bluuebunny/crossref_metadata_2025 huggingface dataset:
FGF homologous factors are secreted from cells to induce FGFR‐mediated anti‐apoptotic response
Authors: Biadun Martyna , Sochacka Martyna , Karelus Radoslaw , Baran Karolina , Czyrek Aleksandra , Otlewski Jacek , Krowarsch Daniel , Opalinski Lukasz , Zakrzewska Malgorzata
Published: June 2023

FGF homologous factors (FHFs) are the least described group of fibroblast growth factors (FGFs). The FHF subfamily consists of four proteins: FGF11, FGF12, FGF13, and FGF14. Until recently, FHFs were thought to be intracellular, non‐signaling molecules, despite sharing structural and sequence similarities with other members of FGF family that can be secreted and activate cell signaling by interacting with surface receptors. Here, we show that despite lacking a canonical signal peptide for secretion, FHFs are exported to the extracellular space. Furthermore, we propose that their secretion mechanism is similar to the unconventional secretion of FGF2. The secreted FHFs are biologically active and trigger signaling in cells expressing FGF receptors (FGFRs). Using recombinant proteins, we demonstrated their direct binding to FGFR1, resulting in the activation of downstream signaling and the internalization of the FHF‐FGFR1 complex. The effect of receptor activation by FHF proteins is an anti‐apoptotic response of the cell.
Fibrocytes enhance mammary gland fibrosis in obesity
Authors: Kuziel Genevra , Moore Brittney N. , Haugstad Grace P. , Arendt Lisa M.
Published: June 2023

Obesity rates continue to rise, and obese individuals are at higher risk for multiple types of cancer, including breast cancer. Obese mammary fat is a site of chronic, macrophage‐driven inflammation, which enhances fibrosis within adipose tissue. Elevated fibrosis within the mammary gland may contribute to risk for obesity‐associated breast cancer. To understand how inflammation due to obesity enhanced fibrosis within mammary tissue, we utilized a high‐fat diet model of obesity and elimination of CCR2 signaling in mice to identify changes in immune cell populations and their impact on fibrosis. We observed that obesity increased a population of CD11b+ cells with the ability to form myofibroblast‐like colonies in vitro. This population of CD11b+ cells is consistent with fibrocytes, which have been identified in wound healing and chronic inflammatory diseases but have not been examined in obesity. In CCR2‐null mice, which have limited ability to recruit myeloid lineage cells into obese adipose tissue, we observed reduced mammary fibrosis and diminished fibrocyte colony formation in vitro. Transplantation of myeloid progenitor cells, which are the cells of origin for fibrocytes, into the mammary glands of obese CCR2‐null mice resulted in significantly increased myofibroblast formation. Gene expression analyses of the myeloid progenitor cell population from obese mice demonstrated enrichment for genes associated with collagen biosynthesis and extracellular matrix remodeling. Together these results show that obesity enhances recruitment of fibrocytes to promote obesity‐induced fibrosis in the mammary gland.
Rate of Refracture After Removal of Hardware in Pediatric Femur Fractures
Authors: Siu Jeremy W. , Chan Chloe , Swarup Ishaan , Sabatini Coleen S.
Published: June 2023

Purpose:

Both flexible intramedullary nails (FINs) and plate osteosynthesis are commonly used for the treatment of femoral shaft fractures in pediatric patients. The purpose of this study is to determine the refracture rate after hardware removal in pediatric femur fractures.

Methods:

This is a retrospective cohort study that utilized the Pediatric Health Information System database to determine the number of pediatric patients ages 4 to 10 who underwent surgical fixation of a femur fracture and subsequent hardware removal between the years 2015 and 2019. All patients had a minimum of a 2-year follow-up to assess for refracture. Patients with metabolic bone disease, neuromuscular conditions, bone fragility disorders, nutritional deficiencies, and pathologic fractures were excluded.

Results:

Of the total, 2805 pediatric patients with 2881 femoral shaft fractures who underwent FIN (48.4%), plate fixation (36.1%), splinting/casting (14.9%), or external fixation (0.6%) were included. The mean age of patients with index fracture was 7.2 years (SD, 2.1) and 69% were males. Eight hundred eighty patients (60%) in the FIN group had their hardware removed compared with 693 patients (68%) in the plate fixation group (P = 0.07), at an average of 287 ± 191 days versus 320 ± 203 days (P = 0.03). Refracture occurred in 13 patients (1.5%) who had their hardware retained and in 21 patients (1.4%) who had their hardware removed (P = 0.732). Among 65% of patients who underwent hardware removal, refracture occurred in 7 patients with FIN (0.8%) and 14 patients with plate fixation (2.2%) (P = 0.04). Refracture occurred within 365 days from hardware removal in 1 patient with FIN (0.1%) and 7 patients with plate fixation (1%) (P = 0.01). In logistic regression, patients with FIN fixation had lower odds of refracture after hardware removal compared with plate fixation (adjusted odds ratio: 0.39; 95% CI: 0.15-0.97). Age and payor status did not reach statistical significance in multivariate analysis.

Conclusions:

The rate of refracture after hardware removal for pediatric patients with a femoral shaft fracture was similar between patients with hardware retained and removal. However, patients with FIN had a lower rate of refracture AFTER hardware removal compared with plate fixation. This information can be helpful for advising families regarding the risks of refracture after hardware removal.

