly analyze genomic and donor-reported data, specifically focusing on the recent whole genome sequencing data from 500 donors. Whole genome sequencing data will be used to calculate the genetic ancestry of each donor compared to their self-reported ancestry and previously predicted ancestry from a 41-SNP ancestry panel. Additionally, we will calculate genomewide breast cancer polygenic risk scores and compare these with the survey-based Tyrer-Cuzick and Gail score risk measures. We will assess how the polygenic risk score further stratifies the donors that have germline pathogenic variants in a known breast cancer gene. For the ~125 sequenced donors that went on to develop breast cancer we will also investigate correlations between family history of cancer, age of diagnosis, prior gynecological history and lifestyle differences. All generated results will remain in the PHC for access by future KTB collaborators to continue to build the utility and value of the KTB data. Conclusions: We have shown how hosting KTB data in the PHC opens new opportunities for advanced precision health research for breast cancer researchers worldwide. As more specimens and diverse data sets including genomic, longitudinal and imaging information are being tracked and deposited into KTB, this resource will continue to grow to enable diverse research needs. Citation Format: Steven M Bray, Swee Seong Wong, Baiju G Parikh, Kevin C Wood, Samuel T Rysdyk, Jill E Henry, Natascia Marino, Milan Radovich, Anna Maria V Storniolo. Advanced precision health resources in the Susan G Komen tissue bank at the IU simon comprehensive cancer center [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-14.

Most corn (Zea mays) seeds planted in the United States in recent years are coated with a seed treatment containing neonicotinoid insecticides. Abrasion of the seed coating generates insecticide‐laden planter dust that disperses through the landscape during corn planting and has resulted in many “bee‐kill” incidents in North America and Europe. We investigated the linkage between corn planting and honey bee colony success in a region dominated by corn agriculture. Over 3 yr we consistently observed an increased presence of corn seed treatment insecticides in bee‐collected pollen and elevated worker bee mortality during corn planting. Residues of seed treatment neonicotinoids, clothianidin and thiamethoxam, detected in pollen positively correlated with cornfield area surrounding the apiaries. Elevated worker mortality was also observed in experimental colonies fed field‐collected pollen containing known concentrations of corn seed treatment insecticides. We monitored colony growth throughout the subsequent year in 2015 and found that colonies exposed to higher insecticide concentrations exhibited slower population growth during the month of corn planting but demonstrated more rapid growth in the month following, though this difference may be related to forage availability. Exposure to seed treatment neonicotinoids during corn planting has clear short‐term detrimental effects on honey bee colonies and may affect the viability of beekeeping operations that are dependent on maximizing colony size in the springtime. Environ Toxicol Chem 2021;40:1212–1221. © 2020 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Purpose: Glioblastoma (GBM) is the most common malignant brain tumor in adults. Various immunotherapeutic approaches to improve patient survival are being developed, but the molecular mechanisms of immunotherapy resistance are currently unknown. Here, we explored the ability of a humanized radiolabeled CD8-targeted minibody to noninvasively quantify tumor-infiltrating CD8-positive (CD8+) T cells using PET. Experimental Design: We generated a peripheral blood mononuclear cell (PBMC) humanized immune system (HIS) mouse model and quantified the absolute number of CD8+ T cells by flow cytometry relative to the [64Cu]Cu-NOTA-anti-CD8 PET signal. To evaluate a patient-derived orthotopic GBM HIS model, we intracranially injected cells into NOG mice, humanized cohorts with multiple HLA-matched PBMC donors, and quantified CD8+ tumor-infiltrating lymphocytes by IHC. To determine whether [64Cu]Cu-NOTA-anti-CD8 images brain parenchymal T-cell infiltrate in GBM tumors, we performed PET and autoradiography and subsequently stained serial sections of brain tumor tissue by IHC for CD8+ T cells. Results: Nontumor-bearing NOG mice injected with human PBMCs showed prominent [64Cu]Cu-NOTA-anti-CD8 uptake in the spleen and minimal radiotracer localization to the normal brain. NOG mice harboring intracranial human GBMs yielded high-resolution PET images of tumor-infiltrating CD8+ T cells. Radiotracer retention correlated with CD8+ T-cell numbers in spleen and tumor tissue. Our study demonstrates the ability of [64Cu]Cu-NOTA-anti-CD8 PET to quantify peripheral and tumor-infiltrating CD8+ T cells in brain tumors. Conclusions: Human CD8+ T cells infiltrate an orthotopic GBM in a donor-dependent manner. Furthermore, [64Cu]Cu-NOTA-anti-CD8 quantitatively images both peripheral and brain parenchymal human CD8+ T cells.

