bluuebunny/crossref_metadata_2025 huggingface dataset:
Marangoni spreading on liquid substrates in new media art
Authors: Chan San To , Fried Eliot
Published: February 2024

With the advent of new media art, artists have harnessed fluid dynamics to create captivating visual narratives. A striking technique known as dendritic painting employs mixtures of ink and isopropanol atop paint, yielding intricate tree-like patterns. To unravel the intricacies of that technique, we examine the spread of ink/alcohol droplets over liquid substrates with diverse rheological properties. On Newtonian substrates, the droplet size evolution exhibits two power laws, suggesting an underlying interplay between viscous and Marangoni forces. The leading edge of the droplet spreads as a precursor film with an exponent of 3/8, while its main body spreads with an exponent of 1/4. For a weakly shear-thinning acrylic resin substrate, the same power laws persist, but dendritic structures emerge, and the texture of the precursor film roughens. The observed roughness and growth exponents (3/4 and 3/5) suggest a connection to the quenched Kardar–Parisi–Zhang universality class, hinting at the existence of quenched disorder in the liquid substrate. Mixing the resin with acrylic paint renders it more viscous and shear-thinning, refining the dendrite edges and further roughening the precursor film. At larger paint concentrations, the substrate becomes a power-law fluid. The roughness and growth exponents then approach 1/2 and 3/4, respectively, deviating from known universality classes. The ensuing structures have a fractal dimension of 1.68, characteristic of diffusion-limited aggregation. These findings underscore how the nonlinear rheological properties of the liquid substrate, coupled with the Laplacian nature of Marangoni spreading, can overshadow the local kinetic roughening of the droplet interface.
Advancements in the treatment of age-related macular degeneration: a comprehensive review
Authors: Papaioannou Christos
Published: February 2024

Age-related macular degeneration (AMD) stands as a leading cause of irreversible blindness, particularly affecting central vision and impeding daily tasks. This paper provides a thorough exploration of AMD, distinguishing between its two main subtypes—Wet and Dry AMD—while shedding light on the prevalence and risk factors, including age, genetics, and smoking.

The focus shifts to the current and future treatment landscape, examining both Dry and Wet AMD. Regarding Dry AMD, interventions such as antioxidant supplementation and ongoing clinical trials offer hope. Notable among these is Pegcetacoplan which is the only Food and Drug Administration (FDA)-approved medication, displaying promising results in reducing geographic atrophy lesions.

For Wet AMD, anti-Vascular Endothelial Growth Factor therapies like Ranibizumab (Lucentis®) have been instrumental, and newer drugs like Faricimab and OPT-302 show comparable efficacy with extended dosing intervals. Additionally, gene therapies such as RGX-314 present a potential paradigm shift, reducing or eliminating the need for frequent injections. Biosimilars offer cost-effective alternatives.

The paper also delves into the integration of technology and artificial intelligence in AMD management, highlighting the role of smartphone apps for patient monitoring and artificial intelligence algorithms for diagnosis and surveillance. Furthermore, patient perspectives on artificial intelligence demonstrate a positive correlation between understanding and trust.

The narrative concludes with a glimpse into ground-breaking technologies, including retinal implants and bionic chips, offering hope for vision restoration. Overall, this paper underscores the multifaceted approach in addressing AMD, combining traditional and innovative strategies, paving the way for a more promising future in AMD treatment.
A systematic review of patient-reported outcome measures in patients with anti-neutrophil cytoplasmic antibody associated vasculitis
Authors: Floyd Lauren , Ahmed Muhammad , Morris Adam D , Nixon Andrew C , Mitra Sandip , Dhaygude Ajay , Rowland Christine
Published: February 2024

Objectives

ANCA-associated vasculitis (AAV) is associated with significant morbidity, fatigue, pain and poor health-related quality of life (HRQoL). This review aims to assess the comprehensiveness of existing patient reported outcome measures (PROMs) used in AAV and identify associations with poorer HRQoL outcomes.

Methods

A literature review of studies using PROMs, including those labelled HRQoL in people with AAV as a primary or secondary study outcome were screened and reviewed up to July 2023. Quality was assessed using the Critical Appraisal Skills Programme.

Results

A total of 30 articles were included which utilised 22 different PROM tools, 76.7% (n = 23) used the SF-36 or a variation as a generic measure of health status and or HRQoL. Two studies developed a disease-specific PROM. The AAV-PRO showed good psychometric properties but potential limitations in capturing all relevant aspects of the disease experience for AAV patients. Factors associated with poorer HRQoL included: neurological and sinonasal involvement, women and younger patients. A total of 86.6% of studies showed no meaningful relationships between the SF-36 and BVAS, VDI or disease duration. Depression and anxiety were common and socioeconomic factors such as unemployment were significantly associated with poorer mental health outcomes. Glucocorticoids were found to be independently associated with worse SF-36 scores.

Conclusion

Generic PROMs are useful in measuring significant changes but lack sensitivity to specific symptoms and unique AAV-related issues, while existing disease-specific PROMs have some limitations and may not fully capture the AAV patient’s perspective on disease and treatment burden.
Associations between plasma metabolism-associated proteins and future development of giant cell arteritis: results from a prospective study
Authors: Wadström Karin , Jacobsson Lennart T H , Mohammad Aladdin J , Warrington Kenneth J , Matteson Eric L , Jakobsson Magnus E , Turesson Carl
Published: February 2024

Objective

The aim of this study was to investigate the relationship between biomarkers associated with metabolism and subsequent development of GCA.

