bluuebunny/crossref_metadata_2025 huggingface dataset:
Remembering to Resume: A Randomized Trial Comparing Combined Interruption Management Training and Simulation-Based Education to Simulation-Based Education Alone
Authors: Hill Peggy P. , Díaz Desiree A. , Anderson Mindi , Talbert Steven , Maraj Crystal
Published: June 2023

AIM

This study aimed to determine if purposeful presimulation interruption management training impacts cognitive load and successful completion of simulation objectives more than the experience alone.

BACKGROUND

Practicing nurses are frequently interrupted, increasing the risk for error and task time. Novices are particularly vulnerable to interruption consequences.

METHOD

A between-subjects design and block randomization of prelicensure baccalaureate nursing students (n = 146) was used to compare group differences in cognitive load, use of interruption management strategies, and completion of simulation required elements. Potential relationships between outcomes and age, mindfulness, and experience were explored.

RESULTS

An analysis of covariance demonstrated significantly lower perceived mental demand for those receiving training. Older learners and those receiving training implemented more interruption management strategies.

CONCLUSION

Combining simulation-based education (SBE) with purposeful training enhances interruption management more than SBE alone. Frequent interruption training and SBE are recommended to enhance risk awareness.
Prescribe to Save Lives: An Intervention to Increase Naloxone Prescribing Among HIV Clinicians
Authors: Friedmann Peter D. , Jawa Raagini , Wilson Donna , Ramsey Susan E. , Hoskinson Randall , McKenzie Michelle , Walley Alexander Y. , Green Traci C. , Bratberg Jeffrey , Rich Josiah D.
Published: June 2023

Objectives

Overdose is a major cause of preventable death among persons living with HIV. This study aimed to increase HIV clinicians' naloxone prescribing, which can reduce overdose mortality.

Methods

We enrolled 22 Ryan White–funded HIV practices and implemented onsite, peer-to-peer training, posttraining academic detailing, and pharmacy peer-to-peer contact around naloxone prescribing in a nonrandomized stepped wedge design. Human immunodeficiency virus clinicians completed surveys to assess attitudes toward prescribing naloxone at preintervention and 6 and 12 months postintervention. Aggregated electronic health record data measured the number of patients with HIV prescribed and the number of HIV clinicians prescribing naloxone by site over the study period. Models controlled for calendar time and clustering of repeated measures among individuals and sites.

Results

Of 122 clinicians, 119 (98%) completed a baseline survey, 111 (91%) a 6-month survey, and 93 (76%) a 12-month survey. The intervention was associated with increases in self-reported “high likelihood” to prescribe naloxone (odds ratio [OR], 4.1 [1.7-9.4]; P = 0.001). Of 22 sites, 18 (82%) provided usable electronic health record data that demonstrated a postintervention increase in the total number of clinicians who prescribed naloxone (incidence rate ratio, 2.9 [1.1-7.6]; P = 0.03) and no significant effects on sites having at least one clinician who prescribed naloxone (OR, 4.1 [0.7-23.8]; P = 0.11). The overall proportion of all HIV patients prescribed naloxone modestly increased from 0.97% to 1.6% (OR, 2.2 [0.7-6.8]; P = 0.16).

Conclusion

On-site, practice-based, peer-to-peer training with posttraining academic detailing was a modestly effective strategy to increase HIV clinicians' prescribing of naloxone.
Comparative Effectiveness Research on Spinal versus General Anesthesia for Surgery in Older Adults
Authors: Neuman Mark D. , Sieber Frederick , Dillane Derek
Published: June 2023

Comparative effectiveness research aims to understand the benefits and harms of different treatments to assist patients and clinicians in making better decisions. Within anesthesia practice, comparing outcomes of spinal versus general anesthesia in older adults represents an important focus of comparative effectiveness research. The authors review methodologic issues involved in studying this topic and summarize available evidence from randomized studies in patients undergoing hip fracture surgery, elective knee and hip arthroplasty, and vascular surgery. Across contexts, randomized trials show that spinal and general anesthesia are likely to be equivalent in terms of safety and acceptability for most patients without contraindications. Choices between spinal and general anesthesia represent “preference-sensitive” care in which decisions should be guided by patients’ preferences and values, informed by best available evidence.
Radiologic Changes After 10 Years Postreduction in Developmental Dysplasia of the Hip Treated With Different Reduction Methods and Risk Factors for Osteoarthritis
Authors: Tomaru Yohei , Kamegaya Makoto , Saisu Takashi , Oikawa Yasuhiro , Kakizaki Jun , Segawa Yuko , Tsukagoshi Yuta , Kamada Hiroshi , Yamazaki Masashi
Published: June 2023

Background:

This study examined how radiologic indices at 10 years postreduction change over time and influence the final outcome through a comparative study of 3 reduction methods for developmental dysplasia of the hip, including the Pavlik harness, closed reduction, and open reduction (OR).

Methods:

Patients treated from 1990 to 2000 for dysplasia of the hip and followed up for >20 years were included in this study. Radiologic indices at 10 years postreduction and final follow-up (average 24 years postreduction) were measured in the 3 groups. The relative joint space of <66% compared with the healthy side was defined as positive osteoarthritis (OA) at the final follow-up. The relationship between OA and factors such as age, sex, method of reduction, radiologic indices, and Severin and Kalamchi classifications at 10 years postreduction were examined. Clinical evaluation was performed using the modified Harris Hip Score; a score of ≥80 was defined as good performance at the final follow-up.