Teams are often plagued by internal discord, such as negative relationships, which can impede successful team performance. While most teams eventually encounter negative relationships, we have limited knowledge on how teams manage this negativity. In this article, we expand scholarship on teams by exploring an inherent team characteristic, gender composition, to assess its role in how teams cope with negative relationships. On the one hand, social role theory suggests that teams comprised of more women will perform better in the presence of negative relationships. On the other hand, theories and evidence on personality and individual differences suggest that teams comprised of more men will perform better in the presence of negative relationships. We studied 151 student project teams, and found that teams of mostly women performed better than teams of mostly men, when negative relationships existed among team members. We discuss the implications of these findings for research and practice.

Estrogen promotes breast tissue proliferation and telomerase activation. We investigated the effects of reproductive history on cell cycling and telomere length using a DNA methylation-based estimate of telomere length (DNAmTL) in breast and blood from healthy women donors. We demonstrate that DNAmTL is shorter in breast than in blood, and that nulliparous women have longer age-adjusted DNAmTL in both breast and blood, potentially explaining their higher risk of breast cancer.

Over the last three decades, the chemistry of zirconium has facilitated antibody development and the clinical management of disease in the precision medicine era. Scientists have harnessed its reactivity, coordination chemistry, and nuclear chemistry to develop antibody-based radiopharmaceuticals incorporating zirconium-89 (89Zr: t1/2 = 78.4 h, β+: 22.8%, Eβ+max = 901 keV; EC: 77%, Eγ = 909 keV) to improve disease detection, identify patients for individualized therapeutic interventions. and monitor their response to those interventions. However, release of the 89Zr4+ ion from the radiopharmaceutical remains a concern, since it may confound the interpretation of clinical imaging data, negatively affect dosimetric calculations, and hinder treatment planning. In this report, we relate our novel observations involving the use of polyazamacrocycles as zirconium-89 chelators. We describe the synthesis and complete characterization of zirconium 2,2',2″,2‴-(1,4,7,10-tetraazacyclotridecane-1,4,7,10-tetrayl)tetraacetic acid (Zr-TRITA), zirconium 3,6,9,15-Tetraazabicyclo[9.3.1] pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (Zr-PCTA), and zirconium 2,2',2″-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (Zr-NOTA). In addition, we elucidate the solid-state structure of each complex using single-crystal X-ray diffraction analysis. Finally, we found that [89Zr]Zr-PCTA and [89Zr]Zr-NOTA demonstrate excellent stability in vitro and in vivo and provide a rationale for these observations. These innovative findings have the potential to guide the development of safer and more robust immuno-PET agents to improve precision medicine applications.

The objectives addressed in this case study were to reduce and eliminate life-threatening self-injury and aggression in a man diagnosed with autism spectrum disorder (ASD), intellectual disability, post-traumatic stress disorder, and catatonia. Treatment included comprehensive applied behavior analysis (ABA) and pharmacological intervention delivered at a residential care setting in conjunction with electroconvulsive therapy (ECT). A baseline average of 33.7 incidents of combined self-injury and aggression per day decreased to near-zero occurrence over approximately 2 years of ECT that was administered with gradually reduced frequency. In response to ECT, the man also regained previously lost communication, self-care, and social skills; had improved health status; was no longer required to wear protective equipment; and did not experience negative side effects. These results support other reported cases of persons with ASD, catatonia, and serious challenging behavior who responded positively to initial and maintenance ECT. Additional research is necessary to confirm therapeutic benefits from and safe toleration of ECT among this clinical population.