Method

Participants in the population-based Malmö Diet Cancer Study (MDCS; N = 30 447) who were subsequently diagnosed with GCA were identified in a structured process. Matched GCA-free controls were selected from the study cohort. Baseline plasma samples were analysed using the antibody-based OLINK proteomics metabolism panel (92 metabolic proteins). Analyses were pre-designated as hypothesis-driven or hypothesis-generating. In the latter, principal component analysis was used to identify groups of proteins that explained the variance in the proteome.

Results

There were 95 cases with a confirmed incident diagnosis of GCA (median 12.0 years after inclusion). Among biomarkers with a priori hypotheses, adhesion G protein-coupled receptor E2 (ADGRE2) was positively associated [odds ratio (OR) per S.D. 1.67; 95% CI 1.08–2.57], and fructose-1,6-bisphosphatase 1 (FBP1) was negatively associated (OR per S.D. 0.59; 95% CI 0.35–0.99) with GCA. In particular, ADGRE2 levels were associated with subsequent GCA in the subset sampled <8.5 years before diagnosis. For meteorin-like protein (Metrnl), the highest impact on the risk of GCA was observed in those patients sampled closest to diagnosis, with a decreasing trend with longer time to GCA (P = 0.03). In the hypothesis-generating analyses, elevated levels of receptor tyrosine-like orphan receptor 1 (ROR1) were associated with subsequent GCA.

Conclusion

Biomarkers identified years before clinical diagnosis indicated a protective role of gluconeogenesis (FBP1) and an association with macrophage activation (ADGRE2 and Metrnl) and proinflammatory signals (ROR1) for development of GCA.
The natural history of insomnia: evaluating illness severity from acute to chronic insomnia; is the first the worst?
Authors: Boyle Julia T , Morales Knashawn H , Muench Alexandria , Ellis Jason , Vargas Ivan , Grandner Michael A , Posner Donn , Perlis Michael L
Published: February 2024

Study Objectives

The 3P and 4P models represent illness severity over the course of insomnia disorder. The 3P model suggests that illness severity is worst during acute onset. The 4P model suggests that illness severity crescendos with chronicity. The present analysis from an archival dataset assesses illness severity with new onset illness (i.e. from good sleep [GS] to acute insomnia [AI] to chronic insomnia [CI]). Illness severity is quantified in terms of total wake time (TWT).

Methods

GSs (N = 934) were followed up to 1 year with digital sleep diaries, and classified as GS, AI, or CI. Data for CIs were anchored to the first of 14 days with insomnia so that day-to-day TWT was represented prior to and following AI onset. A similar graphic (+/−acute onset) was constructed for number of days per week with insomnia. GS data were temporally matched to CI data. Segmented linear mixed regression models were applied to examine the change in slopes in the AI-to-CI period compared to GS-to-AI period.

Results

Twenty-three individuals transitioned to AI and then CI. Average TWT rose during the first 2 weeks of AI onset (b = 1.8, SE = 0.57, p = 0.001) and was then stable for 3 months (b = −0.02, SE = 0.04, p = 0.53). Average number of affected days was stable from AI to CI (b = 0.0005, SE = 0.002, p = 0.81). That is, while there was week-to-week variability in the number of days affected, no linear trend was evident.

Conclusions

In our sample of CIs, primarily with middle insomnia, the average severity and number of affected days were worst with the onset of AI (worst is first) and stable thereafter.
The Effect of Copy Number Hemiplasy on Gene Family Evolution
Authors: Li Qiuyi , Chan Yao-ban , Galtier Nicolas , Scornavacca Celine
Published: February 2024

The evolution of gene families is complex, involving gene-level evolutionary events such as gene duplication, horizontal gene transfer, and gene loss, and other processes such as incomplete lineage sorting (ILS). Because of this, topological differences often exist between gene trees and species trees. A number of models have been recently developed to explain these discrepancies, the most realistic of which attempts to consider both gene-level events and ILS. When unified in a single model, the interaction between ILS and gene-level events can cause polymorphism in gene copy number, which we refer to as copy number hemiplasy (CNH). In this paper, we extend the Wright–Fisher process to include duplications and losses over several species, and show that the probability of CNH for this process can be significant. We study how well two unified models—multilocus multispecies coalescent (MLMSC), which models CNH, and duplication, loss, and coalescence (DLCoal), which does not—approximate the Wright–Fisher process with duplication and loss. We then study the effect of CNH on gene family evolution by comparing MLMSC and DLCoal. We generate comparable gene trees under both models, showing significant differences in various summary statistics; most importantly, CNH reduces the number of gene copies greatly. If this is not taken into account, the traditional method of estimating duplication rates (by counting the number of gene copies) becomes inaccurate. The simulated gene trees are also used for species tree inference with the summary methods ASTRAL and ASTRAL-Pro, demonstrating that their accuracy, based on CNH-unaware simulations calibrated on real data, may have been overestimated.
Sex‐dependent expression of galectin‐1, a cardioprotective β‐galactoside‐binding lectin, in human calcific aortic stenosis
Authors: Jover Eva , Martín‐Núñez Ernesto , Garaikoetxea Mattie , Matilla Lara , Blanco‐Colio Luis M. , Pérez‐Sáez Juan M. , Navarro Adela , Fernández‐Celis Amaya , Gainza Alicia , Álvarez Virginia , Sádaba Rafael , Tamayo Ibai , Rabinovich Gabriel A. , Martín‐Ventura José L. , López‐Andrés Natalia
Published: February 2024

