bluuebunny/crossref_metadata_2025 huggingface dataset:
131I-6β-iodomethyl-19-norcholesterol adrenal scintigraphy as an alternative to adrenal venous sampling in differentiating aldosterone-producing adenoma from bilateral idiopathic hyperaldosteronism
Authors: Saiga Atsushi , Yokota Hajime , Nagano Hidekazu , Sawada Koichi , Kubota Yoshihiro , Wada Takeshi , Horikoshi Takuro , Tanaka Tomoaki , Uno Takashi
Published: September 2020

Objective

To assess the correlation value between adrenal venous sampling (AVS) and 131I-6β-iodomethyl-19-norcholesterol (NP-59) adrenal scintigraphy in differentiating aldosterone-producing adenoma (APA) from bilateral idiopathic hyperaldosteronism (BHA), and the use of NP-59 scintigraphy as an alternative to AVS.

Methods

Overall, 29 patients with APA or BHA who underwent AVS and dexamethasone-suppression NP-59 scintigraphy were included between 2010 and 2017. The correlation value between AVS and dexamethasone-suppression NP-59 scintigraphy was assessed using each lateralisation index (LIAVS and LI1NP-59). Tumour presence and size were evaluated using computed tomography. The sensitivity and specificity of dexamethasone-suppression NP-59 scintigraphy for APA according to each lateralisation index threshold were calculated.

Results

Of 29 patients, 12 presented with APA and 17 with BHA according to AVS. The correlation value between LIAVS and LI1NP-59 was 0.63 (P < 0.001). If the cut-off points were 2.55 and 1.80 in all cases, the sensitivity and specificity were 0.33 and 1.00 as well as 0.58 and 0.94, respectively. In adrenal microtumours (maximum diameter ≤10 mm), no cases revealed a cut-off point of >1.8. However, in adrenal macrotumours (maximum diameter >10 mm), the cut-off point of 2.55 represented the best compromise (sensitivity: 0.44; specificity: 1.00).

Conclusion

NP-59 scintigraphy can be used as an alternative to AVS if there is a strong lateralisation on NP-59 scintigraphy and adrenal macrotumours observed on the computed tomography when AVS is technically challenging, particularly in the right adrenal vein cannulation, and if contraindications, such as allergy to contrast materials and renal failure, are observed.
Pain and Depression Symptoms During the Third Trimester of Pregnancy
Authors: Vignato Julie , Perkhounkova Yelena , McCarthy Ann Marie , Segre Lisa S.
Published: September 2020

Purpose:

To assess the association between depression symptoms and pain characteristics, including pain intensity, location, and effectiveness of pain management strategies, among women in their third trimester of pregnancy. Design: Descriptive, exploratory cross-sectional study.

Setting:

Mobile health pregnancy application (app).

Participants:

A convenience sample of women in their third trimester of pregnancy from across the United States.

Methods:

Women completed demographic questionnaires, the Brief Pain Inventory, and Edinburgh Postnatal Depression Scale (EPDS) through an online Web site.

Results:

N = 132 women participated. The sample was demographically diverse. . Women ranged in age from 18 to 39 years (M 28.1 ± SD 5.2). Most women were Caucasian (68%), with smaller percentages of Hispanic (12%) and African American (11%) women. Most had commercial insurance (59%) and a partner (85%). Of the 132 women, 79.6% reported moderate-to-severe pain. Approximately 93% experienced back and pelvic pain, whereas 27% experienced moderate-to-severe depression symptoms. Bivariate and linear regression analyses revealed that higher EPDS depression scores were associated with higher levels of pain (p < .01). Other variables significantly associated with higher EPDS scores were White race (p = .04), marital status (p = .05), and headache (p < .01).

Clinical Implications:

In the third trimester of pregnancy, pain affects more than two-thirds of women and may occur with and without depression symptoms. Although the value of universal depression screening during pregnancy is widely recognized, our findings suggest clinical outcomes for pregnant women would improve with a standardized, multidimensional screen for both pain and depression symptoms. Nurses are ideally positioned to assess and advocate for the combined treatment of pain and depression.
Connecting with Families through Virtual Perinatal Education during the COVID-19 Pandemic
Authors: Pasadino Francine , DeMarco Kathleen , Lampert Elizabeth
Published: September 2020

The COVID-19 pandemic has caused many changes in health care. The status quo has been upended. We have been challenged in many ways to maintain our ability to meet the needs of our clients while keeping them safe. The Center for Perinatal Education and Lactation at NYU Langone Hospitals, in one of the initial epicenters of the pandemic in New York City, had to abruptly transition the childbirth education program to a virtual format in March of 2020. The goal for this change was to continue to provide evidence-based support and guidance our to our expectant and new families through this crisis. This report focuses on the process and challenges of transitioning to and implementation of the virtual format in the context of the COVID-19 crisis. We discuss the rapidly evolving programmatic changes to our approach and reflect on the themes and changing landscape of our newly structured model. Questions and answers live discussion webinars “Ask the Educator” on various topics were a valuable tool in connecting with families and allaying anxiety and fear.
Family Functioning Mediates the Relationship Between Activities of Daily Living and Poststroke Depression
Authors: Yang Li , Zhao Qiuli , Liu Hongli , Zhu Xuemei , Wang Kunxiao , Man Jing
Published: September 2020

Background

Poststroke depression is common and includes depressive and somatic symptoms. However, few studies have confirmed the influence of family functioning on poststroke depression or explored the association among daily activities, family functioning, and poststroke depression.

