bluuebunny/crossref_metadata_2025 huggingface dataset:
Missed Opportunities for HIV and Hepatitis C Screening Among Emergency Department Patients With Untreated Opioid Use Disorder
Authors: Lyons Michael S. , Chawarski Marek C. , Rothman Richard , Whiteside Lauren , Cowan Ethan , Richardson Lynne D. , Hawk Kathryn , Tsui Judith I. , Schwartz Robert P. , O’Connor Patrick , D’Onofrio Gail , Fiellin David A. , Edelman E. Jennifer
Published: September 2022

Objective

We assessed the frequency of emergency department (ED) HIV and hepatitis C (HCV) screening in a high-risk cohort of ED patients with untreated opioid use disorder (OUD).

Methods

This analysis used data from a prospective, observational study of English-speaking adults with untreated OUD enrolled from April 2017 to December 2018 in 4 urban, academic EDs. Two cohorts were defined for this analysis by self-reported negative/unknown status for HIV (cohort 1) and HCV (cohort 2). Sites featured structured screening programs throughout the entire enrollment period for HIV and during at least part of the enrollment period for HCV. We calculated the proportion tested for HIV and HCV during the study enrollment ED visit.

Results

Among 394 evaluated ED patients, 328 of 394 (83.2%) were not tested for HIV or HCV and 244 of 393 (62.1%) lacked a usual medical care provider. In cohort 1, 375 reported negative or unknown HIV status; 59/375 (15.7%) overall and 33/218 (15.1%) of those reporting recent injection drug use were tested for HIV. In cohort 2, 231 reported negative of unknown HCV status; 22/231 (9.5%) overall and 9/98 (9.2%) of those reporting recent injection drug use were tested for HCV. The proportion tested by the ED ranged from 3% to 25% for HIV and 4% to 32% for HCV across study sites.

Conclusions

Emergency department HIV and HCV screening remains infrequent among patients with untreated OUD, including those who inject drugs, even in EDs committed to screening. Targeted HIV/HCV screening should be considered as an adjunct strategy until the ideal of universal screening is more fully achieved.
Experiences from the adverse drug event manager
Authors: Horwitz Henrik , Olsen Rasmus H. , von Osmanski Benedikte I. , Solem Espen J.
Published: September 2022

The current report briefly summarizes the experiences and statistics of the Adverse Drug Event Manager (ADEM) covering the Capital Region of Denmark, Denmark, during the period 1 January 2013 to 31 December 2020. During this 8-year period, the ADEM function has reported a total of 4262 adverse drug reactions (ADRs) to the Danish Medicines Agency, and of these, 141 had a fatal outcome (3.3%). The most commonly reported drugs were vaccines, antihypertensive agents, anticoagulants, and antiosteoporosis drugs. Fatal ADRs were predominantly related to anticoagulants. In 2020, the ADEM reported more than two-thirds of all ADRs for the Health Professionals in the Capital Region of Denmark. In addition to reporting ADRs, the ADEM has also had an extensive teaching and research activity and published a considerable number of studies on drug safety.
The Modernization of Clozapine
Authors: Leung Jonathan G. , de Leon Jose , Frye Mark A. , Singh Balwinder , Cotes Robert O. , McElroy Susan L.
Published: September 2022

Purpose

Although clozapine was Food and Drug Administration (FDA) approved more than 3 decades ago, major barriers and gaps in knowledge continue to prevent its effective and safe use. We review modern-day problems encountered with clozapine in the United States (US).

Methods

Information surrounding current administrative, clinical, research, and technological gaps or barriers related to clozapine use in the US was reviewed.

Findings

The history of how clozapine became FDA approved likely contributes to gaps in knowledge. The frequency of safety warnings added to the FDA prescribing information may add to fears about clozapine, as evidence by numerous published survey studies. The clozapine Risk Evaluation and Mitigation Strategy (REMS) program has been modified several times in the last decade, causing access and safety issues for patients, which are discussed. Evidence may suggest that the FDA REMS requirements for hematologic monitoring are too cumbersome, and there may be ability to safely loosen requirements. The COVID-19 pandemic brought forth the ability for extended interval monitoring but also greater awareness of the clozapine-inflammation interaction. Newer guidelines published describe considerations in personalizing clozapine titration based on principles of ethnopsychopharmacology. Emerging technologies to support the use of clozapine are not widely available.

Implications

Clozapine is a unique life-saving drug but it is underused in the US, despite its established efficacy. The 2021 REMS changes led to significant difficulties for providers and patients. We highlight the importance of the clozapine-inflammation interaction, therapeutic drug monitoring, and the ability for individual care based on patient-specific factors. There is an urgent need for advancing technology used for clozapine monitoring, evaluating barriers created by REMS, and establishing consistent practices throughout the US.
Quality of Life and Its Association With HIV-Related Stigma Among People Living With HIV in Kerman, Iran: A Cross-Sectional Study
Authors: Malekmohammadi Neda , Khezri Mehrdad , Rafiee Rad Ali Ahmad , Iranpour Abedin , Ghalekhani Nima , Shafiei bafti Mehdi , Zolala Farzaneh , Sharifi Hamid
Published: September 2022