Objectives The use of ultrabrief pulse (UBP) stimuli and individual seizure threshold determination have been proposed as ways of minimizing the cognitive side effects of electroconvulsive therapy (ECT), but large samples of patients receiving UBP ECT are lacking. This study reports a retrospective cohort of patients receiving an index course of right unilateral UBP ECT and characterizes the amount of charge required to induce a seizure. Methods A single-center retrospective chart review was conducted of adult patients receiving a first lifetime course of ECT using an UBP titration from 2005 to 2017. Results There were 2328 patients that received a dose titration during the study period, with a mean dose of 21.82 ± 21.61 mC applied to induce a seizure. During the early part of the study period, a mean dose of 18.73 ± 8.99 mC was used, with 28% of patients seizing at a dose of less than 19.2 mC. In the later period, the initial step of dose titration was standardized at 19.2 mC, yielding a mean initial dose to induce a seizure of 22.72 ± 24.00 mC. Conclusions Mean seizure thresholds may be lower than reported in previous studies, and a significant proportion of patients may have a seizure threshold lower than the first step of many existing dose titration protocols.

Background : Electroconvulsive therapy (ECT) is the most effective acute treatment for depression, but relapse is common following discontinuation. One strategy for prolonging remission is the use of maintenance ECT, but the clinical evidence supporting its efficacy and safety are limited. We examined the effects of maintenance ECT on depression and cognition. Methods : Participants were from a retrospective cohort of 100 patients receiving ECT at a freestanding psychiatric hospital and who received at least 50 treatments during a single treatment series. QIDS, BASIS-24, and MoCA were assessed at baseline and every 10 treatments thereafter during the clinical course. Results : ECT was associated with a rapid decrease in depression symptoms and overall self-reported mental health status within the first 10 treatments, which was sustained throughout a median of 22.1 months of follow-up. There was no change in cognitive functioning as measured by the MoCA. Bilateral and brief pulse treatment parameters were more common by treatment 50 than at the first treatment. Most participants either continued in ECT at the end of the study period or discontinued due to sustained remission. Limitations : retrospective observational study without control group who did not receive ECT. Conclusions : In this ECT cohort with at least 50 treatments, improvement in depression was sustained on QIDS and BASIS-24 and adverse cognitive effects were not detected by serial MoCAs, supporting the utility of maintenance ECT in this cohort.

Background: Previous studies of breast samples from cosmetic surgeries, benign biopsies associated with abnormal mammograms or cancer-adjacent tissue have identified at least two different transcriptional phenotypes of “normal” human breast tissue (Troester, 2009; Haakensen, 2011), including an “Active” phenotype linked to increased risk of later breast cancer mortality (Roman-Perez, 2012; Troester, 2016). This study compares breast histology and transcriptional phenotypes from healthy parous women with no prior history of breast disease who donated breast core biopsies for research and supplied reproductive histories enabling breast cancer risk calculation. Since the Active transcriptome phenotype was recently associated with increased mammary adipocyte content, we focused on the possibility that adipocyte activation contributes to the Active transcriptome and drives breast cancer risk. Methods: RNA from paraffin-embedded tissue sections sufficient for RNAseq analysis (~100ng) was extracted from 151/200 core biopsies donated to the Komen Tissue Bank by healthy, parous white women (age range: 27-66, median = 45) with no history of breast cancer. Questionnaire data enabled breast cancer risk (Gail) score calculation; and digitized H&E images were used for histologic analyses. A previously validated classifying signature was used in unsupervised hierarchical clustering to identify samples with Active (78/151) vs. Inactive (73/151) transcriptome phenotypes for comparison with donor risk factors, breast tissue composition, and expression of candidate genes and gene signatures. Results: Mean (+/-SD) BMI and Gail score values were 29.60 (+/-7.92) and 1.27 (+/- 1.34), respectively; BMI scores were not significantly different by phenotype, but Gail scores were significantly higher for donors with an Active phenotype (1.46 vs. 1.18; p=0.007, Wilcoxon rank-sum). Active normal breast tissue samples possessed significantly more (%) adipocyte nuclei (p=3.9e-11) and greater adipocyte size (p80% of this donor cohort would not qualify for breast cancer chemoprevention, those with Active transcriptomes had significantly higher Gail scores supporting their increased future risk for breast cancer development. The Active breast transcriptome is strongly associated with increased adipocyte content, size, and overexpression of signatures and genes (including those previously linked to breast cancer progression) indicating a differentially activated adipocyte population. This dysregulated mammary adipocyte microenvironment not only appears to underlie the Active transcriptome phenotype but also precedes and potentially predicts the future histologic development of breast cancer. Citation Format: Christopher C Benz, Taekyu Kang, Christina Yau, Chris Wong, Yulia Newton, Charlie Vaske, Stephen C Benz, Gregor Krings, Roman Camarda, Jill E Henry, Josh Stuart, Mark Powell. The normal breast Active transcriptome associated with future breast cancer risk is driven by a dysregulated adipocyte microenvironment [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-20.