Level of Evidence

Level IV—retrospective cohort study.
“A Lot to Offer”: Nurses as Educators for Medical Residents in an Academic Medical Center Intensive Care Unit
Authors: Petri Camille R. , Beltran Christine P. , Russell Kristin , FitzGerald Jacqueline , Sullivan Amy M. , Anandaiah Asha M.
Published: June 2023

Introduction:

The role of fully trained interprofessional clinicians in educating residents has not been rigorously explored. The intensive care unit (ICU), where multiprofessional teamwork is essential to patient care, represents an ideal training environment in which to study this role. This study aimed to describe the practices, perceptions, and attitudes of ICU nurses regarding teaching medical residents and to identify potential targets to facilitate nurse teaching.

Methods:

Using a concurrent mixed-methods approach, we administered surveys and focus groups to ICU nurses from September to November 2019 at a single, urban, tertiary, academic medical center. Survey data were analyzed with descriptive and comparative statistics. Focus group data were analyzed using the Framework method of content analysis.

Results:

Of nurses surveyed, 75 of 96 (78%) responded. Nurses generally held positive attitudes about teaching residents, describing it as both important (52%, 36/69) and enjoyable (64%, 44/69). Nurses reported confidence in both clinical knowledge base (80%, 55/69) and teaching skills (71%, 49/69), but identified time, uncertainty about teaching topics, and trainee receptiveness as potential barriers. Ten nurses participated in focus groups. Qualitative analysis revealed three major themes: nurse-specific factors that impact teaching, the teaching environment, and facilitators of teaching.

Discussion:

ICU nurses carry positive attitudes about teaching residents, particularly when facilitated by the attending, but this enthusiasm can be attenuated by the learning environment, unknown learner needs, and trainee attitudes. Identified facilitators of nurse teaching, including resident presence at the bedside and structured opportunities for teaching, represent potential targets for interventions to promote interprofessional teaching.
Comparison of various prediction models in the effect of laparoscopic sleeve gastrectomy on type 2 diabetes mellitus in the Chinese population 5 years after surgery
Authors: Yu Chengyuan , Wang Liang , Xu Guangzhong , Chen Guanyang , Sang Qing , Wuyun Qiqige , Wang Zheng , Tian Chenxu , Zhang Nengwei
Published: June 2023

Background:

The effect of bariatric surgery on type 2 diabetes mellitus (T2DM) control can be assessed based on predictive models of T2DM remission. Various models have been externally verified internationally. However, long-term validated results after laparoscopic sleeve gastrectomy (LSG) surgery are lacking. The best model for the Chinese population is also unknown.

Methods:

We retrospectively analyzed Chinese population data 5 years after LSG at Beijing Shijitan Hospital in China between March 2009 and December 2016. The independent t-test, Mann–Whitney U test, and chi-squared test were used to compare characteristics between T2DM remission and non-remission groups. We evaluated the predictive efficacy of each model for long-term T2DM remission after LSG by calculating the area under the curve (AUC), sensitivity, specificity, Youden index, positive predictive value (PPV), negative predictive value (NPV), and predicted-to-observed ratio, and performed calibration using Hosmer–Lemeshow test for 11 prediction models.

Results:

We enrolled 108 patients, including 44 (40.7%) men, with a mean age of 35.5 years. The mean body mass index was 40.3 ± 9.1 kg/m2, the percentage of excess weight loss (%EWL) was (75.9 ± 30.4)%, and the percentage of total weight loss (%TWL) was (29.1± 10.6)%. The mean glycated hemoglobin A1c (HbA1c) level was (7.3 ± 1.8)% preoperatively and decreased to (5.9 ± 1.0)% 5 years after LSG. The 5-year postoperative complete and partial remission rates of T2DM were 50.9% [55/108] and 27.8% [30/108], respectively. Six models, i.e., "ABCD", individualized metabolic surgery (IMS), advanced-DiaRem, DiaBetter, Dixon et al's regression model, and Panunzi et al's regression model, showed a good discrimination ability (all AUC >0.8). The "ABCD" (sensitivity, 74%; specificity, 80%; AUC, 0.82 [95% confidence interval [CI]: 0.74–0.89]), IMS (sensitivity, 78%; specificity, 84%; AUC, 0.82 [95% CI: 0.73–0.89]), and Panunzi et al's regression models (sensitivity, 78%; specificity, 91%; AUC, 0.86 [95% CI: 0.78–0.92]) showed good discernibility. In the Hosmer–Lemeshow goodness-of-fit test, except for DiaRem (P <0.01), DiaBetter (P <0.01), Hayes et al (P = 0.03), Park et al (P = 0.02), and Ramos-Levi et al's (P <0.01) models, all models had a satifactory fit results (P >0.05). The P values of calibration results of the "ABCD" and IMS were 0.07 and 0.14, respectively. The predicted-to-observed ratios of the "ABCD" and IMS were 0.87 and 0.89, respectively.

