bluuebunny/crossref_metadata_2025 huggingface dataset:
Unpacking the recruitment potential of seeds in reconstructed soils and varying rainfall patterns
Authors: Erickson Todd E. , Dwyer John M. , Dalziell Emma L. , James Jeremy J. , Muñoz-Rojas Miriam , Merritt David J.
Published: June 2023

Context Seeding is common practice for ecological restoration, but establishment rates can be low. For seeds to successfully establish they must transition through early life stages of germination, emergence, and (initial) survival. Examining these demographic processes for seeds sown under a range of abiotic conditions can identify failure points and inform techniques to improve seed use. Aims Here we quantified seed and seedling life-stage transitions in five reconstructed soils across four varying levels of simulated rainfall using five species (Acacia hilliana, Acacia inaequilatera, Indigofera monophylla, Triodia pungens, and Triodia wiseana) commonly seeded for mined land restoration of the Pilbara bioregion in north-west Western Australia. Methods Germination, emergence, and survival were measured over a 6 week period and transition probabilities between each life-stage transition were modelled for each treatment combination. Key results For four species, both rainfall amount and/or soil substrate significantly influenced germination probability. Rainfall was the more significant determinant, with germination greatest under the higher rainfall regimes of 120–280 mm, irrespective of soil type. Following germination, emergence of both Acacia spp. was positively influenced by soils containing topsoil, suggesting the microenvironment of soils containing topsoil was most favourable during this emergence phase. The effect of substrate was less clearcut for I. monophylla and Triodia spp, where emergence was most limited in substrates comprised solely of overburden waste material and the lowest rainfall regime exacerbated emergence failure, relative to germination success. When compared to the well-watered, 100% topsoil substrate, seedling survival of all species was most constrained in the 100% overburden waste, demonstrating these reconstructed mining substrates compromise seedling recruitment. Conclusions This study underscores that successful seedling recruitment in this ecosystem is dependent on frequent, and repeated, rainfall events above a certain threshold (≥120 mm) and highlights the beneficial effects of sowing seeds in a substrate containing topsoil. Implications Future seeding technologies should focus on improving the moisture relations of the microsite to offset the recruitment challenges experienced by seeds sown in hostile growing environments such as the overburden wastes tested here.
Multi-objective energy management of island microgrids with D-FACTS devices considering clean energy, storage systems and electric vehicles
Authors: Moradi Mahyar , Abardeh Mohamad Hoseini , Vahedi Mojtaba , Salehi Nasrin , Azarfar Azita
Published: June 2023

The development of microgrids is progressing due to intelligent load demands, clean energy, batteries and electric vehicles. The presence of such systems in microgrids causes power balance inconsistency, leading to increased power losses and deviation in voltage. In this paper, a mixed-integer non-linear programming model is proposed for modelling island microgrid energy management considering smart loads, clean energy resources, electric vehicles and batteries. Similarly, a flexible distributed AC transmission system device is proposed to prevent voltage deviation and reduce power losses. A scenario-based multi-objective function has been proposed to decrease energy losses and voltage deviations and energy outages of clean energy resources, reduce emissions from fossil-fired distributed generation and finally decrease load outages to reduce the vulnerability of the islanded microgrid. Regarding the proposed mixed-integer non-linear model and the high number of variables and constraints, a modified evolutionary algorithm based on particle swarm optimization has been proposed to solve the proposed model, which can be more efficient than other algorithms to achieve global optimal solutions. The model presented is implemented on a 33-node island microgrid and the results illustrate that the proposed algorithm and model are effective in reducing energy losses and voltage deviation, as well as reducing the vulnerability of the microgrid. The simulation results demonstrate that the proposed approach can lead to significant improvements in the performance of the microgrid. Specifically, the approach can result in a 27% reduction in losses, a 6% reduction in pollution and a 31% improvement in voltage. Additionally, the approach allows maximum utilization of renewable energy sources, making it a promising solution for sustainable energy management.
miR-10a induces inflammatory responses in epileptic hippocampal neurons of rats via PI3K/Akt/mTOR signaling pathway
Authors: Lu Yuanming , Wang Wanshi , Ma Yanping , Fan Zilian , Xiong Lan , Zhao Junhao , He Yongwen , Li Chao , Wang Anjie , Xiao Nanping , Wang Tianxun
Published: June 2023

