bluuebunny/crossref_metadata_2025 huggingface dataset:
P27 Chloride intracellular channel 4 is a global regulator of type 1 interferon signalling in systemic sclerosis skin
Authors: Wasson Christopher , Dibb Sophie , Bryon Jessica , Caballero-Ruiz Begoña , Clavane Eva , Wells Rebecca , Kakkar Vishal , De Lorenzis Enrico , Ross Rebecca , Meakin Paul , Del Galdo Francesco
Published: May 2024

Introduction and aims

Systemic sclerosis (SSc) is an autoimmune disease in which an immune-related injury induces fibrosis of the skin and can progress to affect the internal organs in the most serve cases. Aberrant type 1 interferon (IFN) signalling in the keratinocytes plays a major role in SSc disease progression. We have previously shown the chloride intracellular channel 4 (CLIC)4 is upregulated in SSc skin fibroblasts and plays an important role in SSc fibrosis by enhancing transforming growth factor-β signalling. In this study, we investigated the role of CLIC4 in SSc keratinocyte biology.

Methods

Skin biopsies from patients with SSc (N = 6) and healthy controls (HCs) (N = 6) were analysed by immunohistochemistry for the expression of CLIC4 and phosphorylated signal transducer and activator of transcription (STAT)1. The skin keratinocyte cell line HaCaTs was stimulated with a range of type 1 IFN signalling agonists including POLY I:C, POLY dA:dT, ODN 2216 and IFN-α. CLIC4 was inhibited with the chloride channel inhibitors NPPB and IAA-94 or small interfering RNA specific to CLIC4. Conditioned media from HC or SSc dermal fibroblasts was employed for indirect coculture of HaCaTs.

Results

Skin biopsies from SSc showed high levels of CLIC4 in SSc skin fibroblasts, keratinocytes and endothelial cells compared with HC. Indirect coculture of HaCaTs with SSc fibroblast media induced CLIC4 expression in the HaCaTs. The increased CLIC4 expression played an important role in type 1 IFN signalling in keratinocytes as inhibition of CLIC4 blocked Toll-like receptor (TLR)3, TLR9 and cGAS-mediated activation of the type 1 IFN signalling pathway transcription factor STAT1. Additionally, inhibition of CLIC4 prevented SSc fibroblast media from inducing a type 1 IFN response in keratinocytes.

Conclusions

The data presented in this study suggests that CLIC4 is a global regulator of the type 1 IFN signalling cascade in SSc epithelial cells.
P28 Data-independent acquisition mass spectrometry improves spatially resolved analysis of the human skin proteome
Authors: Ozorun Gulsev , Eckersley Alexander , Bradley Eleanor , Watson Rachel , Sherrat Michael , Swift Joe
Published: May 2024

Introduction and aims

Proteomic analysis of the extracellular matrix (ECM) presents challenges because of the highly crosslinked and low-solubility nature of ECM proteins. Traditional homogenization and protein digestion approaches result in the loss of crucial information regarding protein localization and spatial relationships. To address this, spatially resolved proteomics emerges as a powerful tool for exploring heterogeneity within bulk tissues. This study aims to determine the minimum tissue volume required for comprehensive proteome coverage using data-independent acquisition mass spectrometry (DIA-MS) on skin tissue. The study focused on optimizing spatially resolved proteomic techniques to enhance depth-of-analysis while preserving spatial specificity.

Methods

Human abdominal skin biopsies were obtained from a single individual and subsequently cryosectioned. Histological assessment was performed through haematoxylin and eosin staining for visualization purposes. Laser-capture microdissection coupled with mass spectrometry facilitated the precise isolation of target regions. Comparative analyses were performed between data-dependent acquisition mass spectrometry (DDA-MS) and DIA-MS, with a particular emphasis on ECM proteins within the dermis.

Results

Our findings revealed an improvement in proteome coverage with DIA-MS compared with DDA-MS, in addition to clear scaling relationships between the depth-of-analysis and sample concentration. The Results demonstrated the superiority of DIA-MS in achieving robust and comprehensive proteomic profiles, even with minimal tissue volumes. Preliminary findings suggest the capability of DIA-MS in elucidating the complexities of the skin proteome with spatial resolution.

Conclusions

In conclusion, our study highlights the efficacy of DIA-MS in spatially resolved proteomics on skin tissue. The optimized approach presented here offers a reliable and efficient method for obtaining in-depth proteome information with minimal tissue requirements. These Results form the foundation for ongoing experiments, utilizing DIA-MS to advance spatially resolved proteomic analyses of human skin.
P31 Modelling epidermal melanocytes behaviour during plaque psoriasis resolution
Authors: Lussoso Sarah , Kirby Brian , Tobin Desmond
Published: May 2024

Introduction and aims

Melanocytes in the human epidermis exist in the stratum basale at a ratio of 1 melanocyte to approximately 10 keratinocytes. They do not divide, even upon ultraviolet radiation stimulation, and do not appear to apoptose. In psoriasis, this melanocyte/keratinocyte ratio is retained, despite the enormous keratinocyte hyperplasia, inferring a commensurate expansion in melanocyte number. Therefore, here we investigate whether melanocyte number is altered following the reduction of keratinocytes upon treatment of psoriasis plaques with biologic therapy.