Conclusion:

The prediction model IMS was recommended for clinical use because of excellent predictive performance, good statistical test results, and simple and practical design features.
Nanotherapeutics for the Myocardium: A Potential Alternative for Treating Cardiac Diseases
Authors: Kar Abhik , Gupta Soumyadeep , Matilal Arkapravo , Kumar Debaditya , Sarkar Sagartirtha
Published: June 2023

Cardiovascular diseases (CVDs) are the foremost cause of morbidity and mortality worldwide. Current clinical interventions include invasive approaches for progressed conditions and pharmacological assistance for initial stages, which has systemic side effects. Preventive, curative, diagnostic, and theranostic (therapeutic + diagnostic) approaches till date are not very useful in combating the ongoing CVD epidemic, which demands a promising efficient alternative approach. To combat the growing CVD outbreak globally, the ideal strategy is to make the therapeutic intervention least invasive and direct to the heart to reduce the bystander effects on other organs and increase the bioavailability of the therapeutics to the myocardium. The application of nanoscience and nanoparticle-mediated approaches have gained a lot of momentum because of their efficient passive and active myocardium targeting capability owing to their improved specificity and controlled release. This review provides extensive insight into the various types of nanoparticles available for CVDs, their mechanisms of targeting (eg, direct or indirect), and the utmost need for further development of bench-to-bedside cardiac tissue–based nanomedicines. Furthermore, the review aims to summarize the different ideas and methods of nanoparticle-mediated therapeutic approaches to the myocardium till date with present clinical trials and future perspectives. This review also reflects the potential of such nanoparticle-mediated tissue-targeted therapies to contribute to the sustainable development goals of good health and well-being.
Innsbruck-style Retromandibular Anterior Trans-parotid Approach for Condylar Fractures: A Retrospective Review of 39 Fractures
Authors: Sasaki Ryo , Watanabe Yorikatsu , Miyamoto Noriko Sangu , Agawa Kaori , Okamoto Toshihiro
Published: June 2023

Background:

The retromandibular anterior trans-parotid (RAT) approach and a triangular-positioned double mini-plate osteosynthesis (TDO) technique have been reported from Innsbruck Medical University. This minimally invasive technique involves direct visualization of the condyle and is associated with lower incidence of facial palsy.

Methods:

A retrospective review was performed on the RAT approach and TDO technique conducted by a surgeon and team at two hospitals in Tokyo during a period of 3 years and 10 months.

Results:

This technique was performed on 35 patients with 39 condylar fractures. Sixty-nine percent of cases were due to accidental fall, 17% to traffic accidents, and 9% to sports. Furthermore, 92% cases were condylar base fractures. Nighty-seven percent of cases achieved good occlusion. The mean maximum mouth opening was 49 ± 1.3 mm. Postoperatively, facial palsy developed in three patients (7.7%), and two of them developed Frey syndrome at approximately 2.5 years postoperatively (5.1%). All patients completely recovered within 3 months postoperatively. One case each of salivary fistula, visible scar, and condylar resorption was found (2.6%). No case of massive bleeding during surgery, hematoma, or TMJ pain after surgery was found.

Conclusion:

This technique could achieve good occlusion with low incidence of complications and could contribute to early social reintegration among patients.
Productivity Loss of Temporary Work Absenteeism Due to COVID-19 and Its Determinant Factors in Northeastern Iran
Authors: Keyvanlo Zahra , Javan-Noughabi Javad , Heidari Jamebozorgi Majid , Kargar Mohammad , Samadipour Ezat
Published: June 2023

Objective

This study aimed to estimate the lost productivity cost of temporary work absenteeism due to COVID-19.

Methods

This study conducted on all hospitalized patients with COVID-19 in northeastern Iran between February 2020 and March 2022 (10,406 cases). Data were collected from the Hospital Information System. Indirect costs were estimated using the human capital approach. Data were analyzed with the STATA version 17.

Results

The total indirect cost of work absenteeism due to COVID-19 was estimated at $513,688. There was a statistically significant relationship between the mean lost productivity cost and COVID-19 peak, sex, insurance type, age, and hospitalization.

Conclusions

Because the absenteeism costs of COVID-19 had increased in the second peak, which coincided with the summer holidays, the country’s crisis management headquarters should pay more attention to formulating and implementing appropriate preventive programs in future epidemics.
Psychological Impacts of the COVID-19 Pandemic on Canadian Healthcare Workers
Authors: Turner Brianna J. , Welch Brooke E. , Legg Nicole K. , Phiri Peter , Rathod Shanaya , Paterson Theone S. E.
Published: June 2023

Objective

The aim of the study is to describe mental health impacts of the COVID-19 pandemic and identify roles that predict distress among Canadian healthcare workers (HCWs).

Methods

Using data from three cross-sectional Canadian surveys, we compared 799 HCWs to demographically matched controls and compared HCWs with and without COVID-19 patient contact. Participants completed validated measures of depression, anxiety, trauma-related stress, alcohol problems, coping self-efficacy, and sleep quality.

Results

Non-HCWs reported more depression and anxiety in Fall 2020 and more alcohol problems in Fall/Winter 2021 than HCWs. In Winter 2020–2021, HCWs reported more trauma-related stress than non-HCWs. As of early 2021, HCWs with direct patient contact reported worse symptoms across nearly all measures than HCWs without.

Conclusions

Although Canadian HCWs did not report worse mental health than demographically similar peers, mental health supports are needed for HCWs providing direct patient care.
Adding Safety Rules to Surgeon-Authored Virtual Reality Training
Authors: Gao Ruiliang , Kurenov Sergei , Black Erik W. , Peters Jörg
Published: June 2023

Introduction

The Toolkit for Illustration of Procedures in Surgery (TIPS) is an open source virtual reality (VR) laparoscopic simulation-based training environment with force feedback. The TIPS-author is a content creation interface that allows a surgeon educator (SE) to assemble new laparoscopic training modules. New technology enables safety rules to be specified by the SE, automatically tracks specified safety errors, and summarizes and communicates achievements and errors to the surgical trainee.

Methods

The TIPS-author combines and initializes building blocks of anatomy with their physical properties, as selected by the SE from a database. The SE can add any safety rule that can be tested in terms of location, proximity, separation, clip count, and force. Errors are then automatically monitored during simulation and recorded as visual snapshots for feedback to the trainee. The TIPS was field tested at 2 surgical conferences, one before and one after adding the error snapshot feature.