We aimed to analyze sex‐related differences in galectin‐1 (Gal‐1), a β‐galactoside‐binding lectin, in aortic stenosis (AS) and its association with the inflammatory and fibrocalcific progression of AS. Gal‐1 was determined in serum and aortic valves (AVs) from control and AS donors by western blot and immunohistochemistry. Differences were validated by ELISA and qPCR in AS samples. In vitro experiments were conducted in primary cultured valve interstitial cells (VICs). Serum Gal‐1 was not different neither between control and AS nor between men and women. There was no association between circulating and valvular Gal‐1 levels. The expression of Gal‐1 in stenotic AVs was higher in men than women, even after adjusting for confounding factors, and was associated with inflammation, oxidative stress, extracellular matrix remodeling, fibrosis, and osteogenesis. Gal‐1 (LGALS1) mRNA was enhanced within fibrocalcific areas of stenotic AVs, especially in men. Secretion of Gal‐1 was up‐regulated over a time course of 2, 4, and 8 days in men's calcifying VICs, only peaking at day 4 in women's VICs. In vitro, Gal‐1 was associated with similar mechanisms to those in our clinical cohort. β‐estradiol significantly up‐regulated the activity of an LGALS1 promoter vector and the secretion of Gal‐1, only in women's VICs. Supplementation with rGal‐1 prevented the effects elicited by calcific challenge including the metabolic shift to glycolysis. In conclusion, Gal‐1 is up‐regulated in stenotic AVs and VICs from men in association with inflammation, oxidative stress, matrix remodeling, and osteogenesis. Estrogens can regulate Gal‐1 expression with potential implications in post‐menopause women. Exogenous rGal‐1 can diminish calcific phenotypes in both women and men.
MicroRNA‐409‐3p/BTG2 signaling axis improves impaired angiogenesis and wound healing in obese mice
Authors: Bestepe Furkan , Ghanem George F. , Fritsche Colette M. , Weston James , Sahay Sumedha , Mauro Amanda K. , Sahu Parul , Tas Sude M. , Ruemmele Brooke , Persing Sarah , Good Miranda E. , Chatterjee Abhishek , Huggins Gordon S. , Salehi Payam , Icli Basak
Published: February 2024

Wound healing is facilitated by neoangiogenesis, a complex process that is essential to tissue repair in response to injury. MicroRNAs are small, noncoding RNAs that can regulate the wound healing process including stimulation of impaired angiogenesis that is associated with type‐2 diabetes (T2D). Expression of miR‐409‐3p was significantly increased in the nonhealing skin wounds of patients with T2D compared to the non‐wounded normal skin, and in the skin of a murine model with T2D. In response to high glucose, neutralization of miR‐409‐3p markedly improved EC growth and migration in human umbilical vein endothelial cells (HUVECs), promoted wound closure and angiogenesis as measured by increased CD31 in human skin organoids, while overexpression attenuated EC angiogenic responses. Bulk mRNA‐Seq transcriptomic profiling revealed BTG2 as a target of miR‐409‐3p, where overexpression of miR‐409‐3p significantly decreased BTG2 mRNA and protein expression. A 3′ untranslated region (3′‐UTR) luciferase assay of BTG2 revealed decreased luciferase activity with overexpression of miR‐409‐3p, while inhibition had opposite effects. Mechanistically, in response to high glucose, miR‐409‐3p deficiency in ECs resulted in increased mTOR phosphorylation, meanwhile BTG‐anti‐proliferation factor 2 (BTG2) silencing significantly decreased mTOR phosphorylation. Endothelial‐specific and tamoxifen‐inducible miR‐409‐3p knockout mice (MiR‐409IndECKO) with hyperglycemia that underwent dorsal skin wounding showed significant improvement of wound closure, increased blood flow, granulation tissue thickness (GTT), and CD31 that correlated with increased BTG2 expression. Taken together, our results show that miR‐409‐3p is a critical mediator of impaired angiogenesis in diabetic skin wound healing.
Use of Intraoperative Neuromonitoring: A Review
Authors: Vucicevic Rajko S. , Salazar Luis M. , Federico Vincent P. , Sayari Arash J.
Published: February 2024

The purpose of this review is to provide an updated overview of intraoperative neuromonitoring (IONM), including its applications in cervical, thoracic, lumbar, and spinal deformity surgical procedures, and its cost-effectiveness, serving as a reference for education and clinical decision-making.
Higher CCR5 density on CD4+ T-cells in mothers and infants is associated with increased risk of in-utero HIV-1 transmission
Authors: Shalekoff Sharon , Dias Bianca Da Costa , Loubser Shayne , Strehlau Renate , Kuhn Louise , Tiemessen Caroline T.
Published: February 2024

Objective:

CCR5-tropic viruses are preferentially transmitted during perinatal HIV-1 infection. CCR5 density on CD4+ T-cells likely impacts susceptibility to HIV-1 infection.