Use of salt substitutes containing potassium chloride is a potential strategy to reduce sodium intake, increase potassium intake, and thereby lower blood pressure and prevent the adverse consequences of high blood pressure. In this review, we describe the rationale for using potassium-enriched salt substitutes, summarize current evidence on the benefits and risks of potassium-enriched salt substitutes and discuss the implications of using potassium-enriched salt substitutes as a strategy to lower blood pressure. A benefit of salt substitutes that contain potassium chloride is the expected reduction in dietary sodium intake at the population level because of reformulation of manufactured foods or replacement of sodium chloride added to food during home cooking or at the dining table. There is empirical evidence that replacement of sodium chloride with potassium-enriched salt substitutes lowers systolic and diastolic blood pressure (average net Δ [95% CI] in mm Hg: –5.58 [–7.08 to –4.09] and –2.88 [–3.93 to –1.83], respectively). The risks of potassium-enriched salt substitutes include a possible increased risk of hyperkalemia and its principal adverse consequences: arrhythmias and sudden cardiac death, especially in people with conditions that impair potassium excretion such as chronic kidney disease. There is insufficient evidence regarding the effects of potassium-enriched salt substitutes on the occurrence of hyperkalemia. There is a need for additional empirical research on the effect of increasing dietary potassium and potassium-enriched salt substitutes on serum potassium levels and the risk of hyperkalemia, as well as for robust estimation of the population-wide impact of replacing sodium chloride with potassium-enriched salt substitutes.

The primary aims of this study were to (1) assess the preoperative expectations of patients undergoing shoulder surgery, and (2) determine the relationship between preoperative patient demographics, PROs, and preoperative patient expectations. It was hypothesized that younger patients with worse function and worse health status had higher expectations of shoulder surgery. Data from a total of 319 patients (319 shoulders) from 2015–2018 were analyzed. Patients completed a series of questionnaires covering demographics and patient-reported outcome measures. Expectations of treatment were evaluated using the Musculoskeletal Outcomes Data Evaluation and Management System. Bivariate analyses were performed to determine the significance of identified associations. The study population consisted of 186 males and 133 females. The mean age was 46.9 (± 17.2), and the mean BMI was 30.1 (± 6.8). Overall, patients had high expectations of shoulder surgery, with a mean score of 84.7 (± 19.3). The most commonly performed procedure in the study population was arthroscopic rotator cuff repair. There was a significant association between pre-treatment expectations and ethnicity, previous shoulder surgery, employment status, income level, tobacco use, preoperative opioid use, depression, and ASA score. The findings suggest that patients undergoing shoulder surgery have high overall preoperative expectations, which were significantly associated with ethnicity, surgical history, opioid use, and employment status, and with multiple patient-reported outcome measures including physical function, pain interference, fatigue, and depression. Nevertheless, by discussing expectations preoperatively, orthopaedic surgeons can help patients develop high but realistic expectations to improve outcomes and satisfaction. IV.