Results

Sixty-four respondents at 2 surgical conferences assessed the utility of TIPS on a Likert scale. While other ratings remained unchanged for an overall score of 5.24 of 7 (7 = very useful), the rating of the statement “The TIPS interface helps learners understand the force necessary to explore the anatomy” improved from 5.04 to 5.35 of 7 after the snapshot mechanism was added.

Conclusions

The ratings indicate the viability of the TIPS open source SE-authored surgical training units with safety rules. Presenting SE-determined procedural missteps via the snapshot mechanism at the end of the training increases perceived utility.
Female reproductive fluid attracts more and better sperm: implications for within-ejaculate cryptic female choice
Authors: Cattelan Silvia , Devigili Alessandro , Santacà Maria , Gasparini Clelia
Published: June 2023

Mounting evidence shows that the female reproductive fluid (FRF) can differently affect sperm performance of different males by biasing paternity share among competing males. Here, we tested for the first time the potential of ‘within-ejaculate cryptic female choice’ mediated by the FRF in the zebrafish (
Danio rerio
). Using a recently developed sperm selection chamber, we separated and collected FRF-selected from non-selected sperm to compare the two subpopulations of sperm in terms of sperm number, viability, DNA integrity and fertilizing ability. We showed that the sperm attracted by FRF are more numerous, more viable and with higher DNA integrity. In addition, FRF-selected sperm fertilized more eggs, but if this is due to fertilization ability
per se
or numerical advantage remains to be tested. Our results suggest that FRF can select sperm with a better phenotype, highlighting the crucial and impactful role that FRF might play in the process of fertilization and post-mating sexual selection dynamics, along with the potential implications for sperm selection in assisted reproductive techniques.
Chimpanzees prepare for alternative possible outcomes
Authors: Engelmann Jan M. , Völter Christoph J. , Goddu Mariel K. , Call Josep , Rakoczy Hannes , Herrmann Esther
Published: June 2023

When facing uncertainty, humans often build mental models of alternative outcomes. Considering diverging scenarios allows agents to respond adaptively to different actual worlds by developing contingency plans (covering one's bases). In a pre-registered experiment, we tested whether chimpanzees (
Pan troglodytes
) prepare for two mutually exclusive possibilities. Chimpanzees could access two pieces of food, but only if they successfully protected them from a human competitor. In one condition, chimpanzees could be certain about which piece of food the human experimenter would attempt to steal. In a second condition, either one of the food rewards was a potential target of the competitor. We found that chimpanzees were significantly more likely to protect both pieces of food in the second relative to the first condition, raising the possibility that chimpanzees represent and prepare effectively for different possible worlds.
Differences in airborne stability of SARS-CoV-2 variants of concern is impacted by alkalinity of surrogates of respiratory aerosol
Authors: Haddrell Allen , Otero-Fernandez Mara , Oswin Henry , Cogan Tristan , Bazire James , Tian Jianghan , Alexander Robert , Mann Jamie F. S. , Hill Darryl , Finn Adam , Davidson Andrew D. , Reid Jonathan P.
Published: June 2023

The mechanistic factors hypothesized to be key drivers for the loss of infectivity of viruses in the aerosol phase often remain speculative. Using a next-generation bioaerosol technology, we report measurements of the aero-stability of several SARS-CoV-2 variants of concern in aerosol droplets of well-defined size and composition at high (90%) and low (40%) relative humidity (RH) upwards of 40 min. When compared with the ancestral virus, the infectivity of the Delta variant displayed different decay profiles. At low RH, a loss of viral infectivity of approximately 55% was observed over the initial 5 s for both variants. Regardless of RH and variant, greater than 95% of the viral infectivity was lost after 40 min of being aerosolized. Aero-stability of the variants correlate with their sensitivities to alkaline pH. Removal of all acidic vapours dramatically increased the rate of infectivity decay, with 90% loss after 2 min, while the addition of nitric acid vapour improved aero-stability. Similar aero-stability in droplets of artificial saliva and growth medium was observed. A model to predict loss of viral infectivity is proposed: at high RH, the high pH of exhaled aerosol drives viral infectivity loss; at low RH, high salt content limits the loss of viral infectivity.
Emergent technological variation in archaeological landscapes: a primate perspective
Authors: Reeves Jonathan S. , Proffitt Tomos , Malaivijitnond Suchinda , Luncz Lydia V.
Published: June 2023

Archaeological evidence informs our understanding of the evolution of hominin behaviour. Such evidence is traditionally used to reconstruct hominin activities and intentions. In the Plio-Pleistocene, the presence or absence of specific tools and variation in artefact density is often used to infer foraging strategies, cognitive traits and functional activities. However, the Plio-Pleistocene archaeological record is known to be time-averaged and forms through the aggregation of repeated behavioural events over time. Thus, archaeological patterns do not reflect discrete episodes of activity, but rather the interaction of behaviour with environmental factors over time. However, little is known about how such interactions produce archaeological variation diversity. Primate archaeology can help address this research gap by providing the opportunity to observe how behaviour produces material patterns in a natural setting. This study, thus, examines how varying the material properties of stone and resource availability influence the artefactual signature of nut-cracking in a population of long-tailed macaques from Lobi Bay, Yao Noi island, Thailand. Results show that these interactions can produce a structured and diverse material signature in terms of artefact density and frequency of specific artefact types. These findings demonstrate how material patterns can emerge from long-term interactions between behaviour and environmental factors.
Rapamycin supplementation ofDrosophila melanogasterlarvae results in less viable adults with smaller cells
Authors: Szlachcic Ewa , Dańko Maciej J. , Czarnoleski Marcin
Published: June 2023