Design:

Fifty-two mother–infant dyads were enrolled. All mothers were living with HIV-1, 27 of the infants acquired HIV-1 in utero and 25 infants remained uninfected.

Methods:

CCR5 density, together with frequencies of CD4+ and CD8+ T-cells expressing immune activation (CCR5, ICOS and HLA-DR) and immune checkpoint (TIGIT and PD-1) markers, were measured in whole blood from the dyads close to delivery.

Results:

Compared with mothers who did not transmit, mothers who transmitted HIV-1 had less exposure to ART during pregnancy (P = 0.015) and higher plasma viral load close to delivery (P = 0.0005). These mothers, additionally, had higher CCR5 density on CD4+ and CD8+ T-cells and higher frequencies of CCR5, ICOS and TIGIT-expressing CD8+ T-cells. Similarly, compared with infants without HIV-1, infants with HIV-1 had higher CCR5 density on CD4+ and CD8+ T-cells and higher frequencies of CCR5, TIGIT, and PD-1-expressing CD4+ and CD8+ T-cells as well as higher frequencies of HLA-DR-expressing CD8+ T-cells. CCR5 density on maternal CD4+ T-cells remained significantly associated with transmission after adjusting for maternal viral load and CD4+ T cell counts. Mother–infant dyads with shared high CCR5 density phenotypes had the highest risk of transmission/acquisition of infection compared with dyads with shared low-CCR5 density phenotypes.

Conclusion:

This study provides strong evidence of a protective role for a combined mother–infant low CD4+ T-cell CCR5 density phenotype in in-utero transmission/acquisition of HIV-1.
Immunization Simulation Using Actual-Size Infant Manikins for Medical Students in Indonesia
Authors: Gunardi Hartono , Wirahmadi Angga , Medise Bernie Endyarni , Sekartini Rini , Muktiarti Dina , Findyartini Ardi , Nadhif Muhammad Hanif , Sirait Agaprita E. , Soedjatmiko Soedjatmiko , Tengkawan Jeslyn
Published: February 2024

Introduction

Manikins are tools used in simulation training for medical students to develop important skills, one of which is immunization. However, conventional manikins often do not resemble the actual size of an infant's arm or leg. This study aimed to determine the impact of using actual-size manikins on students' knowledge and practical skills, evaluate their confidence in immunization practice, and assess students' responses and feedback regarding the practice using actual-size manikins.

Methods

This was a quasi-experimental study involving medical students at the Faculty of Medicine, Universitas Indonesia, from October 2020 to April 2021. Students in the intervention group used newly developed actual-size infant arm and leg manikins, while the control group used conventional manikins. All students underwent the objective structured clinical examination (OSCE) and the scores were compared between the 2 groups. Within the intervention group, data on pretest and posttest scores, feedback questionnaires, and self-confidence assessments were also obtained and analyzed.

Results

A total of 205 students were included. Statistically significant difference was found in the OSCE scores between the intervention and control groups (P < 0.01). Students in the intervention group (n = 108) showed significant improvement in knowledge scores after the workshop (P < 0.01). Most students (81.7%) expressed confidence in administering vaccines to live patients after practicing with manikins. In addition, 98.2% of students (n = 107) acknowledged the benefits of practicing with actual-size manikins in accurately determining the injection sites.

Conclusions

Simulation with the actual-size manikins significantly improved students' knowledge and practical immunization skills, leading to increased confidence and competence in their immunization skills.
Genotypic characterization of bacterial isolates causing urinary tract infections among adults at Kiambu Level 5 Hospital, Kenya: selected extended-spectrum β-lactamase genes and biofilm formation
Authors: Wanja Fredrick K. , Omwenga Eric O. , Ngugi Caroline W. , Maina John N. , Kiiru John N.
Published: February 2024

The menace of antimicrobial resistance affecting public health is rising globally. Many pathogenic bacteria use mechanisms such as mutations and biofilm formation, significantly reducing the efficacy of antimicrobial agents. In this cross-sectional study, we aimed to determine the prevalence of selected extended-spectrum β-lactamase (ESβL) genes and analyse the biofilm formation abilities of the isolated bacteria causing urinary tract infection among adult patients seeking Medicare at Kiambu Level 5 Hospital, Kenya. The double-disc synergy test was used for phenotypic identification of ESβL-producing isolates, while microtitre plate assays with some modifications were used for the biofilm formation test. Ten isolates were bioassayed for ESβL genes out of 57 bacterial isolates obtained from urine samples. This study found the bla

TEM
genes to be the most prevalent ESβL type [10/10 (100 %)], followed by blaOXA
and blaSHV
genes at 4/10 (40 %) and 3/10 (30 %), respectively. In addition, co-carriage of blaTEM
and blaSHV
was 50 % lower than that of blaTEM+bla
OXA genes at 66.7 % among

Escherichia coli

isolates studied. Biofilm formation was positive in 36/57 (63.2 %) of the isolates tested, with most being Gram-negative [25/36 (69.4 %)].