This study aimed to evaluate the quality of life (QoL) and its association with HIV-related stigma among people living with HIV (PLHIV) in Kerman province, southeast Iran. A convenience sample of 104 PLHIV was recruited. Data on QoL were collected using the HIV/AIDS-Targeted QoL instrument. Internal and external stigma were measured using an instrument developed by UNAIDS. The average QoL score was 52.5 (SD =13.9). In multivariable model, PLHIV who experienced higher external stigma score (B = −1.9; 95% confidence interval [CI]: −2.6 to −1.1) and higher internal stigma score (B = −1.1; 95% CI: −1.5 to −0.6) had lower level of QoL. The low level of QoL among PLHIV in Iran indicates the need for initiatives to increase QoL among this population. Our data suggest that QoL in PLHIV could be improved by interventions aimed at reducing stigma in both community and health care settings.
An Adolescent's Motivation to Pursue Bariatric Surgery
Authors: Garcia Mayra G. , Watt Jennifer L. , Six-Means Amy
Published: September 2022

Introduction

Childhood obesity has become a significant cause for concern in pediatric health care. Adolescents seek medical care for guidance in the treatment of obesity and comorbidities. Bariatric surgery has become a treatment option for adolescents with obesity. There is a limited understanding of an adolescent's decision to pursue bariatric surgery. The objective of this meta-aggregation review is to identify what is known about the motivations of adolescents to pursue bariatric surgery.

Methods

Studies were considered if they included adolescents 12–20 years old who have had or are considering bariatric weight loss surgery in all healthcare settings. Using a three-step search approach, published studies were identified in this meta-aggregation review. Each study was appraised by two independent reviewers using the John Hopkins Evidence Level Quality Guide. Synthesized findings were identified.

Results

Fifty-seven unequivocal findings were extracted from six studies and placed into six categories. These categories were further compiled into three synthesized findings. Findings indicate that adolescent bariatric patients need an external stimulus for surgery and are often motivated by the right time for surgery, as a last resort, and with external support. Motivators for surgery also included a desire for a healthy life and to reach personal goals. Negative body image and self-esteem as well as a desire for social acceptance are other motivators for surgery. Three synthesized themes identified were stimulus for surgery, sense of self, and healthy life.

Conclusions

Adolescent bariatric surgery is a growing treatment option offered to adolescents with obesity. Little is written about the motivations of adolescents seeking bariatric surgery, and it is not well researched. Further research involving qualitative work with adolescents with obesity who are considering bariatric surgery should be conducted.
Fundamental drivers of nurses’ experiences of ICU surging during the coronavirus disease 2019 (COVID-19) pandemic
Authors: Endacott Ruth , Blot Stijn
Published: September 2022

Purpose of review

Nurses working in intensive care units have been heavily impacted by the coronavirus disease 2019 (COVID-19) pandemic. This review summarizes the current state of the evidence regarding intensive care nurses experience of the pandemic.

Recent findings

The pandemic has had an impact on: nursing workload, the organization of nurse staffing, experiences of staff redeployed into ICU, nurses’ perceptions of the safety and quality of patient care, and staff health. In the few comparative studies, mental health was worse for nurses than other healthcare workers in intensive care. Despite some of this evidence being published early in the pandemic, no studies were found to evaluate interventions to improve nurses’ experiences.

Summary implications for practice or research

Many of the adverse impacts of the pandemic are interdependent; for example, reducing nurses’ workload is likely to have benefits for mental health indicators.

Adverse mental health outcomes are likely to have an impact on future recruitment and retention for intensive care nursing.

More studies are needed to understand the longer term impact of the pandemic on intensive care nurses.
Healthspan Extension through Innovative Genetic Medicines
Authors: Garcia Henry , Brown Douglas , Scholz Matthew , Lewis John D.
Published: September 2022

Genetic medicine has emerged as an innovative class of therapeutics, allowing the development of new and powerful approaches to address a myriad of diseases that were previously untreatable. At the same time, our improved understanding of the mechanisms underlying aging has created novel opportunities to intervene therapeutically in the aging process itself through the targeting of key pathways driving this process. As individuals age, the onset of a multitude of age-related diseases can significantly impact lifespan. The ultimate goal of their treatment is the maximization of healthy, disease-free years, or healthspan. Here, we discuss a number of promising genetic medicine approaches to target both general and specific mechanisms of age-related disease, and their potential impact on healthspan extension. Essential to this topic is the challenge of nucleic acid delivery, and we discuss the technologies that have been developed to address this challenge in highly promising preclinical and clinical development efforts. In particular, we describe a next-generation delivery technology for healthspan applications called proteo-lipid vehicles.
Evaluating Patient Identification Practices During Intrahospital Transfers: A Human Factors Approach
Authors: Suclupe Stefanie , Kitchin Joanne , Sivalingam Rajhkumar , McCulloch Peter
Published: September 2022

Introduction

Reliable patient identification is essential for safe care, and failures may cause patient harm. Identification can be interfered with by system factors, including working conditions, technology, organizational barriers, and inadequate communications protocols. The study aims to explore systems factors contributing to patient identification errors during intrahospital transfers.

Methods

We conducted a qualitative study through direct observation and interviews with porters during intrahospital patient transfers. Data were analyzed using the Systems Engineering Initiative for Patient Safety human factors model. The patient transfer process was mapped and compared with the institutional Positive Patient Identification policy. Potential system failures were identified using a Failure Modes and Effects Analysis.