Methods

Matching lesional and nonlesional epidermis sets of patients (n = 4) at day 0 and after 4 and 12 weeks of treatment were compared with healthy controls. To assess the presence of apoptotic melanocytes, the terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) assay was performed. Immunohistochemistry with microphthalmia-associated transcription factor (melanocyte marker) and Ki-67 (proliferation marker) was used to assess melanocyte proliferation. Finally, melanocyte number per mm of basal layer and melanocyte/keratinocyte ratio were estimated by image analysis using ImageJ.

Results

Proliferating melanocytes were detected in nonlesional and lesional samples and in resolving plaques after 4 and 12 weeks of treatment but not in healthy epidermis. Melanocyte number per mm of basal layer was significantly higher in nonlesional than lesional sections compared with healthy controls (P < 0.01) suggesting that melanocyte expansion already occurs prior to lesion establishment, revealing early melanocyte deregulation. After 4 and 12 weeks of treatment the number of melanocytes in lesional and nonlesional sections was still significantly higher than controls (P < 0.05) and had not returned to normal despite the dramatic reduction in keratinocytes. The TUNEL assay did not detect evidence of melanocyte apoptosis.

Conclusions

This study shows that rare melanocyte proliferation occurs in nonlesional psoriasis skin and in resolving lesional skin. Given our inability to detect apoptotic melanocytes, it remains unclear how melanocyte numbers return to normal after plaque resolution These unique findings support a role for melanocytes in psoriasis pathogenesis and encourage further investigation.
P35 Adaptation of a phenotypic screening assay to incorporate 384-well plates: opening the door to high-throughput screening
Authors: Feltham Kieran , Lapthorn Alice , Ilg Marcus , Dziewulski Peter , Cellek Selim
Published: May 2024

Introduction and aims

High-throughput screening has significantly impacted drug discovery by increasing speed of experiments and reducing reagent and sample costs. We have previously developed several screening assays to measure myofibroblast inhibition via quantification of α-smooth muscle actin (α-SMA) expression, in a 96-well format. Currently, there are no drugs for the treatment of hypertrophic scarring, a major side-effect of burn injuries that occurs by myofibroblast transformation, leaving a huge gap in this sector. The aim for this project was to adapt our current assay for use in 384-well microplates.

Methods

Human primary dermal fibroblasts were transformed to myofibroblasts using 10 ng mL−1 transforming growth factor (TGF)-β1. α-SMA expression was measured using the In-Cell enzyme-linked immunosorbent assay method, with cell viability measured using DRAQ5 nuclear staining. Assay accuracy and reliability was determined by calculating the robust z-factor, with guidelines set to an average score over 0.5, with a minimum score per plate above 0.4. To further validate the assay, concentration-response curves (CRCs) for the drug vehicle [dimethyl sulfoxide (DMSO)] and our tool compound (SB-505124) were constructed at varying concentrations, in coincubation with TGF-β1.

Results

Optimization of well metrics was performed, producing an average robust z-factor of 0.52, confirming the assay Results are reliable and reproducible. The DMSO CRC produced no significant drop in cell viability at concentrations that are expected to be used in the screening of compounds. Our tool compound (SB-505124) produced a concentration-dependant curve for the inhibition of myofibroblast transformation.

Conclusions

A 384-well assay has been designed, tested and validated for the determination of myofibroblast transformation in human primary dermal fibroblasts. The assay has been shown to deliver an average robust z-factor of above 0.5, it contains a positive control and is compatible with compounds stored in up to 100% DMSO.
P37 Drug repurposing for treatment of recessive dystrophic epidermolysis bullosa cutaneous squamous cell carcinoma
Authors: Pritchard John , Dayal Jasbani , Schoenherr Christina , Raponi Michela , Anand Jayanthi , McGarry Lynn , Corbyn Ryan , Carlin Leo , Blyth Karen , Inman Gareth
Published: May 2024

Background

Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited skin disorder that leads to severe wounding and blistering of the skin. Patients with RDEB develop aggressive cutaneous squamous cell carcinoma (cSCC) with a mortality rate of approximately 90% by age 55 years. The current primary treatment is wide excision of tumours, often leading to amputations. Identifying new therapeutic avenues for RDEB cSCC remains a priority. Here, we approach this in two ways. Firstly, we identified a SMAD4-dependent sphingosine pathway response to endogenous transforming growth factor (TGF)-β, essential for RDEB cSCC proliferation which could be targeted as a potential therapeutic strategy. Secondly, we utilized a US Food and Drug Administration (FDA) screen of > 3000 drugs to identify potential druggable pathways that could be used to treat RDEB cSCC.

Methods

RDEB cSCC cell lines were used to test Siponimod, a sphingosine-1 receptor modulator, on proliferation, clonogenicity and invasion in vitro. Siponimod was used in vivo to test tumour growth effect of targeting the sphingosine pathway. We carried out an FDA-approved drug screen on four RDEB cSCC cell lines using the Opera Phenix high-throughput microscope to identify targets.

Results

Treatment of RDEB cSCC cell lines with Siponimod showed compromised proliferation compared with untreated cells in addition to significant reduction in colony formation. There was a significant decrease in the invasive capability of RDEB SCC cells. Treatment of normal human keratinocytes showed no effect on proliferation. Our FDA-approved screen identified multiple drugs that target MEK, mechanistic target of rapamycin complex, histone deacetylase, signal transducer and activator of transcription, and topoisomerase I/II in the top 50 hits. The most common target was DNA damage/repair pathways, but cytoskeletal signalling, transmembrane transporters and proteases were identified as other potential avenues for treatment of RDEB cSCC.