Escherichia coli

[15/36 (41.7 %)],

Klebsiella

species [7/36 (19.4 %)] and

Staphylococcus aureus

[7/36 (19.4 %)] were the dominant biofilm formers. However, there was no significant difference in biofilm formation among all tested isolates, with all isolates recording P-values >0.05. In light of these findings, biofilm formation potential coupled with antimicrobial resistance genes in urinary tract infection isolates may lead to difficult-to-treat infections.
Clinical impact and public health challenges of a PVL-MRSA bacteraemia outbreak amongst people who inject drugs in South Yorkshire, UK
Authors: Beaumont Matthew , Subramanian Bala , Agwuh Ken , Ryan Yan , Pichon Bruno
Published: February 2024

Background. Panton–Valentine leukocidin (PVL)

Staphylococcus aureus

(SA) is an emergent public health concern. PVL toxin has been mostly associated with methicillin-sensitive

S. aureus

(MSSA)-related skin and soft tissue infections occurring in high-risk groups such as people who inject drugs (PWID). The emergence of PVL methicillin-resistant

S. aureus

(MRSA) infection is causing severe and life-threatening disease in PWID.

Clinical cases. We present an outbreak of eight PVL-MRSA bacteraemia cases at a UK teaching hospital between 2018 and 2022. An additional four patients developed bacteraemia with PVL-negative MRSA of the same multilocus sequence type (MLST). All patients were PWID and aged 33–51 years old. Four patients developed MRSA bacterial endocarditis. Three patients died. These cases represent the initial cases detected at Doncaster and Bassetlaw Teaching Hospitals of what is an ongoing and developing outbreak.

Management. An outbreak investigation has been undertaken in association with the UK Health Security Agency. Epidemiological factors have been explored, including via direct contact at a local sheltered accommodation and the possibility of a contaminated drug supply. Whole-genome sequencing confirmed that all isolates were closely related and of the same MLST (sequence type 5). A community substance misuse group disseminated health education on the prevention of PVL-MRSA. Preventing infection in PWID presents a major challenge due to the impact of addiction on engagement with services and the significant barriers faced by our patients in observing infection prevention measures.

Conclusion. PVL-MRSA is of major public health concern and outbreak investigation and mapping out local epidemiological patterns plays a vital role in preventing further spread throughout the community. Additionally, this work enables targeted and early treatment in patients in high-risk categories for disease. These cases of PVL-MRSA infection in PWID highlights the transmissibility, pathogenic potential and severe clinical disease spectrum within this population. Further work is required to tackle transmission and infection from this pathogenic strain.
Changes to an intensive care unitAcinetobacter baumanniipopulation following COVID-19 disruptions and targeted infection prevention interventions
Authors: Liu Haiyang , Moran Robert A. , Doughty Emma L. , Hua Xiaoting , Snaith Ann E. , Zhang Linghong , Chen Xiangping , Guo Feng , van Schaik Willem , McNally Alan , Yu Yunsong
Published: February 2024

Carbapenem-resistantAcinetobacter baumannii(CRAB) is a persistent nosocomial pathogen that poses a significant threat to global public health. A three-month cross-sectional observational study was conducted in a 28-bed ICU in Hangzhou, China. The same ICU was sampled for the same duration and with a similar methodology in 2019, 20 months prior to the outset of this study. Following COVID-19-associated delays, a series of IPC measures targeting patients, staff and the ICU environment were implemented for 8 months prior to and throughout this study. A total of 5,341 samples were collected from the ICU environment (n = 4450) and patients (n = 891).A. baumanniiisolates were obtained from 9·5% of these samples (n = 505). MostA. baumanniiisolated in this ICU were CRAB (419/518; 80·9%). Fewer CRAB were isolated here (407 from 363 sampling occasions) than in 2019 (502 from 336 sampling occasions). However, MIC50/MIC90values for imipenem increased from 32/64 mg/L in the 2019 study to 64/128 mg/L here. This was accompanied by the proportion of global clone 2 (GC2) isolates falling from 99·5% in 2019 to 50·8% (213/419) in 2021. The phylogenetic diversity of GC2 increased, apparently driven by regular introductions of distinct clusters in association with patients. The remaining CRAB (40·2%; 206/419) were a highly clonal population of ST164, which appears to have persisted in the ICU since an introduction in mid-2020. We found clusters of GC2 and ST164 isolates with identical core genomes in different room or bed unit environments, and in multiple patients, indicative of transmission in the ICU.