Epilepsy is a common chronic neurological disorder worldwide. MicroRNAs (miRNAs) play an important role in the pathogenesis of epilepsy. However, the mechanism of the regulatory effect of miR-10a on epilepsy is unclear. In this study, we investigated the effect of miR-10a expression on the PI3K/Akt/mTOR signaling pathway and inflammatory cytokines in epileptic hippocampal neurons of rats. The miRNA differential expression profile of rat epileptic brain was analyzed using bioinformatic approaches. Neonatal Sprague–Dawley rat hippocampal neurons were prepared as epileptic neuron models in vitro by replacing culture medium with magnesium-free extracellular solution. The hippocampal neurons were transfected with miR-10a mimics, and transcript levels of miR-10a, PI3K, Akt and mTOR were detected by quantitative reverse transcription-PCR, and PI3K, mTOR, Akt, TNF-α, IL-1β, IL-6 protein expression levels were detected by Western blot. Cytokines secretory levels were detected by ELISA. Sixty up-regulated miRNAs were identified in the hippocampal tissue of epileptic rats and might affect the PI3K-Akt signaling pathway. In the epileptic hippocampal neurons model, the expression levels of miR-10a were significantly increased, with decreasing levels of PI3K, Akt and mTOR, and increasing levels of TNF-α, IL-1β and IL-6. The miR-10a mimics promoted the expression of TNF-α, IL-1β and IL-6. Meanwhile, miR-10a inhibitor activated PI3K/Akt/mTOR pathway and inhibited cytokines secretion. Finally, cytokine secretion was increased by treated with PI3K inhibitor and miR-10a inhibitor. The miR-10a may promote inflammatory responses in rat hippocampal neurons by inhibiting the PI3K/Akt/mTOR pathway, suggesting that miR-10a may be one of the target therapeutic molecules for epilepsy treatment.
Hypothesizing an algorithm from one example: the role of specificity
Authors: Muggleton FREng S. H.
Published: June 2023

Statistical machine learning usually achieves high-accuracy models by employing tens of thousands of examples. By contrast, both children and adult humans typically learn new concepts from either one or a small number of instances. The high data efficiency of human learning is not easily explained in terms of standard formal frameworks for machine learning, including Gold’s learning-in-the-limit framework and Valiant’s probably approximately correct (PAC) model. This paper explores ways in which this apparent disparity between human and machine learning can be reconciled by considering algorithms involving a preference for specificity combined with program minimality. It is shown how this can be efficiently enacted using hierarchical search based on identification of certificates and push-down automata to support hypothesizing compactly expressed maximal efficiency algorithms. Early results of a new system called DeepLog indicate that such approaches can support efficient top-down construction of relatively complex logic programs from a single example.

This article is part of a discussion meeting issue ‘Cognitive artificial intelligence’.
Socially intelligent machines that learn from humans and help humans learn
Authors: Gweon Hyowon , Fan Judith , Kim Been
Published: June 2023

A hallmark of human intelligence is the ability to understand and influence other minds. Humans engage in inferential social learning (ISL) by using commonsense psychology to learn from others and help others learn. Recent advances in artificial intelligence (AI) are raising new questions about the feasibility of human–machine interactions that support such powerful modes of social learning. Here, we envision what it means to develop socially intelligent machines that can learn, teach, and communicate in ways that are characteristic of ISL. Rather than machines that simply predict human behaviours or recapitulate superficial aspects of human sociality (e.g. smiling, imitating), we should aim to build machines that can learn from human inputs and generate outputs for humans by proactively considering human values, intentions and beliefs. While such machines can inspire next-generation AI systems that learn more effectively from humans (as learners) and even help humans acquire new knowledge (as teachers), achieving these goals will also require scientific studies of its counterpart: how humans reason about machine minds and behaviours. We close by discussing the need for closer collaborations between the AI/ML and cognitive science communities to advance a science of both natural and artificial intelligence.

This article is part of a discussion meeting issue ‘Cognitive artificial intelligence’.
Understanding computational dialogue understanding
Authors: Wahlster Wolfgang
Published: June 2023

In this paper, we first explain why human-like dialogue understanding is so difficult for artificial intelligence (AI). We discuss various methods for testing the understanding capabilities of dialogue systems. Our review of the development of dialogue systems over five decades focuses on the transition from closed-domain to open-domain systems and their extension to multi-modal, multi-party and multi-lingual dialogues. From being somewhat of a niche topic of AI research for the first 40 years, it has made newspaper headlines in recent years and is now being discussed by political leaders at events such as the World Economic Forum in Davos. We ask whether large language models are super-parrots or a milestone towards human-like dialogue understanding and how they relate to what we know about language processing in the human brain. Using ChatGPT as an example, we present some limitations of this approach to dialogue systems. Finally, we present some lessons learned from our 40 years of research in this field about system architecture principles: symmetric multi-modality, no presentation without representation and anticipation feedback loops. We conclude with a discussion of grand challenges such as satisfying conversational maxims and the European Language Equality Act through massive digital multi-linguality—perhaps enabled by interactive machine learning with human trainers.