Results:

Sixty-five patients (totaling 74 hips) were included. There were no significant differences in radiologic indices between the 10-year postreduction time and final follow-up. Excluding 9 bilateral patients, based on the relative joint space, 21% of the patients (13/56 hips), were positive for OA. Univariate analysis showed that the incidence of positive OA was significantly associated with OR and Kalamchi grade 4 at 10 years postreduction. The modified Harris Hip Score was 80 or higher in 90% of the cases at the final follow-up.

Conclusions:

No significant changes in hip morphology were observed at 10 years postreduction. The Kalamchi classification at 10 years postreduction and OR were significantly associated with the incidence of OA at the final follow-up. Therefore, patients who undergo OR and/or display Kalamchi grade 4 have a high risk of developing OA and would require individual instructions for their daily lives to prevent further progression of OA and longer follow-up.

Level of Evidence:

Level Ⅲ—case-control study.
Development of a Predictive Model for Hospital-Acquired Pressure Injuries
Authors: Pouzols Sophie , Despraz Jérémie , Mabire Cédric , Raisaro Jean-Louis
Published: June 2023

Hospital-acquired pressure injuries are a challenge for healthcare systems, and the nurse's role is essential in their prevention. The first step is risk assessment. The development of advanced data-driven methods based on machine learning techniques can improve risk assessment through the use of routinely collected data. We studied 24 227 records from 15 937 distinct patients admitted to medical and surgical units between April 1, 2019, and March 31, 2020. Two predictive models were developed: random forest and long short-term memory neural network. Model performance was then evaluated and compared with the Braden score. The areas under the receiver operating characteristic curve, the specificity, and the accuracy of the long short-term memory neural network model (0.87, 0.82, and 0.82, respectively) were higher than those of the random forest model (0.80, 0.72, and 0.72, respectively) and the Braden score (0.72, 0.61, and 0.61, respectively). The sensitivity of the Braden score (0.88) was higher than that of long short-term memory neural network model (0.74) and the random forest model (0.73). The long short-term memory neural network model has the potential to support nurses in clinical decision-making. Implementation of this model in the electronic health record could improve assessment and allow nurses to focus on higher-priority interventions.
Functional Recovery After Lung Transplantation Using a Comprehensive Rehabilitation Model
Authors: DiPerna Christen L. , Tucker Lindsay K. , Rice Danielle E. , Shank Cori L. , Kettler Abigail J. , Terry Colin L. , Ulerich Linda M. , Roe David W. , Hage Chadi A.
Published: June 2023

Purpose:

Functional recovery after lung transplant is crucial to long-term outcomes. Despite rehabilitation, few reach the threshold of healthy function. The purpose of this study was to assess the potential benefit of rehabilitation in the Center of Life for Thoracic Transplant (COLTT) program by (1) measuring time to functional recovery, (2) identifying factors associated with functional recovery, (3) examining program outcomes, and (4) examining COLTT impact on unplanned hospital readmission.

Methods:

The study retrospectively examined 105 patients in COLTT after hospital discharge. Functional measures collected at enrollment and completion included 6-minute walk distance, walking speed, 1-minute sit-to-stand test, and single-leg stance. Demographic and hospital stay data were examined for associations between time to achieve COLTT goals and readmissions.

Results:

The median number of visits in COLTT was 18 (9–53). Significant functional gains were made across all outcome measures and near thresholds for healthy individuals. Age, hospital and intensive care unit (ICU) length of stay (LOS), lung disease type, and ventilation time were significantly associated with COLTT visits. The 30-day hospital readmission free rate after hospital discharge was 71.4%.

Conclusions:

Healthy adult functional outcomes were achieved in 18 visits. Age, hospital and ICU LOS, lung disease type, and prolonged ventilation are associated with functional recovery.
Improving On-time Administration of the Initial Hepatitis B Vaccine in the NICU
Authors: Gontasz Michelle M. , Chalk Bethany S. , Liang Caroline
Published: June 2023

Introduction:

Despite the updated American Academy of Pediatrics recommendation for universal administration of the hepatitis B vaccine for newborns, delays in routine prophylaxis are common in the Neonatal Intensive Care Unit (NICU). Delayed immunization can increase perinatal acquisition risks and lead to subsequent delays in routine childhood immunization. This study aimed to increase the on-time administration of the birth dose of the hepatitis B vaccine from 46% to ≥70% at a level III and level IV NICU within the same health system.

Methods:

The stakeholder group developed project interventions using quality improvement methods, including implementing unit guidelines and a prompt in the progress note template. The outcome measure was the percent on-time administration of the initial hepatitis B vaccine for inborn NICU patients born to hepatitis B-negative mothers. The process measure was the percent on-time administration or a valid reason to delay immunization following the guidelines. Statistical process control P-charts graphically represented the measures to assess for change from January 2019 to May 2021.

Results:

In total, 2192 patients were included. The percent on-time administration improved from 48% to 57%. The percentage of on-time administration or valid reason to delay increased from 76% to 80%.