Results

A total of 60 patient transfer handovers were observed. In none of the evaluable cases observed, patient identification was conducted correctly according to the hospital policy at every step of the process. The principal system factor responsible was organizational failure, followed by technology and team culture issues. The Failure Modes and Effects Analysis methodology revealed that miscommunication between staff and lack of key patient information put patient safety at risk.

Conclusions

Patient identification during intrahospital patient transfer is a high-risk event because several factors and many people interact. In this study, the disconnect between the policy and the reality of the workplace left staff and patients vulnerable to the consequences of misidentification. Where a policy is known to be substantially different from work as done, urgent revision is required to eliminate the serious risks associated with the unguided evolution of working practice.
Self-reported Antiretroviral Adherence: Association With Maternal Viral Load Suppression in Postpartum Women Living With HIV-1 From Promoting Maternal and Infant Survival Everywhere, a Randomized Controlled Trial in Sub-Saharan Africa and India
Authors: Nevrekar Neetal , Butler Kevin , Shapiro David E. , Atuhaire Patience , Taha Taha E. , Makanani Bonus , Chinula Lameck , Owor Maxensia , Moodley Dhayendre , Chipato Tsungai , McCarthy Katie , Flynn Patricia M. , Currier Judith , Fowler Mary Glenn , Gupta Amita , Suryavanshi Nishi
Published: September 2022

Introduction:

Optimal adherence to antiretroviral therapy (ART) is crucial to promoting maternal–infant health.

Setting:

Fourteen sites in 7 countries within sub-Saharan Africa and India.

Methods:

The multicomponent, open-label strategy PROMISE trial enrolled breastfeeding mother–infant pairs not meeting in-country criteria for maternal ART (mART) initiation in the postpartum component within 5 days of delivery. Randomization was to mART versus infant NVP (iNVP) prophylaxis. Infants in the mART arm also received 6 weeks of iNVP. Self-reported adherence was assessed in a secondary analysis. Time-to-event analyses were performed to explore the association between adherence and maternal viral load (mVL) in the mART arm.

Results:

Two thousand four hundred thirty-one mother–infant pairs were enrolled between 2011 and 2014; the baseline maternal median CD4 was 686 (IQR 553–869), and the median mVL was 322 copies/mL (IQR 40–1422). Self-reported adherence was lower in the mART arm compared with the iNVP arm (no missed doses within 4 weeks of all study visits: 66% vs 83%; within 2 weeks: 71% vs 85%; P < 0.0001). The iNVP adherence at week 6 was high in both arms: 97% in mART arm; 95% in iNVP arm. Time-to-event analyses showed that adherence to mART was associated with time to first mVL ≥400 copies/mL (P < 0.0001). Missing 1 full day of doses over 3 days was associated with a 66% risk of mVL ≥1000 copies/mL (HR: 1.66; 95% CI: 1.37, 1.99).

Conclusions:

Postpartum women were less adherent to their own ART than mothers providing their infant's nevirapine prophylaxis. The self-reported missed mART doses were associated with high mVL. Strategies to optimize postpartum mART adherence are urgently needed.

Clinical Trial Number:

ClinicalTrials.gov: NCT01061151; closed to follow-up.
Postsurgical pain management among obstetrics and gynecology patients in a teaching hospital in Tabriz, Iran: a best practices implementation project
Authors: Hajebrahimi Sakineh , Vaezi Maryam , Moslemi Tabrizi Farnaz , Asghari Khatooni Azam , Zahed Khadijeh
Published: September 2022

Objectives:

The purpose of this project was to improve the compliance of patients’ pain management process after surgery using evidence-based criteria at the Al-Zahra Educational Hospital in Tabriz.

Introduction:

Reducing and relieving pain are among the basic rights of patients, and the management of this component should be one of the basic goals of the patient care team. Inadequate pain control can have many unpleasant consequences for the patient and increase hospital costs. Due to the importance of pain control and a gap in this area, it was decided to implement a project to improve pain control in postoperative patients grounded in evidence-based recommendations.

Method:

This project was carried out at a Level III hospital in Iran from December 2019 to June 2020. A baseline audit, based on the JBI Practical Application of Clinical Evidence-Based System (JBI PACES) and Getting Research into Practice (GRiP) audit and feedback tool was conducted with 40 patients in the surgery ward of the hospital. After developing the GRiP table (barriers, strategy, resources and outcome), a follow-up audit was done three times. The different stages of the audit were centered in evidence-based criteria. At each stage of follow-up, 40 patients were randomly selected in the postoperative stage.

Results:

At the baseline audit, out of a total of eight criteria, only criterion 2 corresponded to the audit criteria where there was no pain assessment tool or protocol for pain or for training patients and nurses. Over the three follow-up audits, 100% improvement was achieved in half of the criteria through preparing visual analogue scale pain instruments, and development of a pain protocol and a pain self-care protocol, and a 63% improvement was observed in one of the criteria. Patients’ pain decreased from very severe to mild/moderate in the first few hours in 70% of patients after surgery.