Introduction: Electroconvulsive therapy (ECT) is a critical procedure in psychiatric treatment, but as typically delivered involves the use of bag-mask ventilation (BMV), which during the COVID-19 pandemic exposes patients and treatment staff to potentially infectious aerosols. Objective: To demonstrate the utility of a modified anesthesia protocol for ECT utilizing preoxygenation by facemask and withholding the use of BMV for only those patients who desaturate during the apneic period. Methods: This chart review study analyzes patients who were treated with ECT using both the traditional and modified anesthesia protocols. Results: A total of 106 patients were analyzed, of whom 51 (48.1%) required BMV using the new protocol. Of clinical factors, only patient BMI was significantly associated with the requirement for BMV. Mean seizure duration reduced from 52.0 ± 22.4 to 46.6 ± 17.1 s, but seizure duration was adequate in all cases. No acute physical, respiratory, or psychiatric complications occurred during treatment. Conclusions: A modified anesthesia protocol reduces the use of BMV by more than 50%, while retaining adequate seizure duration.

The fungal pathogen, Nothophaeocryptopus gaeumannii, occurs wherever Douglas-fir is found but disease damage is believed to be limited to the Coast Range and is of no concern outside the coastal fog zone (Shaw, et al., 2011). However, knowledge remains limited on the history and spatial distribution of Swiss Needle Cast (SNC) impacts in the Pacific Northwest (PNW). We reconstructed the history of SNC impacts on mature Douglas-fir trees based on tree ringwidth chronologies from the west slope of the Coast Range to the high Cascades of Oregon. Our findings show that SNC impacts on growth occur wherever Douglas-fir is found in western Oregon and is not limited to the coastal fog zone. The spatiotemporal patterns of growth impact from SNC disease were synchronous across the region, displayed periodicities of 25-30 years, strongly correlated with winter and summer temperatures and summer precipitation, and matched the patterns of enriched cellulosic stable carbon isotope indicative of physiological stress. While winter and summer temperature and summer precipitation influenced pathogen dynamics at all sites, the primary climatic factor of these three limiting factors varied spatially by location, topography, and elevation. In the 20th century, SNC impacts at low- to mid-elevations were least severe during the warm phase of the Pacific Decadal Oscillation (PDO, 1924-1945) and most severe in 1984-1986, following the cool phase of the PDO (1945-1977). At high elevations on the west slope of the Cascade Mountains, SNC impacts were the greatest in the 1990s and 2000s, a period of warmer winter temperatures associated with climate change. Warmer winters will likely continue to increase SNC severity at higher elevations, north along the coast from northern Oregon to British Columbia, and inland where low winter temperatures currently limit growth of the pathogen. Surprisingly, tree-ring records of ancient Douglas-fir logs dated ~53K radioactive years B.P. from Eddyville, OR displayed 7.5- and 20-year periodicities of low growth, similar to those found in modern day coastal Douglas-fir tree-ring records which we interpret as being due to cyclic fluctuations in SNC severity. Our findings indicate that SNC has persisted for as long as its host, and as a result of changing climate, may become a significant forest health problem in areas of the PNW beyond the coastal fog zone.