Conclusions:

Quality improvement methodology facilitated the identification of barriers to on-time hepatitis B prophylaxis in the NICU and the improvement of the timeliness of administration across 2 sites. Guidelines tailored to this population and changes to the progress note template successfully created and sustained change and may benefit other NICUs.
Rare Congenital Frontal Hairline Deformity with Temporo-Parieto-Occipital Multiple Folds of Scalp
Authors: Park Jae Hyun
Published: June 2023

Two cases of congenital hairline deformity are reported. Both cases exhibited multiple wrinkled areas in the lower occipital region, with hair that punctured and irritated the adjacent skin as it grew, creating ulcerated lesions. Both patients had a unilateral folded and raised wrinkled and twisted region stretching from the temporal area to the parietal and occipital areas. There was also a defect in the frontotemporal hairline of the affected side that was not present on the contralateral side. The skin of the forehead was also thinner on the affected side. Both patients were in good physical health and had no other congenital abnormalities or pertinent family history. There were no other skin, neurological, or physical abnormalities. In each case, the excessive skin was excised from the temporo-occipital region and microscopically dissected into follicular units, which were transplanted into the temporal area and the frontal hairline. Histologic examination did not reveal any specific abnormal findings. The transplanted hairs were well engrafted and showed natural results. Congenital anomalies of the hairline or hair-bearing scalp tissue are rare. Cutis verticis gyrata is a rare disease that causes multiple furrows and folds of the scalp. However, the cases reported here exhibited a somewhat different appearance from that of cutis verticis gyrata, as multiple folds were present in the scalp in each case, along with an alopecic lesion. This author has successfully treated 2 cases of this rare form of congenital hair loss that has not yet been reported to our knowledge.
A novel variant of the Listeria monocytogenes type VII secretion system EssC component is associated with an Rhs toxin
Authors: Bowran Kieran , Garrett Stephen R. , van Vliet Arnoud H. M. , Palmer Tracy
Published: June 2023

The type VIIb protein secretion system (T7SSb) is found in

Bacillota

(firmicute) bacteria and has been shown to mediate interbacterial competition. EssC is a membrane-bound ATPase that is a critical component of the T7SSb and plays a key role in substrate recognition. Prior analysis of available genome sequences of the foodborne bacterial pathogen

Listeria monocytogenes

has shown that although the T7SSb was encoded as part of the core genome, EssC could be found as one of seven different sequence variants. While each sequence variant was associated with a specific suite of candidate substrate proteins encoded immediately downstream of essC, many LXG-domain proteins were encoded across multiple essC sequence variants. Here, we have extended this analysis using a diverse collection of 37 930

L

.

monocytogenes

genomes. We have identified a rare eighth variant of EssC present in ten

L. monocytogenes

lineage III genomes. These genomes also encode a large toxin of the rearrangement hotspot (Rhs) repeat family adjacent to essC8, along with a probable immunity protein and three small accessory proteins. We have further identified nine novel LXG-domain proteins, and four additional chromosomal hotspots across

L. monocytogenes

genomes where LXG proteins can be encoded. The eight

L. monocytogenes

EssC variants were also found in other

Listeria

species, with additional novel EssC types also identified. Across the genus, species frequently encoded multiple EssC types, indicating that T7SSb diversity is a primary feature of the genus

Listeria

.
Speaking the host language: how Salmonella effector proteins manipulate the host
Authors: Pillay Timesh D. , Hettiarachchi Sahampath U. , Gan Jiyao , Diaz-Del-Olmo Ines , Yu Xiu-Jun , Muench Janina H. , Thurston Teresa L.M. , Pearson Jaclyn S.
Published: June 2023

Salmonella

injects over 40 virulence factors, termed effectors, into host cells to subvert diverse host cellular processes. Of these 40

Salmonella

effectors, at least 25 have been described as mediating eukaryotic-like, biochemical post-translational modifications (PTMs) of host proteins, altering the outcome of infection. The downstream changes mediated by an effector’s enzymatic activity range from highly specific to multifunctional, and altogether their combined action impacts the function of an impressive array of host cellular processes, including signal transduction, membrane trafficking, and both innate and adaptive immune responses.

Salmonella

and related Gram-negative pathogens have been a rich resource for the discovery of unique enzymatic activities, expanding our understanding of host signalling networks, bacterial pathogenesis as well as basic biochemistry. In this review, we provide an up-to-date assessment of host manipulation mediated by the

Salmonella

type III secretion system injectosome, exploring the cellular effects of diverse effector activities with a particular focus on PTMs and the implications for infection outcomes. We also highlight activities and functions of numerous effectors that remain poorly characterized.
Enrichment of colibactin-associated mutational signatures in unexplained colorectal polyposis patients
Authors: Terlouw D. , Boot A. , Ducarmon Q. R. , Nooij S. , Suerink M. , van Leerdam M.E. , van Egmond D. , Tops C.M. , Zwittink R. D. , Ruano D. , Langers A.M.J. , Nielsen M. , van Wezel T. , Morreau H.
Published: June 2023