Objectives

We examined the independent risk factors of daily activities and family functioning for poststroke depression and identified the mediating effect of family functioning on the association between daily activities and poststroke depression.

Methods

This cross-sectional study design used convenience sampling to recruit 422 stroke survivors from the neurology department of a hospital in Harbin, China, from February to July 2018. We assessed participants’ demographic and clinical variables, including depression, daily activities, and family functioning. Pearson’s correlations and multiple linear regression analyses were conducted, and a path analysis with bootstrapping was utilized to define direct/indirect effects.

Results

Daily activities and family functioning had a significant and direct negative effect on participants’ depression. The indirect effect of 1,000 bootstrap samples after bias correction with a 95% confidence interval was below zero, indicating that family function had a significant mediating effect on the association between depression and daily activities.

Discussion

This study revealed the importance of family functioning in the association between depression and daily activities in stroke survivors. To the best of our knowledge, this study was the first to explore the mediating role of family functioning in poststroke depression, emphasizing the importance of family for the mental health of stroke patients. To reduce the incidence of poststroke depression, interventions that enhance daily activities and family functioning may include nurses, family therapists, rehabilitation physicians, and community workers.
Suicide Risk Management Protocol for a Randomized Controlled Trial of Cardiac Patients Reporting Hopelessness
Authors: Dunn Susan L. , DeVon Holli A. , Collins Eileen G. , Luong Anna , Buursma Madison P. , Gutierrez-Kapheim Melissa , Bronas Ulf G.
Published: September 2020

Background

Investigators conducting studies that include potentially suicidal individuals are obligated to develop a suicide risk management (SRM) protocol. There is little available in the literature to guide researchers in SRM protocol development.

Objectives

The aim of the study was to describe an SRM protocol developed for a randomized controlled trial (RCT) currently enrolling cardiac patients who report moderate to severe levels of hopelessness.

Methods

The SRM protocol identifies suicidal ideation and measures ideation severity through use of the Columbia-Suicide Severity Rating Scale risk factor questions. Based on responses, study participants are deemed safe or at low, moderate, or high risk for suicide. The SRM protocol guides research staff through a plan of action based on risk level. The protocol further guides staff through a plan over the course of this prospective study—from hospital enrollment to home-based visits.

Results

Research staff are well trained to identify suicidal ideation risk factors, initiate specific questioning about suicidal intent, determine level of risk, identify protective factors and a safe environment, and make referrals if needed. Of the 51 patients hospitalized with cardiac disease who reported moderate to severe hopelessness, 43 scored at a safe suicide risk level and 8 scored at low risk. Thirty-five of the 51 patients enrolled in the RCT. Of the 35 participants who received home visits to date, there have been three instances of low and one instance of moderate suicide risk. The SRM protocol has been consistently and accurately used by research personnel in both hospital and home settings. One modification has been made to the protocol since study activation, namely, the addition of an assessment of counseling history and encouragement of continued counseling. Booster training sessions of research staff will continue throughout the course of the RCT.

Discussion

Use of the SRM protocol identifies study participants who are safe or at risk for suicide in both hospital and home settings, and research staff can refer participants accordingly.

Conclusion

The SRM protocol developed for this RCT can serve as a model in the development of SRM protocols for future research in acute care, community, or home-based settings.
The Importance of Autopsy in a Case of Digestive Perforation Undetected by Postmortem Computed Tomography
Authors: Macoin Elisa , Kintz Pascal , Gressel Anne , Leyendecker Pierre , Raul Jean-Sébastien , Walch Alexis
Published: September 2020

Cases of foreign body ingestion in the forensic literature are mainly described in children or psychiatric patients. Postmortem imaging can detect most foreign bodies, but its sensitivity depends, among other things, on the type of item and its location. In some cases, the ingestion of foreign bodies can remain unnoticed and have serious consequences for the patient. We describe the case of a patient who died in a psychiatric seclusion room with no obvious cause and for whom a forensic autopsy was requested. Further investigations showed the existence of a subdural hematoma associated with a midline shift, secondary to a skull fracture that was considered to be the cause of death. Toxicological analyses identified in blood several drugs, including diazepam (24 ng/mL) and its major metabolite nordazepam (24 ng/mL), propranolol (57 ng/mL), paliperidone (9 ng/mL), and loxapine (620 ng/mL). The forensic autopsy revealed the existence of a gastrointestinal perforation after the ingestion of a plastic teaspoon, which the postmortem CT scan had failed to detect. Although technological advances continue to assist the forensic pathologist in his diagnosis, autopsy still has a leading role in forensic investigations and does not yet seem to be replaceable by imaging techniques alone.
Frequency of Polyautoimmunity in Patients With Rheumatoid Arthritis and Systemic Lupus Erythematosus
Authors: Ordoñez-Cañizares M. C. , Mena-Vázquez Natalia , Redondo-Rodriguez Rocio , Manrique-Arija Sara , Jimenez-Núñez Francisco Gabriel , Ureña-Garnica Inmaculada , Fernández-Nebro Antonio
Published: September 2020

Objective

To describe the frequency of polyautoimmunity and multiple autoimmune syndrome in patients with rheumatoid arthritis (RA) and patients with systemic lupus erythematosus (SLE).