Conclusions

There is an unmet need for therapeutic options in RDEB cSCC. Here, we have demonstrated the potential of repurposing previously licensed drugs to identify treatment avenues for RDEB cSCC.
Overall survival after mastectomy versus breast-conserving surgery with adjuvant radiotherapy for early-stage breast cancer: meta-analysis
Authors: Rajan Kiran K , Fairhurst Katherine , Birkbeck Beth , Novintan Shonnelly , Wilson Rebecca , Savović Jelena , Holcombe Chris , Potter Shelley
Published: May 2024

Background

Breast-conserving surgery with adjuvant radiotherapy and mastectomy are currently offered as equivalent surgical options for early-stage breast cancer based on RCTs from the 1970s and 1980s. However, the treatment of breast cancer has evolved and recent observational studies suggest a survival advantage for breast-conserving surgery with adjuvant radiotherapy. A systematic review and meta-analysis was undertaken to summarize the contemporary evidence regarding survival after breast-conserving surgery with adjuvant radiotherapy versus mastectomy for women with early-stage breast cancer.

Methods

A systematic search of MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL), and Embase that identified studies published between 1 January 2000 and 18 December 2023 comparing overall survival after breast-conserving surgery with adjuvant radiotherapy versus mastectomy for patients with unilateral stage 1–3 breast cancer was undertaken. The main exclusion criteria were studies evaluating neoadjuvant chemotherapy, rare breast cancer subtypes, and specific breast cancer populations. The ROBINS-I tool was used to assess risk of bias, with the overall certainty of evidence assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool. Studies without critical risk of bias were included in a quantitative meta-analysis.

Results

From 11 750 abstracts, 108 eligible articles were identified, with one article including two studies; 29 studies were excluded from the meta-analysis due to an overall critical risk of bias, 42 studies were excluded due to overlapping study populations, and three studies were excluded due to reporting incompatible results. A total of 35 observational studies reported survival outcomes for 909 077 patients (362 390 patients undergoing mastectomy and 546 687 patients undergoing breast-conserving surgery with adjuvant radiotherapy). The pooled HR was 0.72 (95% c.i. 0.68 to 0.75, P < 0.001), demonstrating improved overall survival for patients undergoing breast-conserving surgery with adjuvant radiotherapy. The overall certainty of the evidence was very low.

Conclusion

This meta-analysis provides evidence suggesting a survival advantage for women undergoing breast-conserving surgery with adjuvant radiotherapy for early-stage breast cancer compared with mastectomy. Although these results should be interpreted with caution, they should be shared with patients to support informed surgical decision-making.
Older Adult Homicide: Investigating Case, Victim and Perpetrator Characteristics in a National Sample from England and Wales
Authors: Storey Jennifer E , Rogers Michaela M , Hohn Richard E
Published: May 2024

Older adult homicide (OAH) is the most severe, yet understudied, form of older adult abuse. This study examined the case, victim and perpetrator characteristics of OAH. A secondary analysis of national data from England and Wales (2008–2019) was conducted where cases of non-stranger OAH (victims aged sixty years and over) were compared to adult homicide (victims aged eighteen to fifty-nine years) at the case, victim (n = 3,274) and perpetrator (n = 2,763) levels. Logistic regression models used to identify characteristics that were OAH risk factors, showed only a slight increase in predictive power but high accuracy in classifying adult homicide cases. Nevertheless, some risk factors known to be predictors of older adult abuse were significant predictors of OAH (e.g. living with the perpetrator, the perpetrator’s mental state). Implications for research, policy and practice are discussed.
Effects of evening smartphone use on sleep and declarative memory consolidation in male adolescents and young adults
Authors: Höhn Christopher , Hahn Michael A , Gruber Georg , Pletzer Belinda , Cajochen Christian , Hoedlmoser Kerstin
Published: May 2024

Exposure to short-wavelength light before bedtime is known to disrupt nocturnal melatonin secretion and can impair subsequent sleep. However, while it has been demonstrated that older adults are less affected by short-wavelength light, there is limited research exploring differences between adolescents and young adults. Furthermore, it remains unclear whether the effects of evening short-wavelength light on sleep architecture extend to sleep-related processes, such as declarative memory consolidation. Here, we recorded polysomnography from 33 male adolescents (15.42 ± 0.97 years) and 35 male young adults (21.51 ± 2.06 years) in a within-subject design during three different nights to investigate the impact of reading for 90 min either on a smartphone with or without a blue-light filter or from a printed book. We measured subjective sleepiness, melatonin secretion, sleep physiology and sleep-dependent memory consolidation. While subjective sleepiness remained unaffected, we observed a significant melatonin attenuation effect in both age groups immediately after reading on the smartphone without a blue-light filter. Interestingly, adolescents fully recovered from the melatonin attenuation in the following 50 min before bedtime, whereas adults still, at bedtime, exhibited significantly reduced melatonin levels. Sleep-dependent memory consolidation and the coupling between sleep spindles and slow oscillations were not affected by short-wavelength light in both age groups. Nevertheless, adults showed a reduction in N3 sleep during the first night quarter. In summary, avoiding smartphone use in the last hour before bedtime is advisable for adolescents and young adults to prevent sleep disturbances. Our research empirically supports general sleep hygiene advice and can inform future recommendations regarding the use of smartphones and other screen-based devices before bedtime.
Palladium-iron bimetallic-catalyzed cross-coupling reaction of alcohols and nitroarenes using a hydrogen-transfer redox system
Authors: Horikawa Rikiya , Ishii Shoma , Shinozaki Urara , Midorikawa Reika , Mori Takamichi , Kimura Masanari
Published: May 2024