Colibactin, a genotoxin produced by polyketide synthase harboring (pks+) bacteria, induces double-strand breaks and chromosome aberrations. Consequently, enrichment ofpks+Escherichia coliin colorectal cancer and polyposis suggests a possible carcinogenic effect in the large intestine. Additionally, specific colibactin-associated mutational signatures; SBS88 and ID18 in the Catalogue of Somatic Mutations in Cancer database, are detected in colorectal carcinomas. Previous research showed that a recurrentAPCsplice variant perfectly fits SBS88. In this study, we explore the presence of colibactin-associated signatures and fecalpksin an unexplained polyposis cohort. Somatic targeted Next-Generation Sequencing (NGS) was performed for 379 patients. Additionally, for a subset of 29 patients, metagenomics was performed on feces and mutational signature analyses using Whole-Genome Sequencing (WGS) on Formalin-Fixed Paraffin Embedded (FFPE) colorectal tissue blocks. NGS showed somaticAPCvariants fitting SBS88 or ID18 in at least one colorectal adenoma or carcinoma in 29% of patients. Fecal metagenomic analyses revealed enriched presence ofpksgenes in patients with somatic variants fitting colibactin-associated signatures compared to patients without variants fitting colibactin-associated signatures. Also, mutational signature analyses showed enrichment of SBS88 and ID18 in patients with variants fitting these signatures in NGS compared to patients without. These findings further support colibactins ability to mutagenize colorectal mucosa and contribute to the development of colorectal adenomas and carcinomas explaining a relevant part of patients with unexplained polyposis.
Accurate neural control of a hand prosthesis by posture-related activity in the primate grasping circuit
Authors: Agudelo-Toro Andres , Michaels Jonathan A. , Sheng Wei-An , Scherberger Hansjörg
Published: June 2023

Brain-computer interfaces (BCIs) have the potential to restore hand movement for people with paralysis, but current devices still lack the fine control required to interact with objects of daily living. Following understanding of cortical activity during arm reaches, hand BCI studies have focused on velocity control. However, mounting evidence suggests that posture, and not velocity, dominates in hand-related areas during natural movement. To explore whether this signal can causally control a prosthesis, we developed a novel BCI training paradigm centered on the reproduction of hand posture transitions. Macaque monkeys trained with the protocol were able to control a multi-dimensional hand prosthesis at high-accuracy, including execution of the very intricate precision grip. Subsequent analysis revealed that the posture signal in the target grasping areas was a major contributor to control. Population activity exhibited pattern separation and dimensionality increases driven by posture kinematics, and simulations with a grasping circuit model demonstrated the generalizability of our approach. We present for the first time neural posture control of a multi-dimensional hand prosthesis, opening the door for future devices to leverage this additional information channel.
Narrow-window DIA: Ultra-fast quantitative analysis of comprehensive proteomes with high sequencing depth
Authors: Guzman Ulises H , Martinez Del Val Ana , Ye Zilu , Damoc Eugen , Arrey Tabiwang N. , Pashkova Anna , Denisov Eduard , Petzoldt Johannes , Peterson Amelia C. , Harking Florian , Østergaard Ole , Stewart Hamish , Xuan Yue , Hermanson Daniel , Hock Christian , Makarov Alexander , Zabrouskov Vlad , Olsen Jesper V.
Published: June 2023

Mass spectrometry (MS)-based proteomics aims to characterize comprehensive proteomes in a fast and reproducible manner. Here, we present an ultra-fast scanning data-independent acquisition (DIA) strategy consisting on 2-Th precursor isolation windows, dissolving the differences between data-dependent and independent methods. This is achieved by pairing a Quadrupole Orbitrap mass spectrometer with the asymmetric track lossless (Astral) analyzer that provides >200 Hz MS/MS scanning speed, high resolving power and sensitivity, as well as low ppm-mass accuracy. Narrow-window DIA enables profiling of up to 100 full yeast proteomes per day, or ∼10,000 human proteins in half-an-hour. Moreover, multi-shot acquisition of fractionated samples allows comprehensive coverage of human proteomes in ∼3h, showing comparable depth to next-generation RNA sequencing and with 10x higher throughput compared to current state-of-the-art MS. High quantitative precision and accuracy is demonstrated with high peptide coverage in a 3-species proteome mixture, quantifying 14,000+ proteins in a single run in half-an-hour.

Teaser

Accurate and precise label-free quantification with comprehensive proteome coverage using narrow-window DIA
Ultrasonographic measurements of fascicle length overestimate adaptations in serial sarcomere number
Authors: Hinks Avery , Franchi Martino , Power Geoffrey A.
Published: June 2023