The intrinsic sources of mortality relate to the ability to meet the metabolic demands of tissue maintenance and repair, ultimately shaping ageing patterns. Anti-ageing mechanisms compete for resources with other functions, including those involved in maintaining functional plasma membranes. Consequently, organisms with smaller cells and more plasma membranes should devote more resources to membrane maintenance, leading to accelerated intrinsic mortality and ageing. To investigate this unexplored trade-off, we rearedDrosophila melanogasterlarvae on food with or without rapamycin (a TOR pathway inhibitor) to produce small- and large-celled adult flies, respectively, and measured their mortality rates. Males showed higher mortality than females. As expected, small-celled flies (rapamycin) showed higher mortality than their large-celled counterparts (control), but only in early adulthood. Contrary to predictions, the median lifespan was similar between the groups. Rapamycin administered to adults prolongs life; thus, the known direct physiological effects of rapamycin cannot explain our results. Instead, we invoke indirect effects of rapamycin, manifested as reduced cell size, as a driver of increased early mortality. We conclude that cell size differences between organisms and the associated burdens of plasma membrane maintenance costs may be important but overlooked factors influencing mortality patterns in nature.
Hummingbird ingestion of low-concentration ethanol within artificial nectar
Authors: Choi Julia , Lee Lilianne , Maro Aleksey , Corl Ammon , McGuire Jimmy A. , Bowie Rauri C. K. , Dudley Robert
Published: June 2023

Both frugivores and nectarivores are potentially exposed to dietary ethanol produced by fermentative yeasts which metabolize sugars. Some nectarivorous mammals exhibit a preference for low-concentration ethanol solutions compared to controls of comparable caloric content, but behavioural responses to ethanol by nectar-feeding birds are unknown. We investigated dietary preference by Anna's Hummingbirds (
Calypte anna
) for ethanol-enhanced sucrose solutions. Via repeated binary-choice experiments, three adult male hummingbirds were exposed to sucrose solutions containing 0%, 1% or 2% ethanol; rates of volitional nectar consumption were measured over a 3 h interval. Hummingbirds did not discriminate between 0% and 1% ethanol solutions, but exhibited significantly reduced rates of consumption of a 2% ethanol solution. Opportunistic measurements of ethanol concentrations within hummingbird feeders registered values peaking at about 0.05%. Ethanol at low concentrations (i.e. up to 1%) is not aversive to Anna's Hummingbirds and may be characteristic of both natural and anthropogenic nectars upon which they feed. Given high daily amounts of nectar consumption by hummingbirds, chronic physiological exposure to ethanol can thus be substantial, although naturally occurring concentrations within floral nectar are unknown.
General intelligence requires rethinking exploration
Authors: Jiang Minqi , Rocktäschel Tim , Grefenstette Edward
Published: June 2023

We are at the cusp of a transition from ‘learning from data’ to ‘learning what data to learn from’ as a central focus of artificial intelligence (AI) research. While the first-order learning problem is not completely solved, large models under unified architectures, such as transformers, have shifted the learning bottleneck from how to effectively train models to how to effectively acquire and use task-relevant data. This problem, which we frame asexploration, is a universal aspect of learning in open-ended domains like the real world. Although the study of exploration in AI is largely limited to the field of reinforcement learning, we argue that exploration is essential to all learning systems, including supervised learning. We propose the problem ofgeneralized explorationto conceptually unify exploration-driven learning between supervised learning and reinforcement learning, allowing us to highlight key similarities across learning settings and open research challenges. Importantly, generalized exploration is a necessary objective for maintaining open-ended learning processes, which in continually learning to discover and solve new problems, provides a promising path to more general intelligence.
Expansion of a low-cost, saliva-based PCR test for the detection of mpox virus
Authors: Thomas Russell J , Allicock Orchid M. , Yolda-Carr Devyn , Fajardo Katherine , Steel Sydney A. , Blacklock Chessley B. , Zepeda Theresa , Brownlee Maurice , Saladi Shyam , Parkin James , Wyllie Anne L.
Published: June 2023

Background

Current recommendations for the diagnosis of mpox rely on lesion-swabs as the gold-standard specimen type, even though many patients experience symptoms prior to lesion-onset. Alternative sample types, such as saliva, which enable earlier detection could bolster the mpox response by mitigating transmission and facilitating access to antiviral treatments.

Methods

We evaluated five PCR assays and compared their detection of mpox DNA extracted from 30 saliva specimens collected in Spectrum SDNA-1000 tubes. We sequenced seven mpox-positive samples and assessed concordance with the primers and probes of the PCR assays. Following, we incorporated these PCR assays into a simplified, extraction-free protocol to evaluate its feasibility for testing raw (unsupplemented) saliva samples. To further explore the potential of this approach, we investigated the stability of mpox detection in raw saliva diluted 1:10 and 1:100 in mpox-negative saliva, after storage at 4°C, room temperature (∼19°C), 30°C, and 40°C for 72 hours and through simulated shipping conditions.

Results

Despite identifying three nucleotide substitutions in the CDC’s Monkeypox virus Generic Real-Time PCR Test’s primer sequences, we observed no difference in the mean Ct-values generated between assays. We successfully incorporated each assay into our saliva-based extraction-free PCR protocol. Detection in raw saliva following storage at 4°C, ∼19°C, and 30°C remained relatively stable for 24-48 hours and following simulated shipping conditions.