This article is part of a discussion meeting issue 'Cognitive artificial intelligence'.
Characterizing the polygenic architecture of complex traits in populations of East Asian and European descent
Authors: De Lillo Antonella , Wendt Frank R. , Pathak Gita A. , Polimanti Renato
Published: June 2023

To investigate the polygenicity of complex traits in populations of East Asian (EAS) and European (EUR) descents, we leveraged genome-wide data from Biobank Japan, UK Biobank, and FinnGen cohorts. Specifically, we analyzed up to 215 outcomes related to 18 health domains, assessing their polygenic architecture via descriptive statistics, such as the proportion of susceptibility SNPs per trait (πc). While we did not observe EAS-EUR differences in the overall distribution of polygenicity parameters across the phenotypes investigated, there were ancestry-specific patterns in the polygenicity differences between health domains. In EAS, pairwise comparisons across health domains showed enrichment for πcdifferences related to hematological and metabolic traits (hematological fold-enrichment=4.45, p=2.15×10−7; metabolic fold-enrichment=4.05, p=4.01×10−6). For both categories, the proportion of susceptibility SNPs was lower than that observed for several other health domains (EAS-hematological median πc=0.15%, EAS-metabolic median πc=0.18%) with the strongest πcdifference with respect to respiratory traits (EAS-respiratory median πc=0.50%; Hematological-p=2.26×10−3; Metabolic-p=3.48×10−3). In EUR, pairwise comparisons showed multiple πcdifferences related to the endocrine category (fold-enrichment=5.83, p=4.76×10−6), where these traits showed a low proportion of susceptibility SNPs (EUR-endocrine median πc=0.01%) with the strongest difference with respect to psychiatric phenotypes (EUR-psychiatric median πc=0.50%; p=1.19×10−4). Simulating sample sizes of 1,000,000 and 5,000,000 individuals, we also showed that ancestry-specific polygenicity patterns translate into differences across health domains in the genetic variance explained by susceptibility SNPs projected to be genome-wide significant (e.g., EAS hematological-neoplasm p=2.18×10−4; EUR endocrine-gastrointestinal p=6.80×10−4). These findings highlight that traits related to the same health domains may present ancestry-specific variability in their polygenicity.
Strategies to resolve the gap in Adolescent Tuberculosis care at four health facilities in Uganda: The TEEN TB pilot project
Authors: Omongot Samson , Muttamba Winters , Najjingo Irene , Baluku Joseph Baruch , Kitaka Sabrina , Turyahabwe Stavia , Kirenga Bruce
Published: June 2023

Introduction

In 2021, an estimated 10.6 million people fell ill with tuberculosis (TB) globally, 1.2 million of these were children. About 40% of them aged between 5 and 14 years with TB are missed annually. In Uganda, 44% of adolescents with chronic cough of ≥2 weeks do not seek care from health facilities. Therefore, strategies to promote health care-seeking behaviour among adolescents are urgently needed. We piloted a project (TEEN TB project) aimed at improving uptake of tuberculosis (TB) care services among adolescents at Ugandan health facilities.

Methodology

We developed an adolescent TB awareness and screening package using the human centred design. This technique puts real people at the centre of the development process. The package consisted of 3 interventions (TB screening cards, adolescent-TB awareness poster messages and a local TB awareness song) deployed in the project health facilities and their surrounding communities. Data on socio-demographic and clinical characteristics of adolescents were collected for the period between October 2021 and March 2022 at 4 project health facilities (Kawolo, Iganga, Gombe and Kiwoko). We collected before and after intervention data from facility level records to determine the effect of the package.

Results

A total of 394 adolescents were included and the majority (76%) were still in school. Overall, the intervention improved adolescent TB care in the four project health facilities. The average number of adolescents screened increased by 94% from 159 to 309, with an incidence rate ratio (IRR) of 1.9 (95% CI: 1.9-2.0, p <0.001), there was a 2-fold increase among those presumed to have TB; from 13 to 29, IRR of 2.2 (95% CI: 1.9-2.5, p <0.001) and those tested with GeneX-pert and microscopy increased more than 3 times from 8 to 28, IRR of 3.3 (95% CI: 2.8-3.8, p <0.001). There was a minimal increase in the average monthly number of adolescents with a positive result from 1.6 to 2.4 and linkage to TB care services from 2 to 3.1. These were not statistically significant at p=0.170 and p=0.154 respectively.

Conclusion

The project improved uptake of TB services among adolescents along the TB care cascade (screening, TB testing and linkage to care). We recommend a robust and fully powered randomized controlled trial to evaluate the effectiveness of the package.
Women are Prone to Age-Related aortic Stiffness
Authors: Meng Zixuan , Cheng LeLe , Liu Wenjun , Yu Yue , Liu Hui , Yao Guolin , Yang Jian , Wu Yue , Jian Zhijie
Published: June 2023

Aim

To investigate sex differences in the aortic aging by analyzing aortic diameter and tortuosity in different segments of aorta across the age spectrum, using enhanced CT imaging.

Method

Between July 2021 and April 2022, a retrospective study screened patients with chest and abdomen contrast CT images. The outer edge-to-outer edge method was utilized to measure aortic diameters at five aortic levels, while arterial tortuosity of various segments was measured and calculated using imaging software. Mean values were compared at different age groups, including by sex, and correlation with age was determined. To validate the coherence of arterial elasticity and anticipated age-related arterial alterations, a subset of data from a previously published article in BMJ Open was extracted for the purpose of examining the correlation between age and arterial stiffness, stratified by sexes.