Ultrasound-derived measurements of muscle fascicle length (FL) are often used to infer increases (chronic stretch or training) or decreases (muscle disuse or aging) in serial sarcomere number (SSN). Whether FL adaptations measured via ultrasound can truly approximate SSN adaptations has not been investigated. We casted the right hindlimb of 15 male Sprague-Dawley rats in a dorsiflexed position (i.e., stretched the plantar flexors) for 2 weeks, with the left hindlimb serving as a control. Ultrasound images of the soleus, lateral gastrocnemius (LG), and medial gastrocnemius (MG) were obtained with the ankle at 90° and full dorsiflexion for both hindlimbs pre and post-cast. Following post-cast ultrasound measurements, legs were fixed in formalin with the ankle at 90°, then muscles were dissected, and fascicles were teased out for measurement of sarcomere lengths via laser diffraction and calculation of SSN. Ultrasound detected an 11% increase in soleus FL, a 12% decrease in LG FL, and an 8-11% increase in MG FL for proximal fascicles and at full dorsiflexion. These adaptations were partly reflected by SSN adaptations, with a 6% greater soleus SSN in the casted leg than the un-casted leg, but no SSN differences for the gastrocnemii. Weak relationships were observed between ultrasonographic measurements of FL and measurements of FL and SSN from dissected fascicles. Our results showed that ultrasound-derived FL measurements can overestimate an increase in SSN by ∼5%. Future studies should be cautious when concluding a large magnitude of sarcomerogenesis from ultrasound-derived FL measurements, and may consider applying a correction factor.

Key Points Summary

Measurements of muscle fascicle length via ultrasound are often used to infer changes in serial sarcomere number, such as increases following chronic stretch or resistance training, and decreases with aging or muscle disuse

The present study used a rat model of casting the plantar flexor muscles in a stretched position to investigate directly whether ultrasound-derived fascicle length can accurately detect adaptations in serial sarcomere number

Ultrasound detected an ∼11% increase in soleus fascicle length, but measurements on dissected fascicles showed the actual increase in serial sarcomere number was only ∼6%; therefore, measurements of ultrasound-derived fascicle length can overestimate serial sarcomere number adaptations by as much as 5%
Quantitative Analysis of the Optogenetic Excitability of CA1 Neurons
Authors: Schoeters Ruben , Tarnaud Thomas , Weyn Laila , Joseph Wout , Raedt Robrecht , Tanghe Emmeric
Published: June 2023

Optogenetics has emerged as a promising technique for modulating neuronal activity and holds potential for the treatment of neurological disorders such as temporal lobe epilepsy (TLE). However, clinical translation still faces many challenges. This in-silico study aims to enhance the understanding of optogenetic excitability in CA1 cells and to identify strategies for improving stimulation protocols. Employing state-of-the-art computational models, the optogenetic excitability of four CA1 cells, two pyramidal and two interneurons, expressing ChR2(H134R) is investigated. The results demonstrate that confining the opsin to specific neuronal membrane compartments significantly improves excitability. An improvement is also achieved by focusing the light beam on the most excitable cell region. Moreover, the perpendicular orientation of the optical fiber relative to the somato-dendritic axis yields superior results. Inter-cell variability is observed, highlighting the importance of considering neuron degeneracy when designing optogenetic tools. Opsin confinement to the basal dendrites of the pyramidal cells renders the neuron the most excitability. A global sensitivity analysis identified opsin location and expression level as having the greatest impact on simulation outcomes. The error reduction of simulation outcome due to coupling of neuron modeling with light propagation is shown. The results promote spatial confinement and increased opsin expression levels as important improvement strategies. On the other hand, uncertainties in these parameters limit precise determination of the irradiance thresholds. This study provides valuable insights on optogenetic excitability of CA1 cells useful for the development of improved optogenetic stimulation protocols for, for instance, TLE treatment.
Perivascular spaces in Alzheimer’s disease are associated with inflammatory, stress-related, and hypertension biomarkers
Authors: Sibilia Francesca , Sheikh-Bahaei Nasim , Mack Wendy J. , Choupan Jeiran
Published: June 2023

Perivascular spaces (PVS) are fluid-filled spaces surrounding the brain vasculature. Literature suggests that PVS may play a significant role in aging and neurological disorders, including Alzheimer’s disease (AD).

Cortisol, a stress hormone, has been implicated in the development and progression of AD. Hypertension, a common condition in older adults, has been found to be a risk factor for AD. Hypertension may contribute to PVS enlargement, impairing the clearance of waste products from the brain and promoting neuroinflammation. This study aims to understand the potential interactions between PVS, cortisol, hypertension, and inflammation in the context of cognitive impairment.

Using MRI scans acquired at 1.5T, PVS were quantified in a cohort of 465 individuals with cognitive impairment. PVS was calculated in the basal ganglia and centrum semiovale using an automated segmentation approach. Levels of cortisol and angiotensin-converting enzyme (ACE) (an indicator of hypertension) were measured from plasma. Inflammatory biomarkers, such as cytokines and matrix metalloproteinases, were analyzed using advanced laboratory techniques.

Main effect and interaction analyses were performed to examine the associations between PVS severity, cortisol levels, hypertension, and inflammatory biomarkers.

In the centrum semiovale, higher levels of inflammation reduced cortisol associations with PVS volume fraction.

For ACE, an inverse association with PVS was seen only when interacting with TNFr2 (a transmembrane receptor of TNF). There was also a significant inverse main effect of TNFr2.

In the PVS basal ganglia, a significant positive association was found with TRAIL (a TNF receptor inducing apoptosis).