A Pd/Fe bimetallic catalyst in the presence of the Xantphos ligand promoted the cross-coupling reaction of alcohols and nitroarenes via a hydrogen-transfer redox system. The consecutive formation of aldimines from benzyl alcohols and nitroarenes proceeded in three steps in a single manipulation: oxidation of alcohols, reduction of nitroarenes, and dehydrative condensation of aldehydes and aminoarenes.
CMR characterization of patients with heart failure and left bundle branch block
Authors: Tomoaia Raluca , Harrison Peter , Bevis Lydia , Wahab Ali , Thompson Patrick , Saunderson Christopher E D , Levelt Eylem , Dall’Armellina Erica , Garg Pankaj , Greenwood John P , Plein Sven , Swoboda Peter P
Published: May 2024

Aims

We aimed to identify the distinctive cardiovascular magnetic resonance (CMR) features of patients with left bundle branch block (LBBB) and heart failure with reduced ejection fraction (HFrEF) of presumed non-ischaemic aetiology. The secondary aim was to determine whether these individuals exhibit characteristics that could potentially serve as predictors of left ventricular ejection fraction (LVEF) recovery as compared with patients without LBBB.

Methods and results

We prospectively recruited patients with HFrEF (LVEF ≤ 40%) on echocardiography who were referred for early CMR examination. Patients with an established diagnosis of coronary artery disease and known structural or congenital heart disease were excluded. LV recovery was defined as achieving ≥10% absolute improvement to ≥40% in LVEF between baseline evaluation to CMR. A total of 391 patients were recruited including 115 (29.4%) with LBBB. Compared with HF patients without LBBB, those with LBBB exhibited larger left ventricles and smaller right ventricles, but no differences were observed with respect to LVEF (35.8 ± 12 vs. 38 ± 12%, P = 0.105). The overall rate of LV recovery from baseline echocardiogram to CMR (70 [42–128] days) was not significantly different between LBBB and non-LBBB patients (27.8% vs. 31.5%, P = 0.47). Reduced LVEF remained an independent predictor of LV non-recovery only in patients with LBBB.

Conclusion

Patients presenting with HFrEF and LBBB had larger LV cavities and smaller RV cavities than those without LBBB but no difference in prevalence of scar or ischaemia. The rates of LV recovery were similar between both groups, which supports current guidelines to defer device therapy until 3–6 months of guideline-directed medical therapy, rather than early CMR and device implantation.
Pre-eclampsia and long-term risk of arrhythmias
Authors: Havers-Borgersen Eva , Stahl Anna , Johansen Marianne , Jøns Christian , Køber Lars , Fosbøl Emil L
Published: May 2024

Aims

Pre-eclampsia (PE), a pregnancy-induced hypertensive disorder, affects 4–5% of pregnancies worldwide. It is well known that hypertension is associated with an increased risk of arrhythmias; however, data on the association between PE and arrhythmias are sparse.

Methods and results

In this observational cohort study, we identified all primiparous women who gave birth in Denmark (1997–2016) using Danish nationwide registries. The women were stratified on whether they developed PE during primiparous pregnancy and followed from primiparous pregnancy to incident arrhythmia, emigration, death, or end of study (31 December 2018). A total of 523 271 primiparous women with a median age of 28 years were included, and 23 367 (4.5%) were diagnosed with PE. During a median follow-up of 10.1 years, women with and without PE were associated with a higher incidence of arrhythmias (1.42 vs. 1.02%): (i) composite of cardiac arrest, ventricular tachycardia/fibrillation, or implantable cardioverter defibrillator implantation [adjusted hazard ratio (HR) 1.60, 95% confidence interval (CI) 1.14–2.24], (ii) composite of advanced second- or third-degree atrioventricular block, sinoatrial dysfunction, or pacemaker implantation [adjusted HR 1.48 (95% CI 0.97–2.23)], (iii) composite of supraventricular tachyarrhythmias or extra systoles [adjusted HR 1.34 (95% CI 1.19–1.51)], and (iv) composite of all the above-mentioned arrhythmias [adjusted HR 1.37 (95% CI 1.23–1.54)].

Conclusion

Pre-eclamptic women were associated with a significantly and at hitherto unknown long-term increased rate of arrhythmias. This finding suggests that women with PE may benefit from cardiovascular risk assessment, screening, and preventive education.
Designing, piloting and evaluating (through a matched pre- and post-implementation survey) a targeted e-learning resource on antimicrobial resistance for public health professionals
Authors: Taylor Hannah M , Mearkle Rachel A , Huyton Rita A M , Ashiru-Oredope Diane
Published: May 2024

Background

Antimicrobial resistance (AMR) is a significant global public health threat and key priority for the public health, especially health protection, workforce to lead by example. There is a paucity of learning resources on this for public health professionals (PHPs) in the UK. This project aimed to develop and disseminate a tailored interactive learning resource and evaluate impact on self-reported intention to change behaviour.

Methods

Learning objectives were agreed, content developed by the multi-disciplinary team and piloted by PHPs in 2022 alongside a matched pre- and post-implementation evaluation survey. Questions were mapped to the capability–opportunity–motivation–behaviour change model. Before and after responses were calculated to compare change in self-reported knowledge, understanding and behaviour. Significance of change in binary responses was estimated.