Results

208 participants (56.6% men, mean age 60.13±16.33 years old, mean BMI 23.07±4.03 kg/m2, mean BSA 1.70±0.19 m2) were enrolled in this study. The BSA-adjusted aortic diameters showed a positive correlation with age in both sexes, but females demonstrated a more rapid increase in progressive aortic diameters throughout their lifespan than males. In the age groups of 60-69 and above 80 years old, males exhibited significantly larger L1 measurements than females. Conversely, in individuals over 80 years old, females displayed greater L3 values compared to their male counterparts. However, no sexual disparities were observed for L2, L4 and L5 across all ages. Females exhibited greater aortic tortuosity in the descending thoracic region compared to males across all age groups, whereas this sex-based distribution of aortic and abdominal tortuosity was only evident among individuals over 40 years old. The tortuosity of the aorta and descending thoracic aorta exhibits a marked increase with advancing age, particularly in females, while a non-significant linear correlation is observed between abdominal aortic tortuosity and age in both genders. BaPWV consistently increased with age in both males and females, but the increase was more significant in females. Although males initially had higher arterial stiffness, females surpassed them as they aged.

Conclusion

Patterns of vascular aging in aortic morphology differ between the sexes across the life course, with women experiencing more significant changes, especially in advanced age groups.
Cholera deaths during outbreaks in Uvira, eastern Democratic Republic of the Congo, 10-35 months after mass vaccination
Authors: Bugeme Patrick Musole , Xu Hanmeng , Hutchins Chloe , Hulse Juan Dent , Saidi Jaime Mufitini , Rumedeka Baron Bashige , Itongwa Moïse , Mashauri Joël Faraja Zigashane , Lulela Faraja Masembe , Bengehya Justin , Kulondwa Jean-Claude , Debes Amanda K , Ciglenecki Iza , Tshiwedi Esperance , Kitoga Faida , Bodisa-Matamu Tavia , Nadège Taty , Kavunga-Membo Hugo , Lunguya Octavie , Welo Placide Okitayemba , Knee Jackie , Mukadi-Bamuleka Daniel , Azman Andrew S. , Malembaka Espoir Bwenge
Published: June 2023

Our understanding of the burden and drivers of cholera mortality is hampered by limited surveillance and confirmation capacity. Leveraging enhanced clinical and laboratory surveillance in the cholera-endemic community of Uvira, eastern Democratic Republic of Congo, we describe cholera deaths across three epidemics between September 2021-September 2023, following mass vaccination.
Full Publication of Preprint Articles in Prevention Research: An Analysis of Publication Proportions and Results Consistency
Authors: Sommer Isolde , Sunder-Plassmann Vincent , Ratajczak Piotr , Emprechtinger Robert , Dobrescu Andreea , Griebler Ursula , Gartlehner Gerald
Published: June 2023

Introduction

There is concern that preprint articles will lead to an increase in the amount of scientifically invalid work available. The objectives of this study were 1) to determine the proportion of prevention preprints published within 12 months, 2) to assess the consistency of the effect estimates and conclusions between preprint and published articles, and 3) to explore the reasons for the nonpublication of preprints.

Methods

We developed a web crawler to search the preprint server medRxiv for prevention studies posted from January 1 to September 30, 2020. An update search was conducted 12 months later. We dually screened the results for prevention articles and developed a scheme to classify changes in effect sizes and conclusions. We modeled the effect of a set of predictors on the proportion of preprints published in peer-reviewed journals. We also developed a questionnaire for authors of unpublished preprints.

Results

Of the 329 prevention preprints that met our eligibility criteria, almost half (48.9%) were published in a peer-reviewed journal within 12 months of being posted, with the median time being 5.3 months (range 0.1–11.3 months). While 27 out of 161 (16.8%) published preprints showed some change in the magnitude of the primary outcome effect estimate, 4.4% were classified as having a major change. The style or wording of the conclusion changed in 42.2%, while the content of the conclusion changed in 3.1%. Preprints on chemoprevention, with a cross-sectional design, and with public and noncommercial funding had the highest probabilities of publication. The main reasons for the nonpublication of preprints were journal rejection or lack of time.

Conclusion

The reliability of preprint articles for evidence-based decision-making is questionable. Less than half of the preprint articles on prevention research are published in a peer-reviewed journal within 12 months, and significant changes in effect sizes and/or conclusions are still possible during the peer-review process.
Can eraDOCator-60 Decrease MDRs and HAIs? An Evaluation of the Efficacy of eraDOCator-60 in a Randomized Clinical Trial in a Community Hospital
Authors: Johns Martin , Machata Matthew , Liseno Stephanie , del Castillo Joseph
Published: June 2023

Background

There is a significant transmission of contaminants in the healthcare setting. Daily disinfection utilizing ammonium and chlorine-based products can lead to adverse health effects such as asthma, cancer, and other serious health issues.