Patients and Methods

This was a cross-sectional observational study of patients with RA, SLE, and controls without autoimmune rheumatic disease. Cases were those with RA according to the 2010 American College of Rheumatology/European League Against Rheumatism criteria and SLE according to the 2019 American College of Rheumatology/European League Against Rheumatism criteria, consecutively recruited in a rheumatology clinic. Controls were subjects with no rheumatic autoimmune disease (AIDs) recruited in the same area. Patients filled out a questionnaire on polyautoimmunity. Variables of interest were polyautoimmunity (RA or SLE with other AIDs), whereas secondary variables were rheumatic, skin, endocrine, digestive, and neurological AIDs. Multiple autoimmune syndrome is defined as the presence of 3 or more AIDs and a family history of AIDs. Statistical analyses performed were descriptive, bivariate, and multivariate (dependent variable: polyautoimmunity).

Results

The study population comprised 109 patients with RA, 105 patients with SLE, and 88 controls. Polyautoimmunity was recorded in 15 patients with RA (13.8%), 43 with SLE (41%), and 2 controls (2.2%). The most frequent AID in RA was Sjögren syndrome (53.3%), followed by Hashimoto thyroiditis and psoriasis; the most frequent AIDs in SLE were Sjögren syndrome (55.8%) and antiphospholipid syndrome (30.2%), followed by Hashimoto thyroiditis. Obesity was associated with polyautoimmunity in RA (odds ratio [OR], 3.362; p = 0.034). In SLE, joint damage (OR, 2.282; p = 0.038) and anti-RNP antibodies (OR, 5.095; p = 0.028) were risk factors for polyautoimmunity, and hydroxychloroquine was a protective factor (OR, 0.190; p = 0.004).

Conclusions

Polyautoimmunity is frequent in RA and even more frequent in SLE. It was associated with obesity in RA and with joint damage and anti-RNP in SLE. Hydroxychloroquine was a protector.
Ex Vivo Administration of Mesenchymal Stromal Cells in Kidney Grafts Against Ischemia-reperfusion Injury—Effective Delivery Without Kidney Function Improvement Posttransplant
Authors: Lohmann Stine , Eijken Marco , Møldrup Ulla , Møller Bjarne K. , Hunter James , Moers Cyril , Leuvenink Henri , Ploeg Rutger J. , Clahsen-van Groningen Marian C. , Hoogduijn Martin , Baan Carla C. , Keller Anna Krarup , Jespersen Bente
Published: September 2020

Background.

Mesenchymal stromal cell (MSC) therapy may improve renal function after ischemia-reperfusion injury in transplantation. Ex vivo renal intraarterial administration is a targeted delivery method, avoiding the lung vasculature, a known barrier for cellular therapies. In a randomized and blinded study, we tested the feasibility and effectiveness of MSC therapy in a donation after circulatory death autotransplantation model to improve posttransplant kidney function, using an ex vivo MSC delivery method similar to the clinical standard procedure of pretransplant cold graft flush.

Methods.

Kidneys exposed to 75 minutes of warm ischemia and 16 hours of static cold storage were intraarterially infused ex vivo with 10 million male porcine MSCs (Tx-MSC, n = 8) or vehicle (Tx-control, n = 8). Afterwards, the kidneys were autotransplanted after contralateral nephrectomy. Biopsies an hour after reperfusion confirmed the presence of MSCs in the renal cortex. Animals were observed for 14 days.

Results.

Postoperatively, peak plasma creatinine was 1230 and 1274 µmol/L (Tx-controls versus Tx-MSC, P = 0.69). During follow-up, no significant differences over time were detected between groups regarding plasma creatinine, plasma neutrophil gelatinase-associated lipocalin, or urine neutrophil gelatinase-associated lipocalin/creatinine ratio. At day 14, measured glomerular filtration rates were 40 and 44 mL/min, P = 0.66. Renal collagen content and fibrosis-related mRNA expression were increased in both groups but without significant differences between the groups.

Conclusions.

We demonstrated intraarterial MSC infusion to transplant kidneys as a safe and effective method to deliver MSCs to the graft. However, we could not detect any positive effects of this cell treatment within 14 days of observation.
Retinal and Optic Nerve Deformations Due to Orbital Versus Intracranial Venous Hypertension
Authors: Kupersmith Mark J. , Sibony Patrick A.
Published: September 2020

Introduction:

Abnormal forces around the optic nerve head (ONH) due to orbital diseases, intracranial hypertension (IH), glaucoma, and space travel, are associated with alterations of the ONH shape. Elevated cerebral and ophthalmic venous pressure can contribute to stress and strain on the ONH and peripapillary retina. We hypothesize that IH and elevated ophthalmic venous pressure without IH cause different ONH and retinal changes.

Methods:

We compared MRI and spectral domain optical coherence tomography (SDOCT) findings in patients with cavernous sinus arteriovenous shunts (CSAVSs), where orbital venous pressure is known to be elevated, with patients with intracranial dural venous sinus thrombosis and secondary IH. We also compared the results to those obtained in the Idiopathic IH (IIH) Treatment Trial.