Results

The resource was delivered using an interactive, user-friendly and cost-free internal platform. Thirty-one PHPs completed the pilot e-learning and survey. Perceived and actual knowledge increased in parallel. Actual knowledge on AMR burden increased from 6.45 to 35.48% (P = 0.004). Self-reported confidence to explain AMR to others improved by 0.71 (95% CI; 0.38–1.04: P = 0.0001) Likert points on a five-point scale. Motivation to advocate for antimicrobial stewardship (AMS) in day-to-day work, improved by 0.71 (95% CI; 0.34–1.08: P < 0.00001) Likert points. Case scenarios were well-received as an effective way to apply theory to practice.

Conclusion

Ensuring a well-informed and confident public health workforce is vital for reducing the AMR threat and advocating for AMS with the public and partner organizations. This targeted e-learning module is an effective additional learning medium in contributing to PHPs knowledge, understanding and self-reported intention to change behaviours.
Association of Alzheimer’s Disease and Other Neuropathologies With Functional Disability in Persons With and Without Dementia
Authors: Farfel Jose M , Capuano Ana W , Buchman Aron S , Schneider Julie A , Bennett David A
Published: May 2024

Background

Dementia results from multiple neuropathologies causing cognitive impairment sufficiently severe to affect functional status. However, these pathologies and functional impairment are common in persons without dementia. We examined the association of Alzheimer’s disease (AD) and multiple other neuropathologies with instrumental and basic activities of daily living in persons with and without dementia.

Methods

Participants were 1 509 deceased from the Religious Orders Study or Rush Memory and Aging Project. Pathologic AD and 3 other AD indices were examined, in addition to 4 non-AD neurodegenerative pathologies: cerebral amyloid angiopathy (CAA), hippocampal sclerosis, TDP-43, and Lewy bodies, and 4 cerebrovascular pathologies: gross- and microinfarctions, athero- and arteriolosclerosis. Functional assessment included Lawton and Katz Index Instrumental and Basic Activities of Daily Living (IADL and BADL). Ordinal regression models adjusted for age, sex, and education were used to examine the association of neuropathologies with IADL and BADL.

Results

Alzheimer’s disease and the other neuropathologies were associated with impaired IADL (all ps < .001) and with impaired BADL (ps < .01), except for atherosclerosis and CAA, which were not associated with BADL. The effects of most neuropathologies were largely affected by dementia. However, small effects on IADL remained for PHF-tau tangles after adjusting models for dementia. Direct effects of gross infarcts on IADL and BADL and of microinfarcts on BADL remained unchanged after adjusting the models for dementia.

Conclusions

Alzheimer’s disease and all other neuropathologies are strongly associated with functional disability. The association of most neuropathologies with disability was eliminated or attenuated by dementia, except for gross infarcts and microinfarcts.
Comparing health systems readiness for integrating domestic violence services in Brazil, occupied Palestinian Territories, Nepal and Sri Lanka
Authors: Colombini Manuela , Shrestha Satya , Pereira Stephanie , Kalichman Beatriz , Siriwardhana Prabhash , Silva Tharuka , Halaseh Rana , d’Oliveira Ana Flavia , Rishal Poonam , Bhatt Pusp Raj , Shaheen Amira , Joudeh Nagham , Rajapakse Thilini , Alkaiyat Abdulsalam , Feder Gene , Moreno Claudia Garcia , Bacchus Loraine J
Published: May 2024

Domestic violence (DV) is a global prevalent health problem leading to adverse health consequences, yet health systems are often unprepared to address it. This article presents a comparative synthesis of the health system’s pre-conditions necessary to enable integration of DV in health services in Brazil, Nepal, Sri Lanka and occupied Palestinian Territories (oPT). A cross-country, comparative analysis was conducted using a health systems readiness framework. Data collection involved multiple data sources, including qualitative interviews with various stakeholders; focus-group discussions with women; structured facility observations; and a survey with providers. Our findings highlight deficiencies in policy and practice that need to be addressed for an effective DV response. Common readiness gaps include unclear and limited guidance on DV, unsupportive leadership coupled with limited training and resources. Most providers felt unprepared, lacked guidance and felt unsupported and unprotected by managers and their health system. While in Brazil most providers felt they should respond to DV cases, many in Sri Lanka preferred not to. Such organizational and service delivery challenges, in turn, also affected how health providers responded to DV cases leaving them not confident, uncertain about their knowledge and unsure about their role. Furthermore, providers’ personal beliefs and values on DV and gender norms also impacted their motivation and ability to respond, prompting some to become ‘activists’ while others were reluctant to intervene and prone to blame women. Our synthesis also pointed to a gap in women’s use of health services for DV as they had low trust in providers. Our conceptual framework demonstrates the importance of having clear policies and highlights the need to engage leadership across every level of the system to reframe challenges and strengthen routine practices. Future research should also determine the ways in which women’s understanding and needs related to DV help-seeking are addressed.
Combined or High Dose Immunosuppression in Inflammatory Bowel Disease patients who are NUDT15 Homozygous Harbors Risk of Developing Invasive Fungal Infections: A Case Series
Authors: Thomas David Mathew , Mundhra Sandeep Kumar , Prasad Shubham , Swaroop Shekhar , Arora Umang , Ahmed Syed , Bhalla Ashu Seith , Sharma Raju , Das Prasenjit , Kedia Saurabh , Ahuja Vineet
Published: May 2024

Lay Summary

NUDT15 homozygous mutations predispose patients to severe leucopenia, which invites risk of disseminated fungal infections when high doses or a combination of immunosuppressives are administered in this patient population.
An equilibrated estimator for mixed finite element discretizations of the curl-curl problem
Authors: Chaumont-Frelet T
Published: May 2024