Methods

This study evaluated the effectiveness of eraDOCator-60 in a health care facility. This randomized trial took place at Copley Hospital in Morristown, Vermont. Separate areas of the hospital were cleaned and disinfected in one step with eraDOCator-60. A Charm analyzer was utilized to evaluate the efficacy of disinfection before and after 1 minute application of eraDOCator-60. The Charm analyzer detects Adenosine Triphosphate (ATP) presence measured in Relative Light Units (RLUs).

Results

The median number of RLUs decreased from 52,874 s to 0 RLUs after one-minute eraDOCator-60 dwell time in the emergency room; 18.611 RLUs to 0 RLUs in the medical-surgical unit, 41,507 RLUs to 0 RLUs in the cafeteria; 24,932 RLUs to 0 RLUs in the birthing center.

Conclusions

EraDOCator-60 reduced contamination levels on all surfaces in the acute care setting down to a value of zero following a 1-minute dwell time in less than 5% soil load.
HIV-1 latency reversal agent boosting is not limited by opioid use
Authors: Lilie Tyler , Bouzy Jennifer , Asundi Archana , Taylor Jessica , Roche Samantha , Olson Alex , Coxen Kendyll , Corry Heather , Jordan Hannah , Clayton Kiera , Lin Nina , Tsibris Athe
Published: June 2023

The opioid epidemic may impact the HIV-1 reservoir and its reversal from latency in virally suppressed people with HIV (PWH). We studied forty-seven PWH and observed that lowering the concentration of HIV-1 latency reversal agents (LRA), used in combination with small molecules that do not reverse latency, synergistically increases the magnitude of HIV-1 re-activationex vivo, regardless of opioid use. This LRA boosting, which combines a Smac mimetic or low-dose protein kinase C agonist with histone deacetylase inhibitors, can generate significantly more unspliced HIV-1 transcription than phorbol 12-myristate 13-acetate (PMA) with ionomycin (PMAi), the maximal known HIV-1 reactivator. LRA boosting associated with greater histone acetylation in CD4+T cells and modulated T cell activation-induced markers and intracellular cytokine production; Smac mimetic-based boosting was less likely to induce immune activation. We found that HIV-1 reservoirs in PWH contain unspliced and polyadenylated (polyA) virus mRNA, the ratios of which are greater in resting than total CD4+T cells and can correct to 1:1 with PMAi exposure. Latency reversal results in greater fold-change increases to HIV-1 poly(A) mRNA than unspliced message. Multiply spliced HIV-1 transcripts and virion production did not consistently increase with LRA boosting, suggesting the presence of a persistent post-transcriptional block. LRA boosting can be leveraged to probe the mechanisms of an effective cellular HIV-1 latency reversal program.
Mortality from Sickle Cell Disease in Brazil
Authors: Blatyta PF , DiLorenzo C , Gomes I , Salomon T , Sabino EC , Capuani L , Cruz DTS , Maximo C , Flor-Park MV , Mota RA , Werneck Rodrigues DO , Dinardo CL , Almeida-Neto C , Custer B , Kelly S ,   Recipient Epidemiology and Donor Evaluation Study-III (REDS-III) International Component Brazil
Published: June 2023

Introduction

Many individuals with sickle cell disease (SCD) die before age 60, despite early detection via neonatal screening and implementation of treatments such as vaccines and antibiotic prophylaxis and the increasing availability of disease modifying therapies. This study evaluated the causes and independent predictors of mortality in a SCD population in Brazil.

Methods

This analysis was performed within the multicenter Recipient Epidemiology and Donor Evaluation (REDS)-III SCD cohort which was established at 6 participating centers in Brazil from 2013-2018. Participants were randomly selected as eligible and recruited at routine visits. Medical records were reviewed to abstract clinical and laboratory data. Mortality and cause of death were confirmed by local chart review as well as linkage to the Brazilian death certificate database. Key variables were compared between deceased and alive participants using Chi2test for categorical variables and Mann-Whitney test for continuous variables. Stepwise logistic regression then a Cox regression multivariable model was performed to identify independent predictors for mortality within the adult participants.

Results

There were 2,793 participants in the cohort (1,558, 55.8%, <18 years) and 159 (5.7%) were confirmed to be deceased by the end of follow up: 142 adults (>18 years) and 17 children. The median life expectancy was 65.7. Within adults, infection was the main identifiable cause of death (33.3%), followed by pulmonary causes (25.2%) and neurologic causes (14.5%). Five (3.1%) patients had an unknown cause of death. Independent predictors of mortality were age [Hazard Ratio (HR) 1.03; 95% CI 1.01-1.04; p<.01], iron overload (HR 1.68; 95% CI1.09-2.60; p<.02] and previous hospital admission (HR 1.68; 95% CI 1.10-2.56; p<.02).