STUDY QUESTION Is circulating cell-free DNA (cirDNA) from the endometrium elevated during menstruation and in endometriosis? SUMMARY ANSWER Endometrial cirDNA does not increase during menstruation and is not elevated in endometriosis. WHAT IS KNOWN ALREADY Changes in cirDNA associated with common benign conditions are a potential source of false positives in cancer diagnostic applications, but also present an opportunity for biomarker development for diseases such as endometriosis. Elevated cirDNA has been reported in endometriosis patients compared to healthy community controls, but no difference in total or endometrial cirDNA has been found between patients with endometriosis and patients with other gynaecological conditions. Likewise, menstruation is a potential driver of changes in cirDNA levels and tissue profile, but total and endothelial cirDNA do not increase during menstruation. STUDY DESIGN, SIZE, DURATION For endometriosis comparisons, 59 participants with surgically confirmed endometriosis and 27 laparoscopic patients without endometriosis (hospital controls) were prospectively recruited, while 25 healthy community participants (healthy controls) were recruited in a university setting. Total and endometrial cirDNA and cirDNA fragmentation were measured across the three groups. For menstrual comparisons, 36 matched non-menstruating and menstruating samples were collected from healthy women recruited within a university setting, and the endometrial cirDNA was compared between the two groups. PARTICIPANTS/MATERIALS, SETTING, METHODS cirDNA was extracted from venous blood plasma then quantitated by quantitative PCR of ALU repetitive element (115 bp) and TP53 gene sequence (105 bp) for total concentration. cirDNA derived from the endometrium was quantitated by methylation-specific droplet digital PCR of a FAM101A region (69 bp) after bisulfite conversion of the DNA. A cirDNA size fragmentation ratio was obtained by quantifying a long segment of ALU repetitive element (247 bp) and expressing the amount relative to the 115 bp ALU target. MAIN RESULTS AND THE ROLE OF CHANCE No differences in cirDNA level were found in any comparison populations in this study. Mean total cirDNA was unchanged between healthy controls (ALU-115–3.31 ng/ml; TP53–2.73 ng/ml), hospital controls (ALU-115–3.47 ng/ml; TP53–2.83 ng/ml) and endometriosis patients (ALU-115–3.35 ng/ml; TP53–2.66 ng/ml). Likewise, endometrial cirDNA was unchanged between healthy controls (18.3 copies/ml), hospital controls (20.6 copies/ml) and endometriosis patients (22 copies/ml). Endometrial cirDNA did not change during menstruation (non-menstruating: 38 copies/ml; menstruating: 33 copies/ml). Irrespective of endometriosis diagnosis, blood from patients undergoing laparoscopy (hospital controls: 0.77; endometriosis patients: 0.79), had a significantly higher cirDNA size ratio than community-recruited healthy controls (0.64), indicating increased abundance of long cirDNA fragments. LIMITATIONS, REASONS FOR CAUTION It was not possible to completely match the age, BMI and parity between the three cohorts investigated, however of these, only age has been shown to influence circulating DNA levels and not within the age range of our cohort. Blood from community-recruited healthy women and women undergoing laparoscopy was collected via antecubital vein venepuncture (processed within 3 h) and with either peripheral cannula or venepuncture (processed within 6 h), respectively, which could potentially impact the size distribution of circulating DNA fragments. For the collection of non-menstruating phase blood samples, we did not differentiate between follicular phase, ovulation and luteal phase. Thus, only the mensturating samples were collected at a consistent phase, and any fluctuations in cirDNA that occur at the other phases may have obscured small changes during menstruation. WIDER IMPLICATIONS OF THE FINDINGS There is no evidence that cirDNA has potential as a diagnostic biomarker for endometriosis. Endometriosis, representing a common benign gynaecological condition, and menstruation, representing a normal physiological occurrence in women, should not affect methylation-based diagnostics in other disease areas, including oncology. STUDY FUNDING/COMPETING INTEREST(S) N.L.Y.: Australian Government Research Training Program (RTP) Stipend through The University of New South Wales, Translational Cancer Research Network PhD Scholarship Top-Up Award via the Cancer Institute NSW, Beth Yarrow Memorial Award in Medical Science, UNSW Completion Scholarship; C.E.H.: Gynaecological Oncology Fund of the Royal Hospital for Women; K.W.: Ovarian Cancer Research Foundation and CAMILLA AND MARC. C.E.F.: UNSW Women’s Wellbeing Academy and the Australian Human Rights Institute. We declare the following competing interest: K.W. holds stock in Guardant Health, Exact Sciences and Epigenomics AG. No other authors have competing interests. TRIAL REGISTRATION NUMBER N/A.

Mentorship is a fundamental aspect that contributes to the success of a career in science, technology, engineering, and mathematics (STEM), particularly in academia. Research suggests that underrepresented minorities (URMs) often experience less quality mentorship and face barriers to finding successful mentor-mentee relationships. URM trainees in STEM face challenges that are not encountered by their majority peers or mentors, adding another level of complexity to establishing important relationships. Mentors of URM trainees must therefore mentor beyond general scientific training and tailor their mentorship to be more culturally appropriate and inclusive, allowing URM trainees to bring their whole selves to the table and leading to their effective socialization. Herein, we present the perspectives of group leaders and trainees from around the globe to highlight key aspects of creating successful mentor-mentee relationships that are sustainable and productive for both parties.