We propose a new a posteriori error estimator for mixed finite element discretizations of the curl-curl problem. This estimator relies on a Prager–Synge inequality, and therefore leads to fully guaranteed constant-free upper bounds on the error. The estimator is also locally efficient and polynomial-degree-robust. The construction is based on patch-wise divergence-constrained minimization problems, leading to a cheap embarrassingly parallel algorithm. Crucially, the estimator operates without any assumption on the topology of the domain, and unconventional arguments are required to establish the reliability estimate. Numerical examples illustrate the key theoretical results, and suggest that the estimator is suited for mesh adaptivity purposes.
The Wasserstein Distance for Ricci Shrinkers
Authors: Conrado Franciele , Zhou Detang
Published: May 2024

Let $(M^{n},g,f)$ be a Ricci shrinker such that $\text{Ric}_{f}=\frac{1}{2}g$ and the measure induced by the weighted volume element $(4\pi )^{-\frac{n}{2}}e^{-f}dv_{g}$ is a probability measure. Given a point $p\in M$, we consider two probability measures defined in the tangent space $T_{p}M$, namely the Gaussian measure $\gamma $ and the measure $\overline{\nu }$ induced by the exponential map of $M$ to $p$. In this paper, we prove a result that provides an upper estimate for the Wasserstein distance with respect to the Euclidean metric $g_{0}$ between the measures $\overline{\nu }$ and $\gamma $, and which also elucidates the rigidity implications resulting from this estimate.
Forget Me Not: Incidental Findings on Breast MRI
Authors: Chung Maggie , Ton Lauren , Lee Amie Y
Published: May 2024

With the growing utilization and expanding role of breast MRI, breast imaging radiologists may encounter an increasing number of incidental findings beyond the breast and axilla. Breast MRI encompasses a large area of anatomic coverage extending from the lower neck to the upper abdomen. While most incidental findings on breast MRI are benign, identifying metastatic disease can have a substantial impact on staging, prognosis, and treatment. Breast imaging radiologists should be familiar with common sites, MRI features, and breast cancer subtypes associated with metastatic disease to assist in differentiating malignant from benign findings. Furthermore, detection of malignancies of nonbreast origin as well as nonmalignant, but clinically relevant, incidental findings can significantly impact clinical management and patient outcomes. Breast imaging radiologists should consistently follow a comprehensive search pattern and employ techniques to improve the detection of these important incidental findings.
Healthcare Sustainability to Address Climate Change: Call for Action to the Infectious Diseases Community
Authors: Doshi Shreya , Vuppula Sharon , Jaggi Preeti
Published: May 2024

The US healthcare system’s contribution to greenhouse gas emissions and climate change is disproportionately high and harms the public. Several medical specialties are now reassessing how they can mitigate healthcare’s harmful environmental impact. Healthcare sustainability is broadly defined as measures to decrease greenhouse gas emissions, waste, and other pollutants generated during the healthcare delivery process. Prior efforts and programs by infectious diseases (ID) professionals, such as antimicrobial stewardship and infection prevention and control can form a framework for ID professionals to help apply this expertise to healthcare environmental sustainability more broadly. This call to action proposes strategies for ID societies and professionals to incorporate climate change education for trainees, increase research and funding opportunities in healthcare sustainability, and calls for action by ID societies to champion system changes to decrease greenhouse gas emissions.
Effectiveness of In-Theater Mental Health Assessments
Authors: Perez SarahLouise , Dimayuga Hasan U , Estrada Kevin M , Flores Adan , Hall Andrew B
Published: May 2024

Introduction

The leading cause for medical evacuation from the U.S. Central Command area of responsibility is because of mental health conditions. The In-Theater Mental Health Assessment (ITMHA) is a DoD-required screening of deployed personnel. It is vital to examine the efficacy of ITMHA’s potential to significantly impact the mental health outcomes of service members.

Materials and Methods

All ITMHA results of individuals in 2 deployed Army battalions along with a brigade headquarters deployed to U.S. Central Command between October 2022 and October 2023 were collected and analyzed. Descriptive statistics were used to characterize the results of the ITMHA.

Results

Of 670 deployed service members, 157 (23%) scored positive on ITMHA. Ten service members were referred for additional mental health evaluation. The remaining 147 (22%) service members who scored positive were not referred because of a lack of significant impairment or were already engaged in mental health services. One service member in the study was evacuated because of a mental health condition. The most common major life stressors identified were family/relationship issues, sleep problems, and mental health concerns.

Conclusions

The number of deployed personnel identified through the ITMHA as requiring mental health care was modest. The ITMHA has multiple limitations that, if addressed, will improve its utility to mitigate mental health decline in the expeditionary environment.
Types of COVID-19 Disaster Work and Psychological Responses in National Guard Service Members
Authors: Mash Holly B Herberman , Fullerton Carol S , Adler Amy B , Morganstein Joshua C , Reissman Dori B , Biggs Quinn M , La Croix Christina L , Blumhorst Alexandra , Ursano Robert J
Published: May 2024

Introduction

The National Guard (NG) served as a critical component of the U.S. response to the coronavirus disease 2019 pandemic. Understanding the impact of types of pandemic-related disaster work on mental health responses can aid in sustaining NG service members’ health and preparation for subsequent activations and future pandemics.