Discussion

Mortality in Brazilian SCD individuals is shifting from children to adults, with increased rates of death in the third and fourth decades of life. Individuals with SCD are dying 10 years before the general population in Brazil. The main causes of death in our cohort were infections, acute chest syndrome and stroke, highlighting the need for prompt recognition and treatment of these complications. Screening and treatment for iron overload and closer monitoring and consideration of disease modifying therapies for patients with frequent hospital admissions are important as both were identified as independent predictors of mortality.
Comparing the effect profile of CETP in individuals of East Asian and European ancestries
Authors: Dunca Diana , Chopade Sandesh , Gordillo-Marañón María , Hingorani Aroon D. , Kuchenbaecker Karoline , Finan Chris , Schmidt Amand F.
Published: June 2023

Background

Cholesteryl ester transfer protein (CETP) is a lipid drug target under development for coronary heart disease (CHD) in both European and East Asian populations. Previous drug target Mendelian randomization (MR) studies conducted in East Asians failed to show a CHD effect, which has been interpreted as lack of effectiveness of CETP inhibition for CHD prevention in this population.

Objectives

In this study, we inferred the effect of CETP inhibition in individuals of European and East Asian ancestries using drug target Mendelian randomization.

Methods

We leveraged genetic associations ofCETPvariants with major blood lipid fractions for individuals of European (n=1,320,016) and East Asian (n=146,492) ancestries. Colocalization was employed to identify potential cross-ancestry signals ofCETPvariants for plasma concentrations of low-density lipoprotein cholesterol (LDL-C) or high-density lipoprotein cholesterol (HDL-C). Drug target MR was used to estimate ancestry-specific effects of on-targetCETPinhibition. Differences between ancestries were evaluated using interaction tests, applying a multiplicity corrected alpha of 1.9×10-3based on the 26 considered traits.

Results

There was strong support (posterior probability: 1.00) of a shared causalCETPvariant affecting HDL-C in both populations, which was not observed for LDL-C. Employing drug target MR scaled to a standard deviation increase in HDL-C, we found that lower CETP was associated with lower LDL-C, Lp[a], systolic blood pressure and pulse pressure in both groups, but the effects were more pronounced in European individuals (interaction p-values < 1.9×10-3). Lower CETP was protective against CHD, angina, intracerebral haemorrhage and heart failure in both ancestries, for example for CHD in East Asians (OR 0.89, 95%CI 0.84;0.94) compared to Europeans (OR 0.95, 95%CI 0.92;0.99, interaction p-value=0.05).

Conclusions

In conclusion, on-target inhibition of CETP is anticipated to decrease cardiovascular disease in individuals of both European and East Asian ancestries.
Exploring [11C]CPPC as a CSF1R-targeted PET Imaging Marker for Early Parkinson’s Disease Severity
Authors: Mills Kelly A. , Du Yong , Coughlin Jennifer M. , Foss Catherine A. , Horti Andrew G. , Jenkins Katelyn , Skorobogatova Yana , Spiro Ergi , Motley Chelsie S. , Dannals Robert F. , Song Jae-Jin , Choi Yu Ree , Redding-Ochoa Javier , Troncoso Juan , Dawson Valina L. , Kam Tae-In , Pomper Martin G. , Dawson Ted M.
Published: June 2023

Neuroinflammation through enhanced innate immunity is thought play a role in the pathogenesis of Parkinson’s disease (PD). Methods for monitoring neuroinflammation in living patients with PD are currently limited to positron emission tomography (PET) ligands that lack specificity in labeling immune cells in the nervous system. The colony stimulating factor 1 receptor (CSF1R) plays a crucial role in microglial function, an important cellular contributor to the nervous system’s innate immune response. Using immunologic methods, we show that CSF1R in human brain is colocalized with the microglial marker, ionized calcium binding adaptor molecule 1 (Iba1). In PD, CSF1R immunoreactivity is significantly increased in PD across multiple brain regions, with the largest differences in the midbrain versus controls. Autoradiography revealed significantly increased [3H]JHU11761 binding in the inferior parietal cortex of PD patients. PET imaging demonstrated that higher [11C]CPPC binding in the striatum was associated with greater motor disability in PD. Furthermore, increased [11C]CPPC binding in various regions correlated with more severe motor disability and poorer verbal fluency. This study finds that CSF1R expression is elevated in PD and that [11C]CPPC-PET imaging of CSF1R is indicative of motor and cognitive impairments in the early stages of the disease. Moreover, the study underscores the significance of CSF1R as a promising biomarker for neuroinflammation in Parkinson’s disease, suggesting its potential use for non-invasive assessment of disease progression and severity, leading to earlier diagnosis and targeted interventions.

Significance Statement

This study demonstrates that the Colony Stimulating Factor 1 Receptor (CSF1R) colocalizes with microglial markers in the human brain, and the research establishes elevated CSF1R expression in PD autopsy tissues. Employing [11C]CPPC-PET imaging, the study unveils a correlation between increased CSF1R binding and both motor disability and cognitive decline in PD patients. These findings highlight the potential of CSF1R as a novel biomarker for neuroinflammation in PD, offering a non-invasive means to assess disease progression and severity, ultimately contributing to earlier diagnosis and targeted interventions.
Genetic and non-genetic components of family history of stroke and heart disease: a population-based study among adopted and non-adopted individuals
Authors: Mayerhofer Ernst , Parodi Livia , Narasimhalu Kaavya , Harloff Andreas , Georgakis Marios K , Rosand Jonathan , Anderson Christopher D
Published: June 2023

Background

It is increasingly clear that genetic and non-genetic factors account for the association of family history with disease risk in offspring. We sought to distinguish the genetic and non-genetic contributions of family history of stroke and heart disease on incident events by examining adopted and non-adopted individuals.