Background Assessing the global risk of rabies exposure is a complicated task requiring individual risk assessments, knowledge of rabies epidemiology, surveillance capacity and accessibility of rabies biologics on a national and regional scale. In many parts of the world, availability of this information is limited and when available is often dispersed across multiple sources. This hinders the process of making evidence-based health and policy recommendations to prevent the introduction and spread of rabies. Methods CDC conducted a country-by-country qualitative assessment of risk and protective factors for rabies to develop an open-access database of core metrics consisting of the presence of lyssaviruses (specifically canine or wildlife rabies virus variants or other bat lyssaviruses), access to rabies immunoglobulins and vaccines, rabies surveillance capacity and canine rabies control capacity. Using these metrics, we developed separate risk scoring systems to inform rabies prevention guidance for travelers and regulations for the importation of dogs. Both scoring systems assigned higher risk to countries with enzootic rabies (particularly canine rabies), and the risk scoring system for travelers also considered protective factors such as the accessibility of rabies biologics for post-exposure prophylaxis. Cumulative scores were calculated across the assessed metrics to assign a risk value of low, moderate or high. Results A total of 240 countries, territories and dependencies were assessed, for travelers, 116 were identified as moderate to high risk and 124 were low or no risk; for canine rabies virus variant importation, 111 were identified as high-risk and 129 were low or no risk. Conclusions We developed a comprehensive and easily accessible source of information for assessing the rabies risk for individual countries that included a database of rabies risk and protective factors based on enzootic status and availability of biologics, provided a resource that categorizes risk by country and provided guidance based on these risk categories for travelers and importers of dogs into the United States.

Objectives Right unilateral brief pulse (RUL-BP) electroconvulsive therapy (ECT) has been adopted as a technique for reducing the cognitive side effects of ECT relative to sine wave or bilateral treatments, but it is unknown how often patients are transitioned to alternative electrode placements. This study analyzes time in first lifetime acute course RUL-BP ECT. Methods A single-center retrospective chart review was conducted of adult patients receiving a first lifetime course of ECT from 2000 to 2017 beginning with individualized seizure threshold determination using RUL-BP treatment parameters. Results A total of 1383 patients met study criteria and received a mean number of 9.4 ± 3.1 treatments, of which 7.6 ± 3.3 were using RUL-BP stimuli. Only 37.5% of patients were transitioned from RUL to bilateral treatments. Younger patients and those diagnosed with bipolar disorder were more likely to transition from RUL-BP to bilateral treatments, but the overall number of treatments did not differ based on age or primary diagnosis. Conclusions Among patients who begin treatment with RUL-BP ECT, more than 60% use exclusively those parameters throughout their acute course.

OBJECTIVES: Electroconvulsive therapy (ECT) effectively treats depressive disorders, but many patients will have subsequent relapses. While some guidelines suggest prior response to ECT is an indication for ECT in a subsequent mood episode, it is unknown whether response to ECT is correlated between treatment courses. This study explores whether response to ECT at a first treatment correlates with response to treatment in a second independent ECT course. METHODS: Single-center retrospective cohort of patients receiving two different ECT treatment courses between 2011 and 2020 and who self-reported depression symptoms using the Quick Inventory of Depressive Symptomatology (QIDS) at baseline and following treatment #5. RESULTS: 286 patients received two independent ECT series during the study period, of whom 153 received at least 5 treatments in both series. Patients had similar QIDS scores at the start of each treatment series (Pearson’s correlation, r = 0.58, p

We conducted a scoping review of sweet beverages (SB) and cancer outcomes to ascertain SB's relationship with cancer by SB type and cancer type. We used the PRISMA Scoping Review Guidelines to review quantitative studies of SB and cancer. Eligible studies included articles reporting a quantitative association between SB intake and a cancer-related health outcome in humans, including adiposity-related versus non–adiposity-related cancers. Studies included analyses not confounded by artificial sweeteners. SB was defined as beverages with added sugars, 100% fruit juices, or fruit drinks that were not 100% fruit juice. We used a data-charting form to extract study characteristics and results. A total of 38 were included. The sample consisted predominately of adults from European countries outside of the United States or predominately White samples in the United States. Across all conceptualizations of SB, a greater proportion of studies examining carbonated drinks reported SB's relationship with poorer cancer outcomes, which was exacerbated in adiposity-related cancers. The composition of different types of SB (e.g., high fructose corn syrup, natural fructose) as they relate to cancer is important. Studies including more diverse populations that bear a disproportionate burden of both SB intake and cancer are needed. Prevention Relevance: Different sugars in SB may impact cancer differently. Compared with SB made with other types of sugar, drinks made with man-made fructose (carbonated drinks) had poorer cancer outcomes, especially in cancers impacted by obesity. Understanding how different SB affect cancer would help us target which SB to avoid.