Results:

Among 18 patients with dural venous sinus thrombosis, the MRI/magnetic resonance venography displayed partial empty sella (61%) and optic nerve sheath distension (67%). None exhibited ophthalmic vein dilation or signs of orbital congestion. SDOCT of these eyes and IIH eyes showed a similar frequency of abnormal thickening of the mean retinal nerve fiber layer, anterior displacement of the basement membrane opening, peripapillary wrinkles, retinal folds (RF), and choroidal folds (CF). Among 21 patients with CSAVSs, MRI showed ipsilateral dilated superior ophthalmic vein (76%) and orbital congestion (52%) without distension of the optic nerve sheath or globe distortion. SDOCT showed CF (19%), one with overlying RF, and no ONH deformations.

Conclusions:

SDOCT findings for dural venous sinus thrombosis are similar to those seen with IIH but distinct from changes due to local ophthalmic venous hypertension. These data support the concept that IH even if due to a vascular cause and local orbital venous hypertension cause different stresses and strains on the ONH.
Ageing and physical function in East African foragers and pastoralists
Authors: Sayre M. Katherine , Pontzer Herman , Alexander Gene E. , Wood Brian M. , Pike Ivy L. , Mabulla Audax Z. P. , Raichlen David A.
Published: September 2020

Human lifespans are exceptionally long compared with those of other primates. A key element in exploring the evolution of human longevity is understanding how modern humans grow older. Our current understanding of common age-related changes in human health and function stems mostly from studies in industrialized societies, where older adulthood is often associated with an increased incidence of chronic diseases. However, individuals who engage in different lifestyles across industrialized and non-industrialized contexts may display variance in age-related changes in health and function. Here, we explore aspects of physical function in a non-industrialized context using three objective measures of physical function. We assessed physical activity levels, walking endurance and muscle strength in two East African populations: Hadza hunter–gatherers in Tanzania and Pokot pastoralists in Kenya. Both Hadza and Pokot participants displayed significant age-related differences in most, but not all, functional measures. Our results suggest that some age-related differences in physical function seen in industrialized contexts could be consistently experienced by most humans, while other age-related differences may vary across populations. Studies of ageing should expand to include a broad range of populations so we can create a more comprehensive understanding of how senescence varies across different lifestyle contexts.

This article is part of the theme issue ‘Evolution of the primate ageing process’.
Rhesus macaques as a tractable physiological model of human ageing
Authors: Chiou Kenneth L. , Montague Michael J. , Goldman Elisabeth A. , Watowich Marina M. , Sams Sierra N. , Song Jeff , Horvath Julie E. , Sterner Kirstin N. , Ruiz-Lambides Angelina V. , Martínez Melween I. , Higham James P. , Brent Lauren J. N. , Platt Michael L. , Snyder-Mackler Noah
Published: September 2020

Research in the basic biology of ageing is increasingly identifying mechanisms and modifiers of ageing in short-lived organisms such as worms and mice. The ultimate goal of such work is to improve human health, particularly in the growing segment of the population surviving into old age. Thus far, few interventions have robustly transcended species boundaries in the laboratory, suggesting that changes in approach are needed to avoid costly failures in translational human research. In this review, we discuss both well-established and alternative model organisms for ageing research and outline how research in nonhuman primates is sorely needed, first, to translate findings from short-lived organisms to humans, and second, to understand key aspects of ageing that are unique to primate biology. We focus on rhesus macaques as a particularly promising model organism for ageing research owing to their social and physiological similarity to humans as well as the existence of key resources that have been developed for this species. As a case study, we compare gene regulatory signatures of ageing in the peripheral immune system between humans and rhesus macaques from a free-ranging study population in Cayo Santiago. We show that both mRNA expression and DNA methylation signatures of immune ageing are broadly shared between macaques and humans, indicating strong conservation of the trajectory of ageing in the immune system. We conclude with a review of key issues in the biology of ageing for which macaques and other nonhuman primates may uniquely contribute valuable insights, including the effects of social gradients on health and ageing. We anticipate that continuing research in rhesus macaques and other nonhuman primates will play a critical role in conjunction with the model organism and human biodemographic research in ultimately improving translational outcomes and extending health and longevity in our ageing population.

This article is part of the theme issue ‘Evolution of the primate ageing process’.
Broad frequency sensitivity and complex neural coding in the larval zebrafish auditory system
Authors: Poulsen Rebecca E. , Sholz Leandro A. , Constantin Lena , Favre-Bulle Itia , Vanwalleghem Gilles C. , Scott Ethan K.
Published: September 2020

Most animals have complex auditory systems that identify salient features of the acoustic landscape to direct appropriate responses. In fish, these features include the volume, frequency, complexity, and temporal structure of auditory stimuli transmitted through water. Larval fish have simple brains compared to adults, but swim freely and depend on sophisticated sensory processing for survival. Zebrafish larvae, an important model for studying brain-wide neural networks, have thus far been found to possess a rudimentary auditory system, sensitive to a narrow range of frequencies and without evident sensitivity to auditory features that are salient and ethologically important to adult fish. Here, we have combined a novel method for delivering water-borne sounds, a diverse assembly of acoustic stimuli, and whole-brain calcium imaging to describe the responses of individual auditory neurons across the brains of zebrafish larvae. Our results reveal responses to frequencies ranging from 100Hz to 4kHz, with evidence of frequency discrimination from 100Hz to 2.5kHz. Frequency-selective neurons are located in numerous regions of the brain, and neurons responsive to the same frequency are spatially grouped in some regions. Using functional clustering, we identified categories of neurons that are selective for pure tones of a single frequency, white noise, the sharp onset of auditory stimuli, and stimuli involving a gradual crescendo. These results suggest a more nuanced auditory system than has previously been described in larval fish and provide insights into how a young animal’s auditory system can both function acutely and serve as the scaffold of a more complex adult system.
Spatial information transfer in hippocampal place cells depends on trial-to-trial variability, symmetry of place-field firing and biophysical heterogeneities
Authors: Roy Ankit , Narayanan Rishikesh
Published: September 2020