Methods

We examined associations between family history of stroke and heart disease with incident stroke and myocardial infarction (MI) in 495,640 participants of the UK Biobank (mean age 56.5 years, 55% female) stratified by early childhood adoption status into adoptees (n=5,747) and non-adoptees (n=489,893). We estimated hazard ratios (HRs) per affected nuclear family member, and for polygenic risk scores (PRS) for stroke and MI in Cox models adjusted for baseline age and sex.

Results

12,518 strokes and 23,923 MIs occurred over a 13-year follow-up. In non-adoptees, family history of stroke and heart disease were associated with increased stroke and MI risk, with the strongest association of family history of stroke for incident stroke (HR 1.16 [1.12, 1.19]) and family history of heart disease for incident MI (HR 1.48 [1.45, 1.50]). In adoptees, family history of stroke associated with incident stroke (HR 1.41 [1.06, 1.86]), but family history of heart disease did not associate with incident MI (p>0.5). PRS showed strong disease-specific associations in adoptees and non-adoptees. In non-adoptees, the stroke PRS mediated 6% risk between family history of stroke and incident stroke, and the MI PRS mediated 13% risk between family history of heart disease and MI.

Conclusions

Family history of stroke and heart disease increase risk for their respective conditions. Family history of stroke contains a substantial proportion of potentially modifiable non-genetic risk, indicating a need for further research to elucidate these elements for novel prevention strategies, whereas family history of heart disease represents predominantly genetic risk.

Graphic abstract
Patterns of long-term care utilization during the last five years of life among Swedish older adults with and without dementia
Authors: sm-Rahman Atiqur , Meinow Bettina , Hydén Lars-Christer , Kelfve Susanne
Published: June 2023

Aims

The aims of this study were to compare the patterns of long-term care (LTC) use (no care, homecare, residential care) among people with and without dementia aged 70+ in Sweden during their last five years of life and its association with sociodemographic factors and time with a dementia diagnosis.

Methods

This retrospective cohort study included all people who died in November 2019 aged 70 years and older (n=6294) derived from several national registers. A multinomial logistic regression was conducted to identify which sociodemographic factors predicted the patterns of LTC use and predicted proportions were calculated from the margins command.

Results

Results showed that the time with a dementia diagnosis and cohabitation status were important predictors that influence the patterns of LTC use during the last five years of life. Nearly three-quarters of people living with dementia (PlwD) used residential care during the last five years of life. PlwD were more likely to reside in residential care close to death. Women who lived alone, with or without dementia, used residential care to a higher degree compared to married or cohabiting women.

Conclusions

Among people without a dementia diagnosis, as well as those who were newly diagnosed, it was common to have no LTC at all, or use LTC only for a brief period close to death. During the last five years of life, PlwD who were living alone more often entered LTC early and used residential care for a longer time compared to those without dementia.
The fungal intestinal microbiota predict the development of bronchopulmonary dysplasia in very low birthweight newborns
Authors: Willis Kent A. , Silverberg Mary , Martin Isaac , Abdelgawad Ahmed , Tanaka Kosuke , Karabayir Ibrahim , Halloran Brian A. , Myers Erin D. , Desai Jay P. , White Catrina T. , Lal Charitharth V. , Ambalavanan Namasivayam , Peters Brian M. , Jain Viral G. , Akbilgic Oguz , Tipton Laura , Jilling Tamás , Cormier Stephania A. , Pierre Joseph F. , Talati Ajay J.
Published: June 2023

Rationale

Bronchopulmonary dysplasia (BPD) is the most common morbidity affecting very preterm infants. Gut fungal and bacterial microbial communities contribute to multiple lung diseases and may influence BPD pathogenesis.

Methods

We performed a prospective, observational cohort study comparing the multikingdom fecal microbiota of 144 preterm infants with or without moderate to severe BPD by sequencing the bacterial 16S and fungal ITS2 ribosomal RNA gene. To address the potential causative relationship between gut dysbiosis and BPD, we used fecal microbiota transplant in an antibiotic-pseudohumanized mouse model. Comparisons were made using RNA sequencing, confocal microscopy, lung morphometry, and oscillometry.

Results

We analyzed 102 fecal microbiome samples collected during the second week of life. Infants who later developed BPD showed an obvious fungal dysbiosis as compared to infants without BPD (NoBPD,p= 0.0398, permutational multivariate ANOVA). Instead of fungal communities dominated byCandidaandSaccharomyces, the microbiota of infants who developed BPD were characterized by a greater diversity of rarer fungi in less interconnected community architectures. On successful colonization, the gut microbiota from infants with BPD augmented lung injury in the offspring of recipient animals. We identified alterations in the murine intestinal microbiome and transcriptome associated with augmented lung injury.