These findings show for the first time the intricate relationships between PVS structure and the levels of stress-related, hypertension, and inflammatory biomarkers. This research could potentially guide future studies regarding the underlying mechanisms of AD pathogenesis and the potential development of novel therapeutic strategies targeting these inflammation factors.
Functionally and metabolically divergent melanoma-associated macrophages originate from common bone-marrow precursors
Authors: Pizzurro Gabriela A. , Bridges Kate , Jiang Xiaodong , Vidyarthi Aurobind , Miller-Jensen Kathryn , Colegio Oscar R.
Published: June 2023

Melanomas display high numbers of tumor-associated macrophages (TAMs), which correlate with worse prognosis. Harnessing macrophages for therapeutic purposes has been particularly challenging due to their heterogeneity, based on their ontogeny and function and driven by the tissue-specific niche. In the present study, we used the YUMM1.7 model to better understand melanoma TAM origin and dynamics during tumor progression, with potential therapeutic implications. We identified distinct TAM subsets based on F4/80 expression, with the F4/80highfraction increasing over time and displaying tissue-resident-like phenotype. While skin-resident macrophages showed mixed on-togeny, F4/80+TAM subsets in i.d. YUMM1.7 tumors originated almost exclusively from bone-marrow precursors. Mul-tiparametric analysis of macrophage phenotype showed a temporal divergence of F4/80+TAM subpopulations, which also differed from skin-resident subsets, and from their monocytic precursors. Overall, F4/80+TAMs displayed co-ex-pression of M1- and M2-like canonical markers, while RNA-seq and pathway analysis showed differential immunosup-pressive and metabolic profiles. GSEA showed F4/80highTAMs to rely on oxidative phosphorylation, with increased proliferation and protein secretion while F4/80lowcells had high pro-inflammatory and intracellular signaling pathways, with lipid and polyamine metabolism. Overall, the present in-depth characterization provides further evidence of the ontogeny of the evolving melanoma TAMs, whose gene expression profiles matched recently-identified TAM clusters in other tumor models and human cancers. These findings provide evidence for potentially targeting specific immunosup-pressive TAMs in advanced tumor stages.
What fraction of cellular DNA turnover becomes cfDNA?
Authors: Sender Ron , Noor Elad , Milo Ron , Dor Yuval
Published: June 2023

Cell-free DNA (cfDNA) tests use small amounts of DNA in the bloodstream as biomarkers. While it is thought that cfDNA is largely released by dying cells, the proportion of dying cells’ DNA that reaches the bloodstream is unknown. Here, we integrate estimates of cellular turnover rates to calculate the expected amount of cfDNA. By comparing this to the actual amount of cell type-specific cfDNA, we estimate the proportion of DNA reaching plasma as cfDNA. We demonstrate that <10% of the DNA from dying cells is detectable in plasma, and the ratios of measured to expected cfDNA levels vary a thousand-fold among cell types, often reaching well below 0.1%. The analysis suggests that local clearance, presumably via phagocytosis, takes up most of the dying cells’ DNA. Insights into the underlying mechanism may help to understand the physiological significance of cfDNA and improve the sensitivity of liquid biopsies.
Functional identification of soluble uric acid as an endogenous inhibitor of CD38
Authors: Wen Shijie , Arakawa Hiroshi , Yokoyama Shigeru , Shirasaka Yoshiyuki , Higashida Haruhiro , Tamai Ikumi
Published: June 2023

Excessive elevation or reduction of soluble uric acid (sUA) levels has been linked to some of pathological states, raising another subject that sUA at physiological levels may be essential for the maintenance of health. Yet, the fundamental physiological functions and molecular targets of sUA remain largely unknown. Using enzyme assays andin vitroandin vivometabolic assays, we demonstrate that sUA directly inhibits the hydrolase and cyclase activities of CD38 via a reversible non-competitive mechanism, thereby limiting nicotinamide adenine dinucleotide (NAD+) degradation. CD38 inhibition is restricted to sUA in purine metabolism, and a structural comparison using methyl analogs of sUA such as caffeine metabolites shows that 1,3-dihydroimidazol-2-one is the main functional group. Moreover, sUA at physiological levels prevents crude lipopolysaccharide (cLPS)-induced systemic inflammation and monosodium urate (MSU) crystal-induced peritonitis in mice by interacting with CD38. Together, this study unveils an unexpected physiological role for sUA in controlling NAD+availability and innate immunity through CD38 inhibition, providing a new perspective on sUA homeostasis and purine metabolism.
A hypothetical intervention to reduce inequities in anxiety for Multiracial people: simulating an intervention on childhood adversity
Authors: Lam-Hine Tracy , Bradshaw Patrick T. , Allen Amani M. , Omi Michael , Riddell Corinne A.
Published: June 2023

Multiracial people report higher mean Adverse Childhood Experiences (ACEs) scores and prevalence of anxiety than other racial groups. Studies using statistical interactions to estimate racial differences in ACEs-anxiety associations do not show stronger associations for Multiracial people. Using data from Waves 1 (1995-97) through 4 (2008-09) of the National Longitudinal Study of Adolescent to Adult Health (Add Health), we simulated a stochastic intervention over 1,000 resampled datasets to estimate the race-specific cases averted per 1,000 of anxiety if all racial groups had the same exposure distribution of ACEs as Whites. Simulated cases averted were greatest for the Multiracial group, (median = -4.17 cases per 1,000, 95% CI: -7.42, -1.86). The model also predicted smaller risk reductions for Black participants (-0.76, 95% CI: -1.53, -0.19). CIs around estimates for other racial groups included the null. An intervention to reduce racial disparities in exposure to ACEs could help reduce the inequitable burden of anxiety on the Multiracial population. Stochastic methods support consequentialist approaches to racial health equity, and can encourage greater dialogue between public health researchers, policymakers, and practitioners.
Ethical considerations related to drone use for environment and health research: a scoping review protocol
Authors: Hoek Spaans Remy , Drumond Bruna , van Daalen Kim , Derbyshire Alison , Da Silva Adriano , Lana Raquel Martins , Vega Mauricio Santos , Carrasco-Escobar Gabriel , Codeço Claudia , Lowe Rachel
Published: June 2023