Conclusions

This pilot investigation supports a flexible, saliva-based, extraction-free PCR test as a promising approach for diagnosis, outbreak response or ongoing surveillance of mpox. With detection in raw saliva remaining stable for 24-48 hours and through simulated shipping temperatures, saliva-based sampling and simplified testing could reduce diagnostic costs, increase access to testing and address hurdles in low- and middle-income countries.
Effects of on Low T3 syndrome astrocyte homeostasis in patients with bisphenol A-associated intracerebral hemorrhage
Authors: Wang Guoping , Chen Jinhua , Qiao Zhongdong , Guo Dongxing , Guo Ping , Wang Aiven , Sun Wanli , Lyu Jiyuan
Published: June 2023

Background and Purpose

We aimed to assess sex differences in lipid metabolism disorders in patients with BPA-related intracerebral hemorrhage, as well as changes in β3-adrenoceptors and oxidative stress parameters, and to explore potential mechanisms of intestinal flora on the functional homeostasis of cerebral astrocytes.

Methods

Here, a multicenter longitudinal retrospective study was conducted in 200 patients with intracerebral hemorrhage compared with normal controls. Serum thyroid function, blood lipids and subclasses, superoxide dismutase and malondialdehyde were detected. Active oxygen species and reactive oxidative products in brain tissue were detected by fluorescein labeling apparatus. Lipid metabolism and oxidative stress regulate messenger proteins, as well as changes in intestinal flora and astrocyte expression.

Results

Serum lipoprotein β levels of LT3 male patients were significantly increased, with gender differences compared with female patients. β3-adrenergic receptor and Neuregulin –1 expression changes, targeted regulation of fat and reduce oxidative stress response. The increased expression of messenger protein prompts activation of brain astrocytes. The intestinal flora study found that the alpha diversity index in the low T3 group was higher than that in the control group, and Spearman correlation analysis showed that low T3 level was negatively correlated with lipid metabolism disorders and oxidative stress.

Conclusions

Bisphenol A and oxidative stress were significantly related to the high risk of cerebral hemorrhage. The changes of inflammatory cytokines and the ratio expression of connexin 43/Yes associated proteins in the gut brain axis drive activated astrocytes and microglia to jointly maintain the homeostasis of cerebral vascular microenvironment.

Trial registration

The trial is registered at clinical.gov (www.medresman.ChiCTR1900023626)
Association between Fine Particulate Matter Exposure and Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease among a Cognitively Healthy Population-based Cohort
Authors: Casey Emma , Li Zhenjiang , Liang Donghai , Ebelt Stefanie , Levey Allan I. , Lah James J. , Wingo Thomas S. , Hüls Anke
Published: June 2023

Background

Epidemiological evidence suggests air pollution adversely affects cognition and increases the risk of Alzheimer’s disease (AD), but little is known about the biological effects of fine particulate matter (PM2.5) on early predictors of future disease risk.

Objectives

We investigated the association between 1, 3, and 5-year exposure to ambient and traffic-related PM2.5and cerebrospinal fluid (CSF) biomarkers of AD.

Methods

We conducted a cross-sectional analysis using data from 1,113 cognitively healthy adults (aged 45-75 years) from the Emory Healthy Brain Study in Georgia, USA. CSF biomarker concentrations of Aβ42, tTau, and pTau, were collected at enrollment (between 2016-2020) and analyzed with the Roche Elecsys system. Annual ambient and traffic-related residential PM2.5concentrations were estimated at a 1km and 250m resolution, respectively, and 3- and 5-year average exposures were computed for each participant based on time of specimen collection. Associations between PM2.5and CSF biomarker concentrations, considering continuous and dichotomous (dichotomized at clinical cut-offs for AD-biomarker positivity) outcomes, were estimated with multiple linear/logistic regression, respectively, controlling for potential confounders (age, gender, race/ethnicity, body mass index, and neighborhood socioeconomic status).

Results

Interquartile range (IQR; IQR=0.845) increases in 1-year [β: -0.101; 95%-confidence interval (CI): -0.18, -0.02] and 3-year (β: -0.078; 95%-CI: -0.15, -0.00) ambient fine PM2.5exposures were negatively associated with Aβ42CSF concentrations. Associations between ambient PM2.5and Aβ42were similar for 5-year estimates, but not significant (β: -0.076; 95%-CI: -0.160, 0.005). Dichotomized CSF variables revealed similar and significant associations between ambient PM2.5and Aβ42. Associations with traffic-related PM2.5were similar but not significant. PM2.5exposures were not associated with tTau, pTau, tTau/Aβ42, or pTau/Aβ42levels at enrollment.