Objective: Electroconvulsive therapy (ECT) is the most effective acute treatment for depression, but its use in younger patients is rare and heavily regulated in many U.S. states. It is unclear whether age modifies treatment response or tolerability in adolescents, transitional age youth, and young adults. We examined the effects of ECT on depression and cognition in patients aged 16–30 years. Methods: A retrospective cohort study of patients aged 16–30 years receiving ECT between 2011 and 2020 who were evaluated with the Quick Inventory of Depressive Symptomatology (QIDS), the Behavior and Symptom Identification Scale-24 (BASIS-24), and the Montreal Cognitive Assessment (MoCA) at baseline and following treatment #10. Results: Among the 424 patients who met the inclusion criteria, ECT was associated with a decrease in depression symptoms (ΔQIDS −6.7; Kruskal–Wallis rank sum test; χ(2) = 293.37; df = 2; p

Machine learning-based clinical decision support tools for sepsis create opportunities to identify at-risk patients and initiate treatments at early time points, which is critical for improving sepsis outcomes. In view of the increasing use of such systems, better understanding of how they are adopted and used by healthcare providers is needed. Here, we analyzed provider interactions with a sepsis early detection tool (Targeted Real-time Early Warning System), which was deployed at five hospitals over a 2-year period. Among 9,805 retrospectively identified sepsis cases, the early detection tool achieved high sensitivity (82% of sepsis cases were identified) and a high rate of adoption: 89% of all alerts by the system were evaluated by a physician or advanced practice provider and 38% of evaluated alerts were confirmed by a provider. Adjusting for patient presentation and severity, patients with sepsis whose alert was confirmed by a provider within 3 h had a 1.85-h (95% CI 1.66-2.00) reduction in median time to first antibiotic order compared to patients with sepsis whose alert was either dismissed, confirmed more than 3 h after the alert or never addressed in the system. Finally, we found that emergency department providers and providers who had previous interactions with an alert were more likely to interact with alerts, as well as to confirm alerts on retrospectively identified patients with sepsis. Beyond efforts to improve the performance of early warning systems, efforts to improve adoption are essential to their clinical impact and should focus on understanding providers' knowledge of, experience with and attitudes toward such systems.

Early recognition and treatment of sepsis are linked to improved patient outcomes. Machine learning-based early warning systems may reduce the time to recognition, but few systems have undergone clinical evaluation. In this prospective, multi-site cohort study, we examined the association between patient outcomes and provider interaction with a deployed sepsis alert system called the Targeted Real-time Early Warning System (TREWS). During the study, 590,736 patients were monitored by TREWS across five hospitals. We focused our analysis on 6,877 patients with sepsis who were identified by the alert before initiation of antibiotic therapy. Adjusting for patient presentation and severity, patients in this group whose alert was confirmed by a provider within 3 h of the alert had a reduced in-hospital mortality rate (3.3%, confidence interval (CI) 1.7, 5.1%, adjusted absolute reduction, and 18.7%, CI 9.4, 27.0%, adjusted relative reduction), organ failure and length of stay compared with patients whose alert was not confirmed by a provider within 3 h. Improvements in mortality rate (4.5%, CI 0.8, 8.3%, adjusted absolute reduction) and organ failure were larger among those patients who were additionally flagged as high risk. Our findings indicate that early warning systems have the potential to identify sepsis patients early and improve patient outcomes and that sepsis patients who would benefit the most from early treatment can be identified and prioritized at the time of the alert.