Introduction

The use of drones in environment and health research is a relatively new phenomenon. A principal research activity drones are used for is environmental monitoring, which can raise concerns in local communities. Existing ethical guidance for researchers is often not specific to drone technology and practices vary between research settings. Therefore, this scoping review aims to gather the evidence available on how the use of drones is perceived by local communities, as well as current research practices, and ethical guidance related to drone deployment.

Methods and analysis

This scoping review will follow the PRISMA-ScR and the Joana Briggs Institute guidelines. The literature search will be conducted using academic databases and grey literature sources. After pilot testing the inclusion criteria and data extraction tool, two researchers will double-screen and then chart available evidence independently. A content analysis will be carried out to identify patterns of categories or terms used to describe ethical considerations related to drone usage for environmental monitoring in the literature using the R Package RQDA. Discrepancies in any phase of the project are solved through consensus.

Ethics and dissemination

Ethical approval is not required; only secondary data will be used. This protocol is registered on the Open Science Framework (osf.io/a78et). The results will be disseminated through publication in a scientific journal and will be used to inform drone field campaigns in the Wellcome Trust funded HARMONIZE project. HARMONIZE aims to develop cost-effective and reproducible digital infrastructure for stakeholders in climate change hotspots in Latin America & the Caribbean and will use drone technology to collect data on fine scale landscape changes.
Conditional lethality profiling reveals anticancer mechanisms of action and drug-nutrient interactions
Authors: Flickinger Kyle M. , Wilson Kelli M. , Rossiter Nicholas J. , Hunger Andrea L. , Lee Tobie D. , Hall Matthew D. , Cantor Jason R.
Published: June 2023

Chemical screening studies have identified drug sensitivities across hundreds of cancer cell lines but most putative therapeutics fail to translate. Discovery and development of drug candidates in models that more accurately reflect nutrient availability in human biofluids may help in addressing this major challenge. Here we performed high-throughput screens in conventional versus Human Plasma-Like Medium (HPLM). Sets of conditional anticancer compounds span phases of clinical development and include non-oncology drugs. Among these, we characterize a unique dual-mechanism of action for brivudine, an agent otherwise approved for antiviral treatment. Using an integrative approach, we find that brivudine affects two independent targets in folate metabolism. We also traced conditional phenotypes for several drugs to the availability of nucleotide salvage pathway substrates and verified others for compounds that seemingly elicit off-target anticancer effects. Our findings establish generalizable strategies for exploiting conditional lethality in HPLM to reveal therapeutic candidates and mechanisms of action.
Population age and household structures shape transmission dynamics of emerging infectious diseases: a longitudinal microsimulation approach
Authors: Møgelmose Signe , Vijnck Laurens , Neven Frank , Neels Karel , Beutels Philippe , Hens Niel
Published: June 2023

Host population demographics and patterns of host-to-host interactions are important drivers of heterogeneity in infectious disease transmission. To improve our understanding of how population structures and changes therein influence disease transmission dynamics at the individual and population level, we model a dynamic age-and household-structured population using longitudinal microdata drawn from Belgian census and population registers. At different points in time, we simulate the spread of a close-contact infectious disease and vary the age profiles of infectiousness and susceptibility to reflect specific infections (e.g. influenza and SARS-CoV-2) using a two-level mixing model, which distinguishes between exposure to infection in the household and exposure in the community. We find a strong relationship between age and household structures, which, in combination with social mixing patterns and epidemiological parameters, shape the spread of an emerging infection. Disease transmission in the adult population in particular is explained by differential household compositions and not just household size. Moreover, we highlight how demographic processes alter population structures in an ageing population and how these in turn affect disease transmission dynamics across population groups.
Relationship between understanding of gender and LGBTQ and brain health with a focus on the triple network
Authors: Otsuka Taiko , Kokubun Keisuke , Okamoto Maya , Yamakawa Yoshinori
Published: June 2023