Conclusion

In our cross-sectional study, PM2.5exposure was associated with a significant decrease in CSF Aβ42which suggests an accumulation of amyloid plaques in the brain and an increased risk of developing AD.
Modelling 25-hydroxyvitamin D responses to different recommended daily intakes of vitamin D
Authors: You Tao , Muhamad Nadda , Jenner Joseph , Huang Zhonghui
Published: June 2023

The reference nutrient intake for vitamin D in people aged ≥ 4 years is 10 μg/day in the UK, which contrasts with the recommended daily allowance of 15 μg/day for people aged 1-70 years in the USA. Using modelling of published data, we compared 95% confidence intervals for serum concentrations of 25-hydroxyvitamin D3(25(OH)D3) attained in response to these two doses. 97.5% of those taking 10 μg/day vs. 15 μg/day were predicted to attain circulating 25(OH)D concentrations >44 nmol/L vs. 50 nmol/L, respectively.
Efficient estimation for large-scale linkage disequilibrium patterns of the human genome
Authors: Huang Xin , Zhu Tian-Neng , Liu Ying-Chao , Qi Guo-An , Zhang Jian-Nan , Chen Guo-Bo
Published: June 2023

In this study, we proposed an efficient algorithm (X-LD) for estimating LD patterns for a genomic grid, which can be of inter-chromosomal scale or of small segments. Compared with conventional methods, the proposed method was significantly faster, dropped from 𝒪 (nm2) to 𝒪 (n2m)—nthe sample size andmthe number of SNPs, and consequently we were permitted to explore in depth unknown or reveal long-anticipated LD features of the human genome. Having applied the algorithm for 1000 Genome Project (1KG), we found:I) The extended LD, driven by population structure, was universally existed, and the strength of inter-chromosomal LD was about 10% of their respective intra-chromosomal LD in relatively homogeneous cohorts, such as FIN and to nearly 56% in admixed cohort, such as ASW.II) After splitting each chromosome into upmost more than a half million grids, we elucidated the LD of the HLA region was nearly 42 folders higher than chromosome 6 in CEU and 11.58 in ASW; on chromosome 11, we observed that the LD of its centromere was nearly 94.05 folders higher than chromosome 11 in YRI and 42.73 in ASW.III) We uncovered the long-anticipated inversely proportional linear relationship between the length of a chromosome and the strength of chromosomal LD, and their Pearson’s correlation was on average over 0.80 for 26 1KG cohorts. However, this linear norm was so far perturbed by chromosome 11 given its more completely sequenced centromere region. Uniquely chromosome 8 of ASW was found most deviated from the linear norm than any other autosomes. The proposed algorithm has been realized in C++ (called X-LD) and available athttps://github.com/gc5k/gear2, and can be applied to explore LD features in any sequenced populations.
Identification of a novel HKU4-related coronavirus in single-cell datasets and clade viral host analysis
Authors: Jones Adrian , Massey Steven E. , Nemzer Louis R. , Zhang Daoyu , Deigin Yuri , Quay Steven C.
Published: June 2023

HKU4-related coronaviruses (CoVs) are merbecoviruses related to Middle Eastern Respiratory Syndrome coronavirus (MERS-CoV). In 2022 and 2023, two HKU4-related CoV strains were discovered inManis javanica(Malayan pangolin) metagenomic datasets derived from organ samples: HKU4-P251T and MjHKU4r-CoV-1. Together with theTylonycteris robustulabat CoV 162275, which was discovered in 2022, pangolin CoVs HKU4-P251T and MjHKU4r-CoV-1 form a novel phylogenetic clade distinct from all previously documented HKU4-related CoVs. In this study, we identified a novel HKU4-related CoV in a pangolin single-cell sequencing dataset generated by BGI-Shenzhen in Shenzhen, Guangdong, China in 2020. The CoV phylogenetically belongs to the same newly identified clade. The single cell datasets were reported as generated from organ samples of a single pangolin that died of natural causes. 98% of the HKU4-related CoV reads were found in only one of the seven single cell datasets — a large intestine cell dataset, cells of which exhibit low expression of DPP4. Bacterial contamination was found to be moderately correlated with HKU4-related CoV presence. We further identified with high confidence that the RNA-Seq dataset supporting one of four near identical variants of MjHKU4r-CoV-1 is aSus scrofa(wild pig) metagenomic dataset, with only a trace level ofManis javanicagenomic content. The presence of HKU4-related CoV reads in the dataset are almost certainly laboratory research-related and not from a premortal pangolin or pig infection. Our findings raise concerns about the provenance of the novel HKU4-related CoV we identify here, MjHKU4r-CoV-1 and its four near-identical variants.
Predictors of Intense Treatment in the Emergency Department Among Older Adults With Serious Life-Limiting Illnesses: A Five-Year Cross-sectional Analysis of Medicare Claims Data
Authors: Adeyemi Oluwaseun , Siman Nina , Goldfeld Keith , Hill Jacob , Cuthel Allison , DiMaggio Charles , Chodosh Joshua , Grudzen Corita
Published: June 2023

Background

Treatment intensity of end-of-life care is the degree of aggressiveness of medical care aimed at providing life-prolonging medical care to patients with serious life-limiting illnesses. This study aims to assess the demographic and health characteristics associated with older adults with serious life-limiting illnesses who received highly intense end-of-life care.

Methods

For this cross-sectional analysis, we pooled the 2015 to 2019 Medicare claims data of adults 65 years and older who visited at least one of the 29 emergency departments (EDs) enrolled in the Primary Palliative Care for Emergency Medicine. We identified those with serious life-limiting illnesses using a Gagne score of seven or higher. Our outcome measure was treatment intensity, defined using acute care and intensive care unit (ICU) admissions. Acute care admission was measured as a binary variable and ICU admission was measured as a three-point nominal variable. The predictor variables were age, sex, race/ethnicity, and illness severity (Gagne score). To assess the odds of acute care and ICU admissions, we used a generalized estimating equation model and a multinomial regression model, respectively. We performed the same analyses among the population without serious life-limiting illnesses to observe differences in effect sizes of intense treatment.