The relationship between the feature-tuning curve and information transfer profile of individual neurons provides vital insights about neural encoding. However, the relationship between the spatial tuning curve and spatial information transfer of hippocampal place cells remains unexplored. Here, employing a stochastic search procedure spanning thousands of models, we arrived at 127 conductance-based place-cell models that exhibited signature electrophysiological characteristics and sharp spatial tuning, with parametric values that exhibited neither clustering nor strong pairwise correlations. We introduced trial-to-trial variability in responses and computed model tuning curves and information transfer profiles, using stimulus-specific (SSI) and mutual (MI) information metrics, across locations within the place field. We found spatial information transfer to be heterogeneous across models, but to reduce consistently with increasing degrees of variability. Importantly, whereas reliable low-variability responses implied that maximal information transfer occurred at high-slope regions of the tuning curve, increase in variability resulted in maximal transfer occurring at the peak-firing location in a subset of models. Moreover, experience-dependent asymmetry in place-field firing introduced asymmetries in the information transfer computed through MI, but not SSI, and the impact of activity-dependent variability on information transfer was minimal compared to activity-independent variability. Biophysically, we unveiled a many-to-one relationship between different ion channels and information transfer, and demonstrated critical roles forN-methyl-D-aspartate receptors, transient potassium and dendritic sodium channels in regulating information transfer. Our results emphasize the need to account for trial-to-trial variability, tuning-curve shape and biological heterogeneities while assessing information transfer, and demonstrate ion-channel degeneracy in the regulation of spatial information transfer.
Demyelination induces selective vulnerability of inhibitory networks in multiple sclerosis
Authors: Zoupi Lida , Booker Sam A. , Eigel Dimitri , Werner Carsten , Kind Peter C. , Spires-Jones Tara L. , Newland Ben , Williams Anna C.
Published: September 2020

In multiple sclerosis (MS), a chronic demyelinating disease of the central nervous system, neurodegeneration is detected early in the disease course and is associated with the long-term disability of patients. Neurodegeneration is linked to both inflammation and demyelination, but its exact cause remains unknown. This gap in knowledge contributes to the current lack of treatments for the neurodegenerative phase of MS. Here we ask if neurodegeneration in MS affects specific neuronal components and if it is the result of demyelination. Neuropathological examination of secondary progressive MS motor cortices revealed a selective vulnerability of inhibitory interneurons in MS. The generation of a rodent model of focal subpial cortical demyelination proved that this selective neurodegeneration is secondary to demyelination providing the first temporal evidence of demyelination-induced neurodegeneration and a new preclinical model for the study of neuroprotective treatments.
Expression of a modified astrocytic glutamate transporter alleviates Huntington’s hypokinesia, promotes synaptic glutamate clearance and counteracts potentially adverse EAAT2 interactions
Authors: Hirschberg Stefan , Dvorzhak Anton , Rasooli-Nejad Seyed M. A. , Angelov Svilen , Kirchner Marieluise , Mertins Philip , Lättig-Tünnemann Gilla , Harms Christoph , Schmitz Dietmar , Grantyn Rosemarie
Published: September 2020

Rapid removal of glutamate from the sites of glutamate release is an essential step in excitatory synaptic transmission. Despite many years of research, the molecular mechanisms underlying the intracellular regulation of glutamate transport at tripartite synapses have remained unclear. This limits the options for pharmacological treatment of motor disorders associated with glutamate excitotoxicity. Therefore, using the Q175 mouse model of Huntington’s disease (HD), we explored the effects of structural changes in the astrocytic excitatory amino acid transporter type 2 (EAAT2). We report that expression of a C-terminal-modified variant of EAAT2 can alleviate the symptoms of hypokinesia in mice with already advanced HD. At a cellular level, this beneficial outcome correlated with faster synaptic glutamate clearance, higher astrocytic glutamate uptake and larger amounts of native EAAT2 protein. Proteomics data indicate a partial reversal of HD-induced changes in the EAAT2 interactor spectrum. Thus, astrocytic glutamate transport remains a target for therapeutic intervention.
The gut microbiome and its metabolites are necessary for morphine reward
Authors: Hofford Rebecca S. , Mervosh Nicholas L. , Euston Tanner J. , Meckel Katherine R. , Orr Amon T. , Kiraly Drew D.
Published: September 2020

Recent evidence has demonstrated that the gut microbiome has marked effects on neuronal function and behavior. Disturbances to microbial populations within the gut have been linked to myriad models of neuropsychiatric disorders. However, the role of the microbiome in substance use disorders remains understudied. Here we show that animals with their gut microbiome depleted by non-absorbable antibiotics (Abx) exhibit decreased formation of morphine conditioned place preference and demonstrate marked changes in gene expression within the nucleus accumbens (NAc) in response to morphine. Replacement of short-chain fatty acid (SCFA) metabolites, which are reduced by microbiome knockdown, reversed the behavioral and transcriptional effects of microbiome depletion. This identifies SCFA as the crucial mediators of microbiome-brain communication responsible for the effects on morphine reward caused by microbiome knockdown. These studies add important new behavioral, molecular, and mechanistic insight to the role of gut-brain signaling in substance use disorders.
A step-by-step sequence-based analysis of virome enrichment protocol for freshwater and sediment samples
Authors: Pinto Federica , Zolfo Moreno , Beghini Francesco , Armanini Federica , Asnicar Francesco , Silverj Andrea , Boscaini Adriano , Salmaso Nico , Segata Nicola
Published: September 2020