Various studies have been conducted mainly in the fields of social sciences to address the lack of understanding of diversity in Japan regarding gender, LGBTQ, etc., but little progress has been made in promoting diversity in society. In this study, we aimed to clarify the specific brain states of people who have a high understanding of diversity (gender and LGBTQ) using the gray matter brain healthcare quotient (GM-BHQ), a brain health index obtained by MRI image analysis, and the results of a psychological questionnaire on diversity. As a result of the analysis, the GM-BHQ of the Central Executive Network (CEN) tended to be significantly higher than the estimated values from age, gender, and BMI in the group with a high understanding of gender equality. GM-BHQ of the Salience Network (SN) also tended to be relatively high. In addition, the GM-BHQ of SN, default mode network (DMN), and CEN, as well as whole brain GM-BHQ were significantly higher among those with a high understanding of LGBTQ than the estimated values. These results suggest that understanding diversity requires a healthy brain centered on the triple network that governs rational judgment, emotional adjustment, recognition of others, self-recognition, and value judgment of behavior.
Nutritional status of under-5 Rohingya children admitted for diarrheal diseases in primary health centers in Cox’s Bazar, Bangladesh
Authors: Al Fidah Md. Fuad , Efa Syeda Sumaiya , Hossain Md. Emam , Haider Tanvir , Roy Dipankor
Published: June 2023

Background

One of the leading causes of mortality and morbidity in under-5 children is Diarrhea. Malnutrition, in association with the diarrheal disease, affects children negatively. In 2018, Bangladesh saw a massive influx of Rohingya people, with almost 29% of under-5 children.

Objectives

This study aimed to assess the nutritional status of under-5 Rohingya children admitted with acute diarrheal diseases at the primary health centers at Cox’s Bazar.

Methods

This cross-sectional study was conducted among the diarrhea affected under-5 Rohingya children who reported to primary health centers at cox’s bazar. The study was conducted from January to December 2018. The primary caregivers of 276 children who were affected with diarrhea were the respondents. Data were collected by face-to-face interview and record review using a semi-structured questionnaire and checklist respectively. All ethical issues were maintained strictly.

Results

The majority (60.1%) of the participants were male. Only 2.9% of the participants reported passing of visible blood in stool. Oral Rehydration Solution (ORS) was not taken by most of the participants (50.7%) before visit to the hospital. The mean (±SD) age was 18.54 (±12.44) months. Among the participants, 41.3% had underweight (<-2 WAZ score). Statistically, a significant relationship was found between the age of the participants and underweight (p<0.05) with a moderate effect size (Φ=0.21).

Conclusion

The study findings would be helpful to identify the need for raising awareness among caregivers of under-5 children regarding the use for ORS and contribute to reducing morbidity and mortality associated with malnutrition and diarrhea, and improving their overall health outcomes.
Disentangling protein metabolic costs in human cells and tissues
Authors: Chagoyen Mónica , Poyatos Juan F
Published: June 2023

Many intrinsic functional characteristics of cells and tissues shape their genome-wide expression patterns. But what other factors might also modulate these patterns are not fully known. Here, we revisit the general model of costs in which the protein products of highly expressed genes should be short and made up of biosynthetically cheap amino acids. We first use single-cell expression data from a collection of human cell types to confirm this model with a twist: the most highly expressed proteins tend to be particularly short and use expensive amino acids. By clustering how these two factors change with expression across all cell types, we identified a set of archetypal profiles that uniquely balance costs and that occur at different proportion across cell types. Similar profiles were also found by examining the expression data of tissues, which allowed us to recognize those following a more or less costly strategy. We then asked how this model might delineate the expression changes seen in a tumor relative to its normal solid tissue, as it has been argued that energy constraints determine cancer progression. We discovered a strong signal for the overexpression of biosynthetically cheap compact genes in cancer tissues. Our work highlights how both aspects of the metabolic cost of a protein, length and amino acid biosynthesis, represent valuable measures for understanding the different levels of biological organization and also the differences between health and disease.
Trazodone rescues dysregulated synaptic and mitochondrial nascent translatomes in prion neurodegeneration
Authors: Albert-Gasco Hector , Smith Heather L. , Alvarez-Castelao Beatriz , Swinden Dean , Halliday Mark , Janaki-Raman Sudha , Butcher Adrian , Mallucci Giovanna R
Published: June 2023

The unfolded protein response (UPR) is rapidly gaining momentum as a therapeutic target for protein misfolding neurodegenerative diseases, in which its overactivation results in sustained translational repression leading to synapse loss and neurodegeneration. In mouse models of these disorders, from Alzheimer’s to prion disease, modulation of the pathway - including by the licensed drug, trazodone - restores global protein synthesis rates with profound neuroprotective effects. However, the precise nature of the translational impairment, in particular the specific proteins affected in disease, and their response to therapeutic UPR modulation are poorly understood. We used non-canonical amino acid tagging (NCAT) to measurede novoprotein synthesis in the brains of prion-diseased mice with and without trazodone treatment, in both whole hippocampus and cell-specifically. During disease the predominant translatome changes occur in synaptic, cytoskeletal and mitochondrial proteins in both hippocampal neurons and astrocytes. Remarkably, trazodone treatment for just two weeks largely restored the whole disease translatome in the hippocampus to that of healthy, uninfected mice, predominantly with recovery of proteins involved in synaptic and mitochondrial function. In parallel, trazodone treatment restored the disease-associated decline in synapses and mitochondria and their function to wildtype levels. In conclusion, this study increases our understanding of how translational repression contributes to neurodegeneration through synaptic and mitochondrial toxicity via depletion of key proteins essential for their function. Further, it provides new insights into the neuroprotective mechanisms of trazodone through reversal of this toxicity, relevant for the treatment of neurodegenerative diseases via translational modulation.