Materials and Methods

We surveyed 1,363 NG unit (NGU) service members (88% Army; 80% enlisted; 32% 30 to 39 years old; 84% male) following activation in response to the pandemic. Surveys were administered between August and December 2020, which was approximately 2 to 3 months post-activation. Surveys assessed overall activation stress, participation in different types of disaster work, probable post-traumatic stress disorder (PTSD), anxiety and depression, and anger. A disaster work stress scale assessed different types of disaster work during activation and associated stress levels. For each individual, we calculated an overall work task stress (WTS) scaled score, with a maximum score of 100. Logistic regression analyses were conducted to examine the relationship of high-stress disaster work tasks to post-activation PTSD, anxiety and depression, and anger, adjusting for socio-demographic and service-related variables. The study was approved by the Institutional Review Board of the Uniformed Services University (USU) in Bethesda, MD.

Results

Among NGU service members, 12.7% (n = 172) described their activation as very/extremely stressful. The work tasks with the highest scaled scores were as follows: (1) Patient transportation (WTS scaled score = 100); (2) working with the dead (WTS = 82.2); and (3) working with families of coronavirus disease 2019 patients (WTS = 72.7). For each individual’s work tasks, we identified the work task associated with the highest WTS score. The top one-third of WTS scores were classified as the high-stress group. Approximately 9% of participants (n = 111) had probable PTSD, 6.7% (n = 85) had clinically significant anxiety and depression, and 12.3% (n = 156) had high anger. Multivariable logistic regression analyses, adjusting for covariates, found that NGU service members exposed to the highest level of disaster WTS were more likely to report PTSD (odds ratio [OR] = 1.48 [95% confidence interval [CI] = 1.13-1.94], χ2 = 7.98), anxiety and depression (OR = 1.91 [95% CI = 1.17-3.13]; χ2 = 6.67), and anger (OR = 1.63 [95% CI = 1.13-2.37]; χ2 = 6.66) post-activation.

Conclusions

Identifying work tasks associated with high levels of stress can help detect individuals at risk for adverse mental health responses post-exposure. Distinguishing features of high-stress work conditions can be generalized to other types of work conditions and disaster response and are important targets for planning and preventive efforts.
An overlooked source of uncertainty in the mass of the Milky Way
Authors: Oman Kyle A , Riley Alexander H
Published: May 2024

In the conventional approach to decomposing a rotation curve into a set of contributions from mass model components, the measurements of the rotation curve at different radii are taken to be independent. It is clear, however, that radial correlations are present in such data, for instance (but not only) because the orbital speed depends on the mass distribution at all (or, minimally, inner) radii. We adopt a very simple parametric form for a covariance matrix and constrain its parameters using Gaussian process regression. Applied to the rotation curve of the Milky Way, this suggests the presence of correlations between neighbouring rotation curve points with amplitudes of $\lt 10\, \mathrm{km}\, \mathrm{s}^{-1}$ over length scales of 1.5–$2.5\, \mathrm{kpc}$ regardless of the assumed dark halo component. We show that accounting for such covariance can result in a ∼50 per cent lower total mass estimate for the Milky Way than when it is neglected, and that the uncertainty in model parameters increases such that it seems more representative of the uncertainty in the rotation curve measurement. The statistical uncertainty associated with the covariance is comparable to or exceeds the total systematic uncertainty budget. Our findings motivate including more detailed treatment of rotation curve covariance in future analyses.
Evolutionary Dynamics of Chromatin Structure and Duplicate Gene Expression in Diploid and Allopolyploid Cotton
Authors: Hu Guanjing , Grover Corrinne E , Vera Daniel L , Lung Pei-Yau , Girimurugan Senthil B , Miller Emma R , Conover Justin L , Ou Shujun , Xiong Xianpeng , Zhu De , Li Dongming , Gallagher Joseph P , Udall Joshua A , Sui Xin , Zhang Jinfeng , Bass Hank W , Wendel Jonathan F
Published: May 2024

Polyploidy is a prominent mechanism of plant speciation and adaptation, yet the mechanistic understandings of duplicated gene regulation remain elusive. Chromatin structure dynamics are suggested to govern gene regulatory control. Here, we characterized genome-wide nucleosome organization and chromatin accessibility in allotetraploid cotton, Gossypium hirsutum (AADD, 2n = 4X = 52), relative to its two diploid parents (AA or DD genome) and their synthetic diploid hybrid (AD), using DNS-seq. The larger A-genome exhibited wider average nucleosome spacing in diploids, and this intergenomic difference diminished in the allopolyploid but not hybrid. Allopolyploidization also exhibited increased accessibility at promoters genome-wide and synchronized cis-regulatory motifs between subgenomes. A prominent cis-acting control was inferred for chromatin dynamics and demonstrated by transposable element removal from promoters. Linking accessibility to gene expression patterns, we found distinct regulatory effects for hybridization and later allopolyploid stages, including nuanced establishment of homoeolog expression bias and expression level dominance. Histone gene expression and nucleosome organization are coordinated through chromatin accessibility. Our study demonstrates the capability to track high-resolution chromatin structure dynamics and reveals their role in the evolution of cis-regulatory landscapes and duplicate gene expression in polyploids, illuminating regulatory ties to subgenomic asymmetry and dominance.
Frequencies and spectra of aflatoxin B1-induced mutations in liver genomes of NEIL1-deficient mice as revealed by duplex sequencing
Authors: Minko Irina G , Luzadder Michael M , Vartanian Vladimir L , Rice Sean P M , Nguyen Megan M , Sanchez-Contreras Monica , Van Phu , Kennedy Scott R , McCullough Amanda K , Lloyd R Stephen
Published: May 2024