Cultivation-free metagenomic analysis afforded unprecedented details on the diversity, structure and potential functions of microbial communities in different environments. When employed to study the viral fraction of the community that is recalcitrant to cultivation, metagenomics can shed light into the diversity of viruses and their role in natural ecosystems. However, despite the increasing interest in virome metagenomics, methodological issues still hinder the proper interpretation and comparison of results across studies. Virome enrichment experimental protocols are key multi-step processes needed for separating and concentrating the viral fraction from the whole microbial community prior to sequencing. However, there is little information on their efficiency and their potential biases. To fill this gap, we used metagenomic and amplicon sequencing to examine the microbial community composition through the serial filtration and concentration steps commonly used to produce viral-enriched metagenomes. The analyses were performed on water and sediment samples from an Alpine lake. We found that, although the diversity of the retained microbial communities declined progressively during the serial filtration, the final viral fraction contained a large proportion (from 10% to 40%) of non-viral taxa, and that the efficacy of filtration showed biases based on taxonomy. Our results quantified the amount of bacterial genetic material in viromes and highlighted the influence of sample type on the enrichment efficacy. Moreover, since viral-enriched samples contained a significant portion of microbial taxa, computational sequence analysis should account for such biases in the downstream interpretation pipeline.

Importance

Filtration is a commonly used method to enrich viral particles in environmental samples. However, there is little information on its efficiency and potential biases on the final result. Using a sequence-based analysis on water and sediment samples, we found that filtration efficacy is dependent on sample type and that the final virome contained a large proportion of non-viral taxa. Our finding stressed the importance of downstream analysis to avoid biased interpretation of data.
Modeling physician variability to prioritize relevant medical record information
Authors: Tajgardoon Mohammadamin , Cooper Gregory F , King Andrew J , Clermont Gilles , Hochheiser Harry , Hauskrecht Milos , Sittig Dean F , Visweswaran Shyam
Published: September 2020

Objective

Patient information can be retrieved more efficiently in electronic medical record (EMR) systems by using machine learning models that predict which information a physician will seek in a clinical context. However, information-seeking behavior varies across EMR users. To explicitly account for this variability, we derived hierarchical models and compared their performance to non-hierarchical models in identifying relevant patient information in intensive care unit (ICU) cases.

Materials and Methods

Critical care physicians reviewed ICU patient cases and selected data items relevant for presenting at morning rounds. Using patient EMR data as predictors, we derived hierarchical logistic regression (HLR) and standard logistic regression (LR) models to predict their relevance.

Results

In 73 pairs of HLR and LR models, the HLR models achieved an area under the ROC curve of 0.81, 95% CI [0.80, 0.82], which was statistically significantly higher than that of LR models (0.75, 95% CI [0.74-0.76]). Further, the HLR models achieved statistically significantly lower expected calibration error (0.07, 95% CI [0.06-0.08]) than LR models (0.16, 95% CI [0.14-0.17]).

Discussion

The physician reviewers demonstrated variability in selecting relevant data. Our results show that HLR models perform significantly better than LR models with respect to both discrimination and calibration. This is likely due to explicitly modeling physician-related variability.

Conclusion

Hierarchical models can yield better performance when there is physician-related variability as in the case of identifying relevant information in the EMR.
Anti-androgens induce Rab11a-exosome secretion in prostate cancer by suppressing amino acid-sensitive PAT4-mTORC1 signalling
Authors: McCormick Kristie , Sanitt Poohrawind , Fan Shih-Jung , Mason John D , Harris Adrian L , Hamdy Freddie C , Verrill Clare , Bryant Richard J , Goberdhan Deborah C I
Published: September 2020

Advanced prostate cancer is typically treated with anti-androgens to reduce cancer growth, but patients almost inevitably develop treatment resistance and castration-resistant disease. Recently, extracellular vesicles known as exosomes, which are secreted from the endosomal compartments in which they are formed, have been implicated in drug resistance mechanisms. Here we investigate whether growth regulation by the amino acid-dependent kinase complex, mechanistic Target of Rapamycin Complex 1 (mTORC1), and associated extracellular vesicle secretion might be involved in the adaptive responses to anti-androgens. We show that expression and intracellular localisation of the glutamine-sensing PAT4 (SLC36A4) amino acid transporter is increased in malignant versus benign prostatic tissue, mirroring earlierin vivofly studies suggesting that these transporters are more effective at promoting growth from internal versus cell surface membranes. Furthermore, androgens induce PAT4 expression in prostate cancer cell lines and PAT4 is required for a proportion of androgen-stimulated mTORC1 activation and growth. Consistent with previous studies in other cancer cell lines, we find that glutamine depletion, PAT4 knockdown and mTORC1 inhibition all independently increase the production of a specific exosome subtype, Rab11a-exosomes, which has recently been implicated in pro-tumorigenic signalling responses to mTORC1 inhibition. Furthermore, we show that these exosomes are also induced by anti-androgens. We hypothesise that the uptake of Rab11a-exosomes by cells with higher PAT4 levels could provide a growth-promoting boost, enabling them to out-compete others with lower PAT4 expression, resulting in tumours that are more resistant to nutrient-deprivation and anti-androgen treatment.
Functional diversity of microboringOstreobiumalgae isolated from corals
Authors: Massé A. , Tribollet A. , Meziane T. , Bourguet-Kondracki M.L. , Yéprémian C. , Sève C. , Thiney N. , Longeon A. , Couté A. , Domart-Coulon I.
Published: September 2020