Changes to IPC procedures in this ICU were associated with a reduction in the total prevalence of CRAB, and in the number of CRAB isolated from clinical specimens. At the phenotypic level, the CRAB population exhibited increased resistance to carbapenems, and this may be the result of increased antibiotic prescribing over the COVID-19 period. The increased diversity of this CRAB population appears to have been the result of repeated introductions to the ICU with patients, which have continued despite interventions.
The process of developing and piloting a tool in the Maldives and Zimbabwe for assessing disability inclusion in health systems performance
Authors: Kuper Hannah , Heydt Phyllis , Hameed Shaffa , Smythe Tracey , Kujinga Tapiwanashe
Published: February 2024

There are 1.3 billion people with disabilities globally. On average, they experience greater healthcare needs and more barriers accessing healthcare. Yet, health systems have failed to adequately include people with disabilities. The purpose of this study was to develop and pilot-test a tool for assessing disability inclusion in health system performance. We presented the “Missing Billion” disability-inclusive health system framework, which includes 4 system-level components and 5 service delivery components, and outputs and outcomes. We developed a tool, consisting of 48 indicators related to the framework components. We consulted international experts, who considered the framework and indicator set to be logical and comprehensive. The tool was pilot-tested in the Maldives (2020) and Zimbabwe (2021), working with local researchers to collect relevant data through document review and key informant interviews. The pilot data demonstrated that collecting data on the indicators was feasible. The tool highlighted areas where the health systems were performing well in terms of disability inclusion (e.g. governance) and other areas where there were large gaps (e.g. leadership) or lack of data (e.g. accessibility, outputs and outcomes). The indicators were updated and refined. We established a process for undertaking the assessment, highlighting the importance of leadership and ownership by the Ministry of Health, to facilitate data collection and implementation of recommendations. In conclusion, this new tool for assessing disability inclusion in health systems performance can help to identify key issues and guide and monitor action.

Highlights

–

There are 1.3 billion people with disabilities globally, and they often have poorer health and worse healthcare access than others in the population.

–

There is currently no comprehensive tool to assess how inclusive the healthcare system is for people with disabilities. The “Missing Billion” disability inclusive health system conceptual framework was proposed, together with 48 corresponding indicators. The indicator set allows description of the level of disability-inclusion in health systems.

–

The indicators were pilot-tested in the Maldives and Zimbabwe and were able to highlight areas of good practice, and identify where further improvements are needed. Some modifications were needed to the indicator set.

–

This new assessment approach can help policy makers, in particular at Ministries of Health, to identify key issues and guide action, and thereby may ultimately improve health systems for all.
Modelling and Preliminary Clinical Validation of Home-based Menstrual Neuromodulation Therapy
Authors: Radytė Emilė , Stankevičiūtė Laura , Bernatavičius Ervinas , Cook Alexander , Rodrigues Yvinna Tamiris , Lima de Alves Silva Tatiana Camila , Albuquerque Barbosa Cabral Micussi Maria Thereza , Pegado Rodrigo
Published: February 2024

Primary dysmenorrhea (PD), characterised by chronic pelvic pain during menstruation, significantly impairs the quality of life for many women. This paper presents a modelling and clinical validation study of the novel Nettle™ device for at-home transcranial direct current stimulation (tDCS) for alleviating PD symptoms. Specifically, we aimed to investigate the electric field patterns induced by Nettle™ and its immediate efficacy in reducing menstrual pain and improving functionality. Finite element method (FEM) simulations, using realistic head models, assessed the electric field distribution, targeting key brain regions involved in pain processing. A single-centre triple-blinded, sham-controlled study involving 34 women was conducted to compare the effects of active and sham tDCS. Results demonstrated a clinically meaningful decline in menstrual pain symptoms in the active group, with medium effect sizes for both pain reduction (Cohen’s d=0.53) and functionality (Cohen’s d=0.47), based on Nettle™’s protocol focused on the electric field within the medial prefrontal cortex. Limitations include the use of generalised brain models and small sample size, highlighting the need for further research with comprehensive modelling and larger clinical trials to validate and understand the effects of Nettle™ as a menstrual neuromodulation therapy.

Clinical Relevance

This study underscores Nettle™’s potential as a non-invasive, cost-efficient intervention for PD, with implications for broader applications in women’s health.
Modeling reveals the strength of weak interactions in stacked ring assembly
Authors: Lagunes Leonila , Briggs Koan , Martin-Holder Paige , Xu Zaikun , Maurer Dustin , Ghabra Karim , Deeds Eric J.
Published: February 2024

Cells employ many large macromolecular machines for the execution and regulation of processes that are vital for cell and organismal viability. Interestingly, cells cannot synthesize these machines as functioning units. Instead, cells synthesize the molecular parts that must then assemble into the functional complex. Many important machines, including chaperones like GroEL and proteases like the proteasome, are comprised protein rings that are stacked on top of one another. While there is some experimental data regarding how stacked-ring complexes like the proteasome self-assemble, a comprehensive understanding of the dynamics of stacked ring assembly is currently lacking. Here, we developed a mathematical model of stacked trimer assembly, and performed an analysis of the assembly of the stacked homomeric trimer, which is the simplest stacked ring architecture. We found that stacked rings are particularly susceptible to a form of kinetic trapping that we term “deadlock,” in which the system gets stuck in a state where there are many large intermediates that are not the fully-assembled structure, but that cannot productively react. When interaction affinities are uniformly strong, deadlock severely limits assembly yield. We thus predicted that stacked rings would avoid situations where all interfaces in the structure have high affinity. Analysis of available crystal structures indicated that indeed the majority – if not all – of stacked trimers do not contain uniformly strong interactions. Finally, to better understand the origins of deadlock, we developed a formal pathway analysis and showed that, when all the binding affinities are strong, many of the possible pathways are utilized. In contrast, optimal assembly strategies utilize only a small number of patwhays. Our work suggests that deadlock is a critical factor influencing the evolution of macromolecular machines, and provides general principles for not only understanding existing machines but also for the design of novel structures that can self-assemble efficiently.