Increased risk for the development of hepatocellular carcinoma (HCC) is driven by a number of etiological factors including hepatitis viral infection and dietary exposures to foods contaminated with aflatoxin-producing molds. Intracellular metabolic activation of aflatoxin B1 (AFB1) to a reactive epoxide generates highly mutagenic AFB1-Fapy-dG adducts. Previously, we demonstrated that repair of AFB1-Fapy-dG adducts can be initiated by the DNA glycosylase NEIL1 and that male Neil1−/− mice were significantly more susceptible to AFB1-induced HCC relative to wild-type mice. To investigate the mechanisms underlying this enhanced carcinogenesis, WT and Neil1−/− mice were challenged with a single, 4 mg/kg dose of AFB1 and frequencies and spectra of mutations were analyzed in liver DNAs 2.5 months post-injection using duplex sequencing. The analyses of DNAs from AFB1-challenged mice revealed highly elevated mutation frequencies in the nuclear genomes of both males and females, but not the mitochondrial genomes. In both WT and Neil1−/− mice, mutation spectra were highly similar to the AFB1-specific COSMIC signature SBS24. Relative to wild-type, the NEIL1 deficiency increased AFB1-induced mutagenesis with concomitant elevated HCCs in male Neil1−/− mice. Our data establish a critical role of NEIL1 in limiting AFB1-induced mutagenesis and ultimately carcinogenesis.
In vivo X-ray microtomography locally affects stem radial growth with no immediate physiological impact
Authors: Mekarni Laura , Cochard Hervé , Lehmann Marco M , Turberg Pascal , Grossiord Charlotte
Published: May 2024

Microcomputed tomography (µCT) is a nondestructive X-ray imaging method used in plant physiology to visualize in situ plant tissues that enables assessments of embolized xylem vessels. Whereas evidence for X-ray-induced cellular damage has been reported, the impact on plant physiological processes such as carbon (C) uptake, transport, and use is unknown. Yet, these damages could be particularly relevant for studies that track embolism and C fluxes over time. We examined the physiological consequences of µCT scanning for xylem embolism over 3 mo by monitoring net photosynthesis (Anet), diameter growth, chlorophyll (Chl) concentration, and foliar nonstructural carbohydrate (NSC) content in 4 deciduous tree species: hedge maple (Acer campestre), ash (Fraxinus excelsior), European hornbeam (Carpinus betulus), and sessile oak (Quercus petraea). C transport from the canopy to the roots was also assessed through 13C labeling. Our results show that monthly X-ray application did not impact foliar Anet, Chl, NSC content, and C transport. Although X-ray effects did not vary between species, the most pronounced impact was observed in sessile oak, marked by stopped growth and stem deformations around the irradiated area. The absence of adverse impacts on plant physiology for all the tested treatments indicates that laboratory-based µCT systems can be used with different beam energy levels and doses without threatening the integrity of plant physiology within the range of tested parameters. However, the impacts of repetitive µCT on the stem radial growth at the irradiated zone leading to deformations in sessile oak might have lasting implications for studies tracking plant embolism in the longer-term.
Nanodiamonds in biomedical research: Therapeutic applications and beyond
Authors: Alexander Elena , Leong Kam W
Published: May 2024

Nanodiamonds (NDs) comprise a family of carbon-based nanomaterials (i.e. diameter <100 nm) with the same sp3 lattice structure that gives natural diamonds their exceptional hardness and electrical insulating properties. Among all carbon nanomaterials—e.g. carbon nanotubes, nanodots, and fullerenes—NDs are of particular interest for biomedical applications because they offer high biocompatibility, stability in vivo, and a dynamic surface chemistry that can be manipulated to perform a seemingly limitless variety of ultra-specific tasks. NDs are already deepening our understanding of basic biological processes, while numerous laboratories continue studying these nanomaterials with an aim of making seismic improvements in the prevention, diagnosis, and treatment of human diseases. This review surveys approximately 2,000 the most recent articles published in the last 5 years and includes references to more than 150 of the most relevant publications on the biomedical applications of NDs. The findings are categorized by contemporary lines of investigation based on potential applications, namely: genetics and gene editing, drug delivery systems, neural interfacing, biomedical sensors, synthetic biology, and organ and tissue regeneration. This review also includes a brief background of NDs and the methods currently developed for their synthesis and preparation. Finally, recommendations for future investigations are offered.
Separating individual and group-level cooperation in the Public Goods Game
Authors: Nielsen Yngwie Asbjørn , Pfattheicher Stefan
Published: May 2024

Cooperation in the Public Goods Game (PGG) is determined by a mixture of individual differences (e.g. personality, social preferences) and group dynamics (e.g. reciprocation, social norms). However, to our knowledge, no thorough attempt has been made to separate individual and group levels of cooperation and to quantify the variance in cooperation that can be attributed to the group level. In an analysis of 10 open datasets (total N = 4,556, 1,003 groups, 7–50 rounds), we chart the trajectory of individual and group-level variance across rounds of repeated PGGs. We find that the portion of group-level variance increases initially and plateaus around the fifth round, typically at a level between 20 and 50%. In addition, we identify four factors that increase the portion of group-level variance: (i) punishment opportunities; (ii) detailed feedback including all group members' decisions; (iii) small groups (≤4 players); and (iv) groups with homogenous social preferences.