The filamentous chlorophyteOstreobiumsp. dominates shallow marine carbonate microboring communities, and is one of the major agents of reef bioerosion. While its large genetic diversity has emerged, its physiology remains little known, with unexplored relationship between genotypes and phenotypes (endolithicversusfree-living growth forms). Here, we isolated 9 strains affiliated to 2 lineages ofOstreobium(>8% sequence divergence of the plastid generbcL), one of which was assigned to the family Odoaceae, from the fast-growing coral hostPocillopora acutaLamarck 1816. Free-living isolates maintained their bioerosive potential, colonizing pre-bleached coral carbonate skeletons. We compared phenotypes, highlighting shifts in pigment and fatty acid compositions, carbon to nitrogen ratios and stable isotope compositions (δ13C and δ15N). Our data show a pattern of higher chlorophyllband lower arachidonic acid (20:4ω6) content in endolithicversusfree-livingOstreobium. Photosynthetic carbon fixation and nitrate uptake, quantified via 8h pulse-labeling with13C-bicarbonate and15N-nitrate, showed lower isotopic enrichment in endolithic compared to free-living filaments. Our results highlight the functional plasticity ofOstreobiumphenotypes. The isotope tracer approach opens the way to further study the biogeochemical cycling and trophic ecology of these cryptic algae at coral holobiont and reef scales.
PARP inhibition in Ewing sarcoma: impact of germline DNA damage repair defects and activation of immunoregulatory pathways
Authors: Maurer Lisa M. , Venier Rosemarie E. , Mukherjee Elina , Julian Claire M. , Daley Jessica D. , Bailey Nathanael G. , Jacobs Michelle F. , Kumar-Sinha Chandan , Raphel Haley , Weiss Kurt , Janeway Katherine A. , Mody Rajen , Lucas Peter C. , McAllister-Lucas Linda M. , Bailey Kelly M.
Published: September 2020

Ewing sarcoma, an oncofusion-driven primary bone tumor, can occur in the setting of various germline mutations in DNA damage repair pathway genes. We recently reported our discovery of a germline mutation in the DNA damage repair proteinBARD1(BRCA1-associated RING domain-1) in a patient with Ewing sarcoma. BARD1 is recruited to the site of DNA double stranded breaks via the poly(ADP-ribose) polymerase (PARP) protein and plays a critical role in DNA damage response pathways including homologous recombination. PARP inhibitors (PARPi) are effective against Ewing sarcoma cellsin vitro, though have demonstrated limited success in clinical trials to date. In order to assess the impact of BARD1 loss on Ewing sarcoma sensitivity to PARP inhibitor therapy, we generated the novel PSaRC318 patient-derived Ewing tumor cell from our patient with a germlineBARD1mutation and then analyzed the response of these cells to PARPi. We demonstrate that PSaRC318 cells are sensitive to PARP inhibition and by testing the effect of BARD1 depletion in additional Ewing sarcoma cell lines, we confirm that loss of BARD1 enhances PARPi sensitivity. In certain malignancies, DNA damage can activate the IRF1 (interferon response factor 1) immunoregulatory pathway, and the activation of this pathway can drive immunosuppression through upregulation of the immune checkpoint protein PD-L1. In order to determine the ability of PARPi to alter Ewing tumor immunoregulation, we evaluated whether PARPi results in upregulation of the IRF1-PDL1 pathway. Indeed, we now demonstrate that PARPi leads to increased PD-L1 expression in Ewing sarcoma. Together, these data thus far suggest that while Ewing tumors harboring germline mutations in DNA damage repair proteins may in respond to PARPiin vitro, in vivobenefit of PARPi may only be demonstrated when counteracting the immunosuppressive effects of DNA damage by concurrently targeting immune checkpoint proteins.
Using cortical neuron markers to target cells in the dorsal cochlear nucleus
Authors: Malfatti Thawann , Ciralli Barbara , Hilscher Markus M. , Edwards Steven J. , Kullander Klas , Leao Richardson N. , Leao Katarina E.
Published: September 2020