Conclusion:

The use of this best practices implementation project led to the improvement of the postoperative pain management process of patients and the improvement of patient care quality. The use of the JBI Institute Method is recommended to address other current or defective hospital processes.
Personality traits and their role as risk modifiers in gaming disorder and internet use disorders
Authors: Müller Kai W. , Dreier Michael , Wölfling Klaus
Published: September 2022

Purpose of review

After its initial recognition in the DSM-5, Gaming Disorder has now officially been included as a mental disorder in the ICD-11 as a behavioral addiction. In the past decades, research on this phenomenon has increased and in particular theories on its etiopathology have been suggested. In that respect, underlying factors, including neurobiological, social, and psychological factors, have been described. One commonly discussed etiological factor is supposed in specific personality traits. Knowing more about underlying personality factors of Gaming Disorder and other subtypes of internet use disorders would allow for a construction of more sophisticated etiological models, tailored prevention approaches, and would affect the specificity of treatment strategies. This overview provides information on current research on the role of the Big Five personality traits in Gaming Disorder as potential risk modifiers and maintaining factors.

Recent findings

Research has especially identified high neuroticism and low conscientiousness as correlates of Gaming Disorder. Yet, results based on prospective studies are lacking largely, although there is the first evidence that personality traits might not only act as risk modifying factors but could also be influenced by Gaming Disorder.

Suggestions for future research and the need for a more pronounced perspective taking into account the changing dynamics of personality are presented in this contribution. Addressing personality traits in treatment programs could be a promising approach in preventing patients from premature treatment termination and later relapse.
Exploring differential exon usage via short- and long-read RNA sequencing strategies
Authors: Leshkowitz Dena , Kedmi Merav , Fried Yael , Pilzer David , Keren-Shaul Hadas , Ainbinder Elena , Dassa Bareket
Published: September 2022

Alternative splicing produces various mRNAs, and thereby various protein products, from one gene, impacting a wide range of cellular activities. However, accurate reconstruction and quantification of full-length transcripts using short-reads is limited, due to their length. Long-reads sequencing technologies may provide a solution by sequencing full-length transcripts. We explored the use of both Illumina short-reads and two long Oxford Nanopore Technology (cDNA and Direct RNA) RNA-Seq reads for detecting global differential splicing during mouse embryonic stem cell differentiation, applying several bioinformatics strategies: gene-based, isoform-based and exon-based. We detected the strongest similarity among the sequencing platforms at the gene level compared to exon-based and isoform-based. Furthermore, the exon-based strategy discovered many differential exon usage (DEU) events, mostly in a platform-dependent manner and in non-differentially expressed genes. Thus, the platforms complemented each other in the ability to detect DEUs (i.e. long-reads exhibited an advantage in detecting DEUs at the UTRs, and short-reads detected more DEUs). Exons within 20 genes, detected in one or more platforms, were here validated by PCR, including key differentiation genes, such as Mdb3 and Aplp1. We provide an important analysis resource for discovering transcriptome changes during stem cell differentiation and insights for analysing such data.
eSexualHealth: Preferences to Use Technology to Promote Sexual Health Among Men Who Have Sex with Men and Trans and Gender Diverse People
Authors: Abraham Esha , Chow Eric PF , Fairley Christopher K , Lee David , Kong Fabian YS , Mao Limin , Goller Jane L , Medland Nicholas , Bavinton Benjamin R , Sudarto Budiadi , Joksic Stefan , Wong Jessica , Phillips Tiffany R , Ong Jason J
Published: September 2022

Objectives

Gay, bisexual and other men who have sex with men (GBMSM) and trans and gender diverse (TGD) people are disproportionately affected by poorer sexual health outcomes compared to heterosexual populations. We aimed to explore the preferences of GBMSM and TGD for using eHealth for sexual health (eSexualHealth).

Methods

We distributed an anonymous online survey among the lesbian, gay, bisexual, transgender, intersex, queer and other people of diverse sexuality or gender (LGBTIQA+) community in Australia. The survey collected data on sociodemographic characteristics and sexual behaviours, their preferences for app/website functions and preferred HIV and sexually transmitted infection (STI) testing reminders. We used descriptive statistics to summarise the characteristics of the study population. Free-text responses were thematically analysed.

Results

Of 466 participants included, most identified as cisgender males (92.7%). The median age was 48 (interquartile range [IQR]: 37-56). For accessing sexual health-related information, 160 (34.6%) would use either a website or an app, 165 (32.7%) would prefer a website, 119 (25.8%) would prefer an app, and 33 (7.1%) would not use either platform. There was no significant difference between GBMSM and TGD people. Participants were most interested in information about STI clinics, HIV/STI hotspots, and sexual health education. Participants stressed the need for privacy and anonymity when using eHealth. Regarding reminders to test for HIV/STIs, receiving regular SMS was most popular (112/293, 38.2%), followed by regular emails (55/293 18.8%) and a reminder function on their phone (48/293, 16.4%).

Conclusion

Our study suggests a promising future for eHealth among GBMSM and TGD people. Sexual health is still a stigmatised area, and eHealth may circumvent barriers this population faces.