Conclusions

The gut fungal microbiome of infants who will develop BPD is dysbiotic and may contribute to disease pathogenesis.Conclusions: The gut fungal microbiome of infants who will develop BPD is dysbiotic and may contribute to disease pathogenesis.
Reduced brain responsiveness to emotional stimuli with escitalopram but not psilocybin therapy for depression
Authors: Wall Matthew B. , Demetriou Lysia , Giribaldi Bruna , Roseman Leor , Ertl Natalie , Erritzoe David , Nutt David J. , Carhart-Harris Robin L.
Published: June 2023

Psilocybin therapy is an emerging intervention for depression that may be at least as effective as standard first-line treatments i.e., Selective Serotonin Reuptake Inhibitors (SSRIs). Here we assess neural responses to emotional faces (fear, happy, and neutral) using Blood Oxygen-Level Dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) in two groups with major depressive disorder: 1) a ‘psilocybin group’ that received two dosing sessions with 25mg plus six weeks of daily placebo, and 2) an ‘escitalopram group’ that received six weeks of the SSRI escitalopram, plus two dosing sessions with an inactive/placebo dose of 1mg psilocybin. Both groups had an equal amount of psychological support throughout. An emotional face fMRI paradigm was completed at baseline (pre-treatment) and at the six-week post-treatment primary endpoint (three weeks following psilocybin dosing sessions). An analysis examining the interaction between patient group (psilocybin vs. escitalopram) and time-point (pre-vs. post-treatment) showed a robust effect in a distributed network of cortical brain regions. Follow-up analyses showed that post-treatment BOLD responses to emotional faces of all types were significantly reduced in the escitalopram group, with no change, or even a slight increase, in the psilocybin group. Specific analyses of the amygdala showed a reduction of response to fear faces in the escitalopram group, but no effects for the psilocybin group. Despite large improvements in depressive symptoms in the psilocybin group, psilocybin-therapy had only a minor effect on brain responsiveness to emotional stimuli. We suggest that reduced emotional responsiveness may be a biomarker of SSRIs’ antidepressant action that is not shared by psilocybin-therapy.
Association between telomere length and cognitive function among cognitively unimpaired individuals at risk of Alzheimer’s disease
Authors: Rodríguez-Fernández Blanca , Sánchez-Benavides Gonzalo , Genius Patricia , Minguillon Carolina , Fauria Karine , Vivo Immaculata De , Navarro Arcadi , Molinuevo Jose Luis , Gispert Juan D. , Sala-Vila Aleix , Vilor-Tejedor Natalia , Crous-Bou Marta ,   the ALFA study
Published: June 2023

INTRODUCTION

Leukocyte telomere length (LTL) is an objective biomarker of biological aging, and it is proposed to play a crucial role in Alzheimer’s disease (AD) risk. We aimed at evaluating the cross-sectional association between LTL and cognitive performance in middle-aged cognitively unimpaired individuals at increased risk of AD.

METHODS

A total of 1,520 participants from the ALFA cohort were included. Relative telomere length was measured in leukocytes through qPCR. LTL was residualized against age and sex, and associations with cognitive performance were assessed in accelerated and decelerated biological aging individuals based on residual LTL (rLTL). Interactions with sex and genetic risk of AD were tested.

RESULTS

Non-linear associations were found between LTL and episodic memory (EM). Better EM was associated with longer rLTL among women in the accelerated aging group.

DISCUSSION

Results suggest a potential role for telomeres in maintaining cognition in aging with sex-specific patterns.

Highlights:

● There is a non-linear association between telomere length and cognitive performance.

● Longer telomeres are suggested to have a beneficial effect on episodic memory.

● The association between telomeres and cognitive performance might be sex-specific.
Differences in Cardiac Mechanics among Genetically At-Risk First-Degree Relatives: The DCM Precision Medicine Study
Authors: Wilcox Jane E. , Beussink-Nelson Lauren , Cao Jinwen , Kumar Ritika , Jordan Elizabeth , Ni Hanyu , Shah Sanjiv J. , Hershberger Ray E. , Kinnamon Daniel D.
Published: June 2023

Aims

Among genetically at-risk first-degree relatives (FDRs) of probands with dilated cardiomyopathy (DCM), the ability to detect changes in left ventricular (LV) mechanics with normal LV size and ejection fraction (LVEF) remains incompletely explored. We sought to define a pre-DCM phenotype among at-risk FDRs, including those with variants of uncertain significance (VUSs), using echocardiographic measures of cardiac mechanics.

Methods and Results

LV structure and function, including speckle-tracking analysis for LV global longitudinal strain (GLS), were evaluated in 124 FDRs (65% female; median age 44.9 [IQR: 30.6-60.3] years) of 66 DCM probands of European ancestry sequenced for rare variants in 35 