The dorsal cochlear nucleus (DCN) is the first auditory region that integrates somatosensory and auditory inputs. The region is of particular interest for auditory research due to the large incidence of somatic tinnitus and increased aberrant activity in other forms of tinnitus. Yet, the lack of useful genetic markers for in vivo manipulations hinders the elucidation of the DCN contribution to tinnitus pathophysiology. In this work, we assessed whether adeno-associated viral vectors (AAV) containing the calcium/calmodulin-dependent protein kinase 2 alpha (CaMKIIα) promoter and our mouse line of nicotinic acetylcholine receptor alpha 2 subunit (Chrna2)-Cre can be used to target specific DCN populations. The CaMKIIαpromoter is usually applied in studies of principal neurons of neo and paleocortex while Chrna2-cre mice express Cre recombinase in cortical dendrite inhibiting interneurons. We found that CaMKIIαcannot be used to specifically target excitatory fusiform DCN neurons. EYFP expression driven by the CaMKIIαpromoter was stronger in the fusiform layer but labelled cells showed a diverse morphology indicating that they belong to different classes of DCN neurons. Light stimulation after driving Channelrhodopsin2 (ChR2) by the CaMKIIαpromoter generated spikes in some units but firing rate decreased when light stimulation coincide with sound presentation. Expression and activation of eArch3.0 (CaMKIIαdriven) in the DCN produced spike inhibition in some units but, most importantly, sound-driven spikes were delayed by concomitant light stimulation. We explored the existence of Cre+ cells in the DCN of Chrna2-Cre mice by hydrogel embedding technique (CLARITY). There were almost no Cre+ cell bodies in the DCN; however, we observed profuse projections arising from the ventral cochlear nucleus (VCN). Anterograde labeling Cre dependent AAV injected in the VCN revealed two main projections: one arising in the ipsilateral superior olive and the contralateral medial nucleus of the trapezoid body (bushy cells) and a second bundle terminating in the DCN, suggesting the latter to be excitatory Chrna2+ T-stellate cells). Stimulating ChR2 expressing terminals (light applied on the DCN) of VCN Chrna2+ cells increased firing of sound responding and nonresponding DCN units. This work shows that molecular tools intensively used in cortical studies may be useful for manipulating the DCN especially in tinnitus studies.
CRISPR-Cas systems restrict horizontal gene transfer inPseudomonas aeruginosa
Authors: Wheatley Rachel M. , MacLean R. Craig
Published: September 2020

CRISPR-Cas systems provide bacteria and archaea with an adaptive immune system that targets foreign DNA. However, the xenogenic nature of immunity provided by CRISPR-Cas raises the possibility that these systems may constrain horizontal gene transfer. Here we test this hypothesis in the opportunistic pathogenPseudomonas aeruginosa, which has emerged an important model system for understanding CRISPR-Cas function. Across the diversity ofP. aeruginosa, active CRISPR-Cas systems are associated with smaller genomes and a reduced GC content, suggesting that CRISPR-Cas inhibits the acquisition of foreign DNA. Although phage are the major target of CRISPR-Cas spacers, more than 80% of isolates with an active CRISPR-Cas system have spacers that target integrative conjugative elements (ICE) or the conserved conjugative transfer machinery used by plasmids and ICE. Consistent with these results, genomes containing active CRISPR-Cas systems harbor a lower abundance of both prophage and ICE. Crucially, spacers in genomes with active CRISPR-Cas systems map to ICE and phage that are integrated into the chromosomes of closely related genomes lacking CRISPR-Cas immunity, providing direct evidence that CRISPR-Cas constrains horizontal gene transfer in these lineages. In conclusion, we find that CRISPR-Cas acts as an important constraint to horizontal gene transfer, suggesting that CRISPR-Cas may constrain the ability of this pathogen to adapt to new niches and stressors.
Analysis of beta-lactam heteroresistance in CRE suggests a stage in the spectrum of antibiotic resistance
Authors: Band Victor I. , Weiss David S.
Published: September 2020

Antibiotic resistance is a growing crisis that threatens many aspects of modern healthcare. Dogma is that resistance often develops due to acquisition of a resistance gene or mutation, and that when this occurs, all the cells in the bacterial population are phenotypically resistant which we term “homogenous resistance”. In contrast, heteroresistance (HR) is a form of antibiotic resistance where only a subset of cells within a bacterial population are resistant to a given drug. These resistant cells can rapidly replicate in the presence of the antibiotic and cause treatment failures. If and how HR and homogenous resistance are related is unclear. Using carbapenem-resistant Enterobacterales (CRE), we show that HR to beta-lactams develops over years of antibiotic usage and that it is gradually supplanted by homogenous resistance. This suggests the possibility that HR may often develop before homogenous resistance and frequently be a stage in its progression, representing a major shift in our understanding of the evolution of antibiotic resistance.
Root Cause Analysis and Its Effect on Auditors' Judgments and Decisions in an Integrated Audit*
Authors: DeZoort Todd , Doxey Marcus , Pollard Troy
Published: September 2020

This study evaluates whether auditor use of root cause analysis (RCA) for an identified client misstatement affects auditors' assessments of underlying control issues and materiality in an integrated audit setting. We also test whether auditor cognitive style moderates these effects given prior findings that a misfit between task structure and cognitive style undermines performance. This research is motivated by concerns about integrated audit quality and auditors failing to consider control deficiencies indicated by client misstatements. We randomly assigned 147 auditors to four RCA treatments (No RCA, Unstructured RCA, Structured “5 Whys” RCA, Structured “Fishbone” RCA). As predicted, the results suggest that auditors using (not using) structured RCA are more (less) likely to identify control‐related root causes of a financial misstatement and judge the misstatement to be more (less) material. Also consistent with our prediction, we find that the assessed severity of identified control deficiencies mediates RCA's effect on materiality judgments. Finally, the materiality judgment results reveal the expected significant interaction between structured RCA method and auditor cognitive style, suggesting the importance of allowing flexibility in the specific RCA method applied in practice. Overall, the study's results provide evidence that auditor use of RCA as a judgment framework prompts deeper evaluation of audit findings and stronger consideration of critical links between financial reporting and related internal controls in integrated audit settings.