Statement of Significance

Understanding the assembly macromolecular machines is important for understanding a wide range of cellular processes. Here, we use mathematical models to study the assembly of stacked rings, which are a common motif in these machines. Our models revealed that these complexes can readily get “stuck” during assembly when the binding affinity between subunits is too strong. This suggests an evolutionary pressure to favor weaker interactions, and our analysis of solved structures confirmed this prediction. Our findings not only contribute to the fundamental understanding of assembly but also offer insights into the evolutionary pressures shaping the architecture of stacked rings, and have implications for both cell and synthetic biology.
Multimodal single-cell profiling reveals cancer crosstalk between macrophages and stromal cells in poor prognostic cholangiocarcinoma patients
Authors: Heij Lara , Hayat Sikander , Reichel Konrad , Maryam Sidrah , O’Rourke Colm J. , Tan Xiuxiang , van den Braber Marlous , Verhoeff Jan , Halder Maurice , Peisker Fabian , Wiltberger Georg , Bednarsch Jan , Heise Daniel , Deierl Julia Campello , Lang Sven A. , Ulmer Florian , Luedde Tom , Dahl Edgar , Jonigk Danny , Nolting Jochen , Sivakumar Shivan , Siveke Jens , Rocha Flavio G. , Baba Hideo A. , Andersen Jesper B. , Garcia Vallejo Juan J. , Kramann Rafael , Neumann Ulf
Published: February 2024

Background and aims

Cholangiocarcinoma (CCA) is a deadly disease, and this cancer entity is characterized by an abundant stroma. The tumor microenvironment (TME) plays an important role in aggressive behavior and poor response to therapeutics; however, underlying pathways are unknown.

Methods

To fill this gap, we used multiplexed immunohistochemistry, high-dimensional phenotyping, and transcriptomics to analyze human CCA samples and identify cell cluster crosstalk in patients with a poor prognosis.

Results

Our findings confirmed the presence of Tregs and the lack of effector memory cells in the tumor. New findings are the spatiality of the effector memory cells being more present in the peripheral tissue, for some reason these immune cells fail to reach the tumor niche. We revealed cancer crosstalk with macrophages and stromal cells and identified responsible genes in the poor prognosis group. Amongst the responsible ligand pairs are GAS6-AXL belonging to the TAM family. We then identified VCAN-TLR2 to be present and influencing the ECM in a way to supports immune exhaustion. Last, EGFR-TGF-β is expressed in macrophages and this finding is important in Tregs induction and blocking cytotoxic T cell function.

Conclusions

The multiple mechanisms leading to the exclusion of relevant immune cells needed for an anti-cancer response and mechanisms leading to active immune suppression are part of complex cell-cell crosstalk. This study provides a deeper insight into the immune exhausted phenotype in CCA.
Deep learning-based proteomics enables accurate classification of bulk and single-cell samples
Authors: Krull Karl K. , Kühn Arlene , Höhn Julia , Brinker Titus J. , Krijgsveld Jeroen
Published: February 2024

Proteins are the main drivers of cell function and disease, making their analysis a powerful technique to characterize determinants of cell identity and to identify biomarkers. Current proteomic technology has the breadth to profile thousands of proteins and even the sensitivity to access single cells, however limitations in throughput restrict its application, e.g. not allowing classification of samples according to biological or clinical status in large sample cohorts. Therefore, we developed a deep learning-based approach for the analysis of mass spectrometric (MS) data, assigning proteomic profiles to sample identity. Specifically, we designed an architecture referred to as Proformer, and show that it is superior to convolutional neural network-driven architectures, is explainable, and demonstrates robustness towards batch-effects. Based on its tabular approach, we highlight the integration of all four dimensions of proteomic measurements (retention time, mass-to-charge, intensity and ion mobility), and demonstrate enhanced sample discrimination involving a treatment with IFN-γ, despite its subtle effect on the cell’s proteome. In addition, the Proformer is not restricted to proteomic depth, and can classify cells by cell type and their differentiation status even using single-cell proteomic data. Collectively, this work presents a novel deep learning-based model for rapid classification of proteomic data, with important future implications to enhance patient stratification, early detection and single-cell analysis.
Defining the conformational states that enable transglutaminase 2 to promote cancer cell survival versus cell death
Authors: Aplin Cody , Zielinski Kara A. , Pabit Suzette , Ogunribido Deborah , Katt William P. , Pollack Lois , Cerione Richard A. , Milano Shawn K.
Published: February 2024