What is already known about the topic

Gay, bisexual, and other men who have sex with men (GBMSM) and trans- and gender diverse people (TGD) have poorer sexual health outcomes compared to heterosexuals

eHealth (or digital interventions) to improve sexual health is a growing area

What this study adds

Our survey among Australian GBMSM and TGD individuals document their preferences for using eHealth to optimize their sexual health

How this study might affect research, practice or policy

Being aware of preferences for eHealth can inform resource allocation and future development of features wanted by target populations
Multi-modal mass spectrometry imaging reveals single-cell metabolic states in mammalian liver
Authors: Tian Hua , Rajbhandari Presha , Tarolli Jay , Decker Aubrianna M. , Neelakantan Taruna V. , Angerer Tina , Zandkarimi Fereshteh , Daniels Jacob , Remotti Helen , Frache Gilles , Winograd Nicholas , Stockwell Brent R.
Published: September 2022

We have developed a powerful workflow to imaging endogenous metabolism in single cells on frozen tissue, allowing us to discover new cell subtypes in human liver. Performing spatially integrated multiomics in single cells within tissues is at the leading frontier in biology but has been prevented by technological challenges. We developed a critical new technology, cryogenic water cluster ion beam secondary ion mass spectrometry imaging ((H2O)n>28K-GCIB-SIMS)) at 1 µm single-cell resolution. This allowed us to perform multi-modal mass spectrometry imaging (MSI) to detect metabolites, lipids, and proteins in single cells within functional liver zones and diverse cell types in the native tissue state. Our workflow utilizes the desorption electrospray ionization (DESI) mass spectrometry imaging (MSI) to build a reference map of metabolic heterogeneity and zonation across liver functional units. Then cryogenic (H2O)n>28K-GCIB-SIMS and C60-SIMS integrated metabolomics, lipidomic and proteomics, - characterizing the metabolic state in single cells on the same tissue section. We found for the first time that lipids and metabolites can classify liver metabolic zones and liver cell types beyond histological and protein-marker annotation. This provides a multi-modal workflow to define single-cell states in normal physiology and disease in mammalian tissue.
Identification of Rho-dependent termination sitein vivousing synthetic sRNA
Authors: Wang Xun , Paul Abishek N Monford , Jeon Heung Jin , He Jin , Lim Heon M.
Published: September 2022

Rho promotes Rho-dependent termination (RDT) at the Rho-dependent terminator, producing a variable-length region at the 3′-end of mRNA without secondary structure. Determining the exact RDT sitein vivois challenging because the 3′-end of mRNA is rapidly removed by 3′- to 5′-exoribonuclease digestion after RDT. Here, we applied synthetic sRNA (sysRNA) to pinpoint RDT sitesin vivoby exploiting its complementary base-pairing ability to target mRNA. Through the combined assays of rapid amplification of cDNA 3′-ends, primer extension, and capillary electrophoresis, we could precisely locate and quantify mRNA 3′-ends. We found that complementary double-stranded RNA (dsRNA) formed between sysRNA and mRNA was efficiently cleaved by RNase III in the middle of the dsRNA region. The formation of dsRNA seems to protect the cleaved RNA 3′-ends from rapid degradation by 3′- to 5′-exonuclease, thereby stabilizing the mRNA 3′-end. We further verified that the signal intensity at the 3′-end was positively correlated with amounts of mRNA. By constructing a series of sysRNAs with target sites in close proximity, and comparing the difference in signal intensity at the 3′-end of wild-type and Rho-impaired strains, we finally identified a region of increased mRNA expression within 21 bp range, which was determined as RDT site. Our results demonstrated the ability to use sysRNA as a novel tool to precisely localize RDTsin vivoand expanded the range of sysRNA applications.

IMPORTANCE

With the emergence of more new tools for inhibiting gene expression, sysRNA, which was once widely used, has gradually faded out of people′s attention due to its unstable inhibition effect and low inhibition efficiency. However, it remains an interesting topic as a regulatory tool due to its ease of design and low metabolic burden on cells. Here, for the first time, we discovered a new function to identify RDT sitesin vivousing sysRNA. This new feature is important because, since the discovery of the Rho protein in 1969, it has been difficult to specifically identify RDT sitesin vivodue to the rapid processing of RNA 3′-ends by exonucleases, and sysRNA might provide a new way to address this challenge.
ARDSFlag: An NLP/Machine Learning Algorithm to Visualize and Detect High-Probability ARDS Admissions Independent of Provider Recognition and Billing Codes
Authors: Gandomi Amir , Wu Phil , Clement Daniel R , Xing Jinyan , Aviv Rachel , Federbush Matthew , Yuan Zhiyong , Jing Yajun , Wei Guangyao , Hajizadeh Negin
Published: September 2022

Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by bilateral pulmonary infiltrates that cannot be explained entirely by cardiogenic pulmonary edema. ARDS is the primary cause of mortality in COVID-19 patients and one of the leading causes of morbidity and mortality in ICUs. Despite its significance and prevalence, the detection of ARDS remains highly variable and inconsistent. In this work, we develop a tool to automate the diagnosis of ARDS based on the Berlin definition to increase the accuracy of ARDS detection using electronic health record (EHR) fields. ARDSFlag applies machine learning (ML) and natural language processing (NLP) techniques to evaluate Berlin criteria by incorporating structured and unstructured data. The output is the ARDS diagnosis, onset time, and severity. We have also developed a visualization that helps clinicians efficiently assess ARDS criteria retrospectively and in real time. The method includes separate text classifiers trained using large training sets to find evidence of bilateral infiltrates in radiology reports (accuracy of 91.9%±0.5%) and heart failure/fluid overload in radiology reports (accuracy 86.1%±0.5%) and echocardiogram notes (accuracy 98.4%±0.3%). A holdout set of 300 cases, which was blindly and independently labeled for ARDS by two groups of clinicians, shows that the algorithm generates an overall accuracy of 89.0%, with a specificity of 91.7%, recall of 80.3%, and precision of 75.0%. Compared with two other ARDS identification methods used in the literature, ARDSFlag shows higher performance in all accuracy measures (an increase of 25.5% in overall accuracy, 6.5% in specificity, 44.2% in recall, 31.7% in precision, and 38.20% inF1-score over the best of the two detection methods).
The p-rpS6-zone delineates wounding response and the healing process
Authors: Ruth Ring Nadja Anneliese , Dworak Helene , Bachmann Barbara , Schädl Barbara , Valdivieso Karla , Rozmaric Tomaz , Heimel Patrick , Schuetzenberger Kornelia , Leinfellner Gabriele , Ferguson James , Drechsler Susanne , Mildner Michael , Schosserer Markus , Slezak Paul , Meyuhas Oded , Gruber Florian , Grillari Johannes , Redl Heinz , Ogrodnik Mikolaj
Published: September 2022

It is unknown what the spatial boundaries of tissue response to wounding are. Here we show that in mammals the ribosomal protein S6 (rpS6) is phosphorylated in response to skin injury forming a zone of activation surrounding the region of the initial insult. This p-rpS6-zone forms within minutes after wounding and is present until healing is complete. The zone encapsulates markers of the healing process, including proliferation, senescence, and angiogenesis in wounded skin. A mouse model unable to phosphorylate rpS6 shows an initial acceleration of wound closure, but results in disrupted healing. Finally, the p-rpS6-zone accurately reports on the status of dermal vasculature and the effectiveness of healing. In summary, the zone divides an otherwise homogenous tissue into regions with distinct properties.
SPRI: Structure-Based Pathogenicity Relationship Identifier for Predicting Effects of Single Missense Variants and Discovery of Higher-Order Cancer Susceptibility Clusters of Mutations
Authors: Wang Boshen , Lei Xue , Tian Wei , Perez-Rathke Alan , Tseng Yan-Yuan , Liang Jie
Published: September 2022

We report the Structure-based Pathogenicity Relationship Identifier (SPRI), a novel computational tool for accurate evaluation of pathological effects of missense single mutations and prediction of higher-order spatially organized units of mutational clusters. SPRI can effectively extract properties determining pathogenicity encoded in protein structures, and can identify deleterious missense mutations of germ line origin associated with Mendelian diseases, as well as mutations of somatic origin associated with cancer drivers. It compares favorably to other methods in predicting deleterious mutations. Furthermore, SPRI can discover spatially organized pathogenic higher-order spatial clusters (patHOS) of deleterious mutations, including those of low recurrence, and can be used for discovery of candidate cancer driver genes and driver mutations. We further demonstrate that SPRI can take advantage of AlphaFold2 predicted structures and can be deployed for saturation mutation analysis of the whole human proteome.
Competing females strategically combine signals and physical aggression differently from males in a polygynous tropical lizard
Authors: Ranade Devica , Karatgi Ratna , Mahishi Shrinidhi , Isvaran Kavita
Published: September 2022

Intrasexual competition, the intense competition between individuals of the same sex, is a strong evolutionary force that is well known to select for elaborate and spectacular traits in males. In contrast, female-female competition is poorly understood. Although historically expected to be weak, evidence for female-female competition is fast accumulating. Yet, systematic studies of such competition are rare. Here, we frame and test for a strategy of competition in females in a wild population of a classically polygynous lizard,Psammophilus dorsalis. We used models of femaleP. dorsalisto simulate a gradient in perceived competitor threat to individually tagged, wild females on their territories, and comprehensively measured their signalling and aggression responses. Similar experiments were performed with males. Our results clearly demonstrate a complex, threat-sensitive strategy of direct competition among females in this species with conventional sex roles. Females systematically escalate their use of diverse signals along a gradient in threat and show surprisingly high levels of physical aggression. Comparisons with the responses of males to simulated threats reveal distinct sex differences in competition strategies that match theoretical expectations derived from life history. Using these findings, we argue that female-female competition may be complex but cryptic, requiring experimental manipulations to uncover.
Multi-scale spatial modeling of immune cell distributions enables survival prediction in primary central nervous system lymphoma
Authors: Roemer Margaretha G.M. , van de Brug Tim , Bosch Erik , Berry Daniella , Hijmering Nathalie , Stathi Phylicia , Weijers Karin , Doorduijn Jeannette , Bromberg Jacoline , van de Wiel Mark , Ylstra Bauke , de Jong Daphne , Kim Yongsoo
Published: September 2022