Results

Of the 301,083 older adults that visited one of the 29 EDs, 13% had serious life-limiting illnesses. Age was associated with 9% and 7% increased odds of acute care (95% CI: 1.04 – 1.14) and ICU (95% CI: 1.02 – 1.12) admissions. We reported significant associations by sex, race/ethnicity, and illness severity (Gagne score). The effect sizes of the observed association between measures of treatment intensity and the demographic and health characteristics were smaller among those with serious life-limiting illnesses compared to those without serious life-limiting illnesses.

Conclusion

Older adults with serious life-limiting illnesses who present to the ED experience intense treatment. Identifying demographic and health characteristics associated with treatment intensity may inform the need for serious illness conversations in the ED.
Diagnostic Accuracy and Risk Stratification of a Trauma Risk Assessment Tool Among those with Fall Injuries
Authors: Adeyemi Oluwaseun John , Konda Sanjit , DiMaggio Charles , Grudzen Corita R. , Pfaff Ashley , Esper Garrett , Arcila-Mesa Mauricio , Cuthel Allison M. , Poracky Helen , Meyman Polina , Wittman Ian , Chodosh Joshua
Published: June 2023

Aim

The Score for Trauma Triage in the Geriatric and Middle-Aged (STTGMA) is an injury risk-triage tool. This study aims to validate the STTGMA’s accuracy in predicting fall-related mortality among geriatric trauma patients.

Methods

Using a retrospective cohort design, we selected 5,791 geriatric trauma patients (aged 55 years and older) from a single institutional trauma database (2017-2021). The outcome variable was fatal fall injury, measured as a binary variable. The predictor variable was the STTGMA score, measured as a continuous variable and a four-level categorical variable. We report the predictive accuracy (95% confidence interval (CI)) of the STTGMA. We further assessed the relationship between the STTGMA risk categories and hospital length of stay and time-to-death by performing multivariable quantile regression and time-varying Cox proportional hazard analyses, respectively.

Results

A total of 122 patients (2.1%) died during admission and the median hospital length of stay was 2 days. STTGMA exhibited 84% (95% CI: 75.6 – 92.0) accuracy in predicting in-hospital fall-related mortality. Compared to the minimal risk category, geriatric trauma patients classified as low, moderate, and high risks each had significantly longer hospital stays and adjusted mortality risks, in a dose-response pattern.

Conclusion

STTGMA can accurately predict in-hospital mortality and risk-stratify the length of stay and the time to death among geriatric patients with fall injuries.
Characterization of copy number alterations in Pakistani patients with colorectal cancer
Authors: Marcinak Clayton T. , McDonald Bradon R. , Zubairi Hina , Siddique Sabeehuddin , Stephens Michelle D. , Moosajee Munira , Ahmed Rashida , Zafar Syed Nabeel , Murtaza Muhammed , Ghias Kulsoom
Published: June 2023

Purpose

Incidence and mortality rates of colorectal cancer (CRC) in South Asia are expected to rise by 70% between 2020 and 2040. Despite recent advances in the understanding of molecular alterations in CRC, the representation of South Asians in published genomic datasets is very limited. To address this gap, we performed a pilot study based on a transnational collaboration between academic centers in the US and Pakistan to characterize copy number alterations in a Pakistani cohort with CRC.

Methods

We obtained archived formalin-fixed paraffin-embedded (FFPE) tissue samples from 43 CRC patients treated at Aga Khan University (AKU) Hospital. DNA was extracted and evaluated for quality at AKU, and whole genome sequencing library preparation and shallow whole genome sequencing was performed at University of Wisconsin–Madison. Sequencing data was aligned to the human genome, and we used ichorCNA and GISTIC2 to determine relative copy number alterations.

Results

After removing 13 samples with insufficient DNA quality or quantity, tumor sequencing data was analyzed from 30 patients. The cohort consisted of 19 (63.3%) males with a mean age of 50.1 years and standard deviation (SD) of 17.8 years. Twenty-one (70.0%) patients had tumor stage T3 or T4, and 15 (50.0%) had tumors of the colon. A mean of 265 ng (SD, 29 ng) of DNA was extracted from each FFPE tumor sample, and each sample was sequenced to a mean depth of 0.22× (0.21×). Analysis of copy number alterations revealed recurrent gains in regions 8q and 13q, as well as losses in region 8p.

Conclusions

This transnational pilot study helped identify the challenges related to FFPE sample quality that can impede similar efforts in the future. Our results revealed similarities in the most common copy number alterations in CRC identified in native Pakistani patients and published datasets.
Prevalence of Bicuspid Aortic Valve: Systematic Review and Meta-Analysis of Prevalence Studies
Authors: Lester G D. , Jeremy R W.
Published: June 2023

Bicuspid aortic valve (BAV) is frequently reported as the most common congenital cardiac condition, with 1-2% prevalence by citing one or two autopsy studies performed up to forty years ago. Since then, echocardiography population screening studies have reported contemporaneous results, with lower prevalence, given the absence of autopsy selection bias. Therefore, we performed a systematic review and meta-analysis of autopsy and echocardiography studies to provide a more accurate synthesis of BAV prevalence. Following a systematic literature review, we performed a meta-analysis of prevalence studies using MetaXL Software Version 5.3 by EpiGear, St Lucia, Australia. The results of 45,630 autopsy patients reveal a prevalence of 0.81% (0.5-1.2%, p<0.001, n=444) and 296,245 echocardiography screened population of 0.61% (0.39-0.82% p<0.001, n=1,392) BAV prevalence. The average prevalence of 0.61-0.81% between the two studies still shows this is a common congenital cardiac condition, but shows it is less than frequently reported and thus robustly supports the case of cost effectiveness in screening first degree relatives.