Transglutaminase 2 (TG2) is a GTP-binding/protein-crosslinking enzyme that has been investigated as a therapeutic target for Celiac disease, neurological disorders, and aggressive cancers. TG2 has been suggested to adopt two conformational states that regulate its functions: a GTP-bound, closed conformation, and a calcium-bound, crosslinking-active open conformation. TG2 mutants that constitutively adopt an open conformation are cytotoxic to cancer cells. Thus, small molecules that maintain the open conformation of TG2 could offer a new therapeutic strategy. Here, we investigate TG2, using static and time-resolved small-angle X-ray scattering (SAXS) and single-particle cryoelectron microscopy (cryo-EM), to determine the conformational states responsible for conferring its biological effects. We also describe a newly developed TG2 inhibitor, LM11, that potently kills glioblastoma cells and use SAXS to investigate how LM11 affects the conformational states of TG2. Using SAXS and cryo-EM, we show that guanine nucleotide-bound TG2 adopts a monomeric closed conformation while calcium-bound TG2 assumes an open conformational state that can form higher order oligomers. SAXS analysis also suggests how a TG2 mutant that constitutively adopts the open state binds nucleotides through an alternative mechanism to wildtype TG2. Furthermore, we use time-resolved SAXS to show that LM11 increases the ability of calcium to drive TG2 to an open conformation, which is not reversible by guanine nucleotides and is cytotoxic to cancer cells. Taken together, our findings demonstrate that the conformational dynamics of TG2 are more complex than previously suggested and highlight how conformational stabilization of TG2 by LM11 maintains TG2 in a cytotoxic conformational state.

Significance Statement

The multi-functional protein transglutaminase 2 (TG2) undergoes large conformational changes in response to nucleotide and calcium binding, resulting in diverse cellular effects that can differentially promote either cancer cell survival or cell death. Previous biochemical and structural characterizations have revealed that TG2 primarily adopts two conformational states, a closed nucleotide-bound conformation, and an open calcium-bound conformation. In this study, we use advanced structural methods to describe the conformational changes associated with TG2 activation and inhibition and define the mechanism by which small molecule inhibitors maintain TG2 in a structural state that kill cancer cells.
Myoelectric Prosthesis Control using Recurrent Convolutional Neural Network Regression Mitigates the Limb Position Effect
Authors: Williams Heather E. , Shehata Ahmed W. , Cheng Kodi Y. , Hebert Jacqueline S. , Pilarski Patrick M.
Published: February 2024

Although state-of-the-art myoelectric prostheses offer persons with upper limb amputation extensive movement capabilities, users have not been afforded a reliable means to control common movements required in daily living. Many proposed prosthesis controllers use pattern recognition, a method that learns and recognizes patterns of electromyographic (EMG) signals produced by the user’s residual limb muscles to predict and execute device movements. Such control becomes unreliable in high limb positions—a problem known as the limb position effect. Pattern recognition often uses a classification algorithm; simple to implement, but limits user-initiated control to only one device movement at a time, at a single speed. To combat position-related control deficiencies and classification controller constraints, we developed and tested two recurrent convolutional neural network (RCNN) pattern recognition-based solutions: (1) an RCNN classification controller that uses EMG plus positional inertial measurement unit (IMU) signals to offer one-speed, sequential movement control; and (2) an RCNN regression controller that uses the same data capture technique to offer simultaneous control of multiple movements and device movement velocity. We assessed both RCNN controllers by comparing them to a commonly used linear discriminant analysis classification controller (LDA-Baseline). Participants without upper limb impairment were recruited to perform multipositional tasks while wearing a simulated prosthesis. Both RCNN classification and regression controllers showed improved functional task performance over LDA-Baseline, in 11 and 38 out of 115 metrics, respectively. This work contributes an RCNN regression-based controller that provides accurate, simultaneous, and proportional movements to EMG-based technologies including prostheses, exoskeletons, and even muscle-activated video games.
SIRT7 regulates NUCKS1 chromatin binding to elicit metabolic and inflammatory gene expression in senescence and liver aging
Authors: Tran Khoa , Gilbert Michael , Vazquez Berta N. , Ianni Alessandro , Garcia Benjamin A. , Vaquero Alejandro , Berger Shelley
Published: February 2024

Sirtuins, a class of highly conserved histone/protein deacetylases, are heavily implicated in senescence and aging. The regulation of sirtuin proteins is tightly controlled both transcriptionally and translationally and via localization within the cell. While Sirtiun proteins are implicated with aging, how their levels are regulated during aging across cell types and eliciting tissue specific age-related cellular changes is unclear. Here, we demonstrate that SIRT7 is targeted for degradation during senescence and liver aging. To uncover the significance of SIRT7 loss, we performed proteomics analysis and identified a new SIRT7 interactor, the HMG box protein NUCKS1. We found that the NUCKS1 transcription factor is recruited onto chromatin during senescence and this is mediated by SIRT7 loss. Further, depletion of NUCKS1 delayed senescence upon DNA damage leading to reduction of inflammatory gene expression. Examination of NUCKS1 transcriptional regulation during senescence revealed gene targets of transcription factors NFKB1, RELA, and CEBPβ. Consistently, in both Sirt7 KO mouse liver and in naturally aged livers, Nucks1 was recruited to chromatin. Further, Nucks1 was bound at promoters and enhancers of age-related genes, including transcription factor Rela, and, moreover, these bound sites had increased accessibility during aging. Overall, our results uncover NUCKS1 as a novel interactor of SIRT7, and show that loss of SIRT7 during senescence and liver aging promotes NUCKS1 chromatin binding to regulate metabolic and inflammatory genes.