To understand the clinical significance of the tumor microenvironment (TME), it is essential to study the interactions between malignant and non-malignant cells in clinical specimens. Here, we established a computational framework for a multiplex imaging system to comprehensively characterize spatial contexts of the TME at multiple scales, including close and long-distance spatial interactions between cell type pairs. We applied this framework to a total of 1,393 multiplex imaging data newly generated from 88 primary central nervous system lymphomas with complete follow-up data and identified significant prognostic subgroups mainly shaped by the spatial context. A supervised analysis confirmed a significant contribution of spatial context in predicting patient survival. In particular, we found an opposite prognostic value of macrophage infiltration depending on its proximity to specific cell types. Altogether, we provide a comprehensive framework to analyze spatial cellular interaction that can be broadly applied to other technologies and tumor contexts.
Spatial tumour gene signature discriminates neoplastic from non-neoplastic compartments in colon cancer: unravelling predictive biomarkers for relapse
Authors: Sallinger Katja , Gruber Michael , Müller Christin-Therese , Bonstingl Lilli , Pritz Elisabeth , Pankratz Karin , Gerger Armin , Smolle Maria Anna , Aigelsreiter Ariane , Surova Olga , Svedlund Jessica , Nilsson Mats , Kroneis Thomas , El-Heliebi Amin
Published: September 2022

Background

Therapeutic management of stage II colon cancer remains difficult regarding the decision whether adjuvant chemotherapy should be administered or not. Low rates of recurrence are opposed to chemotherapy induced toxicity and current clinical features are limited in predicting disease relapse. Predictive biomarkers are urgently needed and we hypothesise that the spatial tissue composition of relapsed and non-relapsed colon cancer stage II patients reveals relevant biomarkers.

Methods

The spatial tissue composition of stage II colon cancer patients was examined by in situ sequencing technology with sub-cellular resolution. A panel of 175 genes was designed investigating specific cancer-associated processes and components of the tumour microenvironment. We identified a tumour gene signature to subclassify tissue into neoplastic and non-neoplastic tissue compartments based on spatial expression patterns generated by in situ sequencing (GTC-tool – Genes-To-Count).

Results

The GTC-tool automatically identified tissue compartments that were used to quantify gene expression of biological processes upregulated within the neoplastic tissue in comparison to non-neoplastic tissue and within relapsed versus non-relapsed stage II colon patients. Three differentially expressed genes (FGFR2, MMP11 and OTOP2) in the neoplastic tissue compartments of relapsed patients in comparison to non-relapsed patients were identified predicting recurrence in stage II colon cancer.

Conclusions

In depth spatial in situ sequencing revealed novel potential predictive biomarkers for disease relapse in colon cancer stage II patients. Our developed open-access GTC-tool allows to accurately capture the tumour compartment and quantify spatial gene expression in colon cancer tissue.
miR-28 plus ibrutinib as a novel combination therapy for Diffuse Large B Cell Lymphoma
Authors: Fuertes Teresa , Álvarez-Corrales Emigdio , Ubieto-Capella Patricia , Serrano-Navarro Álvaro , Gómez-Escolar Carmen , de Molina Antonio , Méndez Juan , Ramiro Almudena R. , de Yébenes Virginia G.
Published: September 2022

Diffuse large B cell lymphoma (DLBCL) is the most common aggressive B cell lymphoma and accounts for nearly 40% of cases of B cell non-Hodgkin lymphoma. DLBCL is generally treated with R-CHOP chemotherapy, but many patients do not respond or relapse after treatment. Here, we analyzed the therapeutic potential of the tumor suppressor microRNA-28 (miR-28) for DLBCL, alone and in combination with the Bruton’s tyrosine kinase inhibitor ibrutinib. Combination therapy with miR-28 plus ibrutinib potentiated the anti-tumor effects of monotherapy with either agent by inducing a specific transcriptional cell-cycle arrest program that impairs DNA replication. Moreover, we found that downregulation of the miR-28-plus-ibrutinib gene signature correlates with better survival of ABC-DLBCL patients. These results provide evidence for the effectiveness of a new miRNA-based ibrutinib combination therapy for DLBCL and unveil the miR-28-plus-ibrutinib gene signature as a new predictor of outcome in ABC-DLBCL patients.

STATEMENT OF SIGNIFICANCE

This study demonstrates that a miRNA-based combination therapy with ibrutinib is superior to both monotherapies in DLBCL. miR-28 plus ibrutinib combined therapy inhibits DLBCL growth through the induction of a transcriptional program that impairs DNA replication. Our results provide a new gene signature with prognostic value for ABC-DLBCL.
Analysis of noisy transient signals based on Gaussian process regression
Authors: Baglaeva I. , Iaparov B. , Zahradník I. , Zahradníková A.
Published: September 2022

Dynamic systems such as cells or tissues generate, either spontaneously or in response to stimuli, transient signals that carry information about the system. Characterization of recorded transients is often hampered by a low signal-to-noise ratio (SNR). Reduction of the noise by filtering has limited use due to partial signal distortion. Occasionally, transients can be approximated by a mathematical function, but such a function may not hold correctly if recording conditions change. We introduce here the model-independent approximation method for general noisy transient signals based on the Gaussian process regression (GPR). The method was implemented in the software TransientAnalyzer, which detects transients in a record, finds their best approximation by the Gaussian process, constructs a surrogate spline function, and estimates specified signal parameters. The method and software were tested on a cellular model of the calcium concentration transient corrupted by various SNR levels and recorded at a low sampling frequency. Statistical analysis of the model data sets provided the error of estimation <7.5% and the coefficient of variation of estimates <17% for peak SNR=5. The performance of GPR on signals of diverse experimental origin was even better than fitting by a function. The software and its description are available on GitHub.

Statement of Significance

Transient signals convey information on the state and function of the studied system. However, the estimation of their characteristic parameters is complicated by the noise present in the recordings. Methods used for noise reduction have various disadvantages, such as distortion of the time course by filtering, the difficult superposition of many transients for accurate averaging, or a lack of a model for data fitting. In this work, we present a general method for the automatic analysis of noisy transient signals based on Gaussian process regression and its implementation in Python. The method can analyze recorded transients reliably at peak SNR ≥ 2 with a precision equivalent to the model-fitting methods.
The clone wars: the Japanese knotweed (Fallopia japonica) vs the black vine weevil (Otiorhynchus sulcatus) – characterization of a potential herbivory
Authors: Teulier Loic , Puijalon Sara , Boisselet Christelle , Piola Florence
Published: September 2022

The Japanese knotweed (Fallopia japonica) is considered as highly invasive in Europe and is largely widespread in France, without any established predator. This short study first characterized the herbivory of Fallopia by the black vine weevil (Otiorhynchus sulcatus), a commonly encountered coleopteran in France. Through an experimental design of leaf choices, between Fragaria spp. and Fallopia spp., our results show that the insects prefer Fallopia, even if it is presented for the first time. Even if this simple observation may appear as trivial, it highlights a novel plant-insect interaction and may start new insight in plant control or invasion management.
Inferring sparse structure in genotype-phenotype maps
Authors: Petti Samantha , Reddy Gautam , Desai Michael M.
Published: September 2022

Correlation among multiple phenotypes across related individuals may reflect some pattern of shared genetic architecture: individual genetic loci affect multiple phenotypes (an effect known as pleiotropy), creating observable relationships between phenotypes. A natural hypothesis is that pleiotropic effects reflect a relatively small set of common “core” cellular processes: each genetic locus affects one or a few core processes, and these core processes in turn determine the observed phenotypes. Here, we propose a method to infer such structure in genotype-phenotype data. Our approach,sparse structure discovery(SSD) is based on a penalized matrix decomposition designed to identify latent structure that is low-dimensional (many fewer core processes than phenotypes and genetic loci), locus-sparse (each locus affects few core processes) and/or phenotype-sparse (each phenotype is influenced by few core processes). Our use of sparsity as a guide in the matrix decomposition is motivated by the results of a novel empirical test indicating evidence of sparse structure in several recent genotype-phenotype data sets. First, we use synthetic data to show that our SSD approach can accurately recover core processes if each genetic locus affects few core processes or if each phenotype is affected by few core processes. Next, we apply the method to three datasets spanning adaptive mutations in yeast, genotoxin robustness assay in human cell lines, and genetic loci identified from a yeast cross, and evaluate the biological plausibility of the core process identified. More generally, we propose sparsity as a guiding prior for resolving latent structure in empirical genotype-phenotype maps.
Learning the sound inventory of a complex vocal skill via an intrinsic reward
Authors: Toutounji Hazem , Zai Anja T. , Tchernichovski Ofer , Hahnloser Richard H.R. , Lipkind Dina
Published: September 2022

Reinforcement learning (RL) is thought to underlie the acquisition of vocal skills like birdsong and speech, where sounding like one’s “tutor” is rewarding. Yet, we find that the standard actor-critic RL model of birdsong learning fails to account for juvenile zebra finches’ efficient learning of an inventory of multiple syllables. But when we replace a single actor with multiple independent actors that jointly maximize a common intrinsic reward, then birds’ empirical learning trajectories are accurately reproduced. Importantly, the influence of each actor (syllable) on the magnitude of global reward is competitively determined by its acoustic similarity to target syllables. This leads to each actor matching the target it is closest to, and occasionally, to the competitive exclusion of an actor from the learning process (i.e., the learned song). We propose that a competitive-cooperative multi-actor (MARL) algorithm is key for the efficient learning of the action inventory of a complex skill.
The ubiquitin conjugase Rad6 mediates ribosome pausing during oxidative stress
Authors: Meydan Sezen , Barros Géssica C. , Simões Vanessa , Harley Lana , Cizubu Blanche K. , Guydosh Nicholas R. , Silva Gustavo M.
Published: September 2022

Oxidative stress causes K63-linked ubiquitination of ribosomes by the E2 ubiquitin conjugase, Rad6. How Rad6-mediated ubiquitination of ribosomes affects global translation, however, is unclear. We therefore performed Ribo-seq and Disome-seq in Saccharomyces cerevisiae, and found that oxidative stress caused ribosome pausing at specific amino acid motifs, and this also led to ribosome collisions. However, these redox pausing signatures were lost in the absence of Rad6 but did not depend on the ribosome-associated quality control (RQC) pathway. We also found that Rad6 is needed to inhibit overall translation in response to oxidative stress and its deletion leads to increased expression of antioxidant genes. Finally, we observed that the lack of Rad6 leads to changes during translation initiation that affect activation of the integrated stress response (ISR) pathway. Our results provide a high-resolution picture of the gene expression changes during oxidative stress and unravel an additional stress response pathway affecting translation elongation.

HIGHLIGHTS

Rad6 is required for sequence-specific ribosome pausing under oxidative stress.

Rad6 affects translation independently of the RQC pathway.

Cells lacking Rad6 show dysregulated translational repression upon oxidative stress.

Loss of Rad6 leads to altered activation of the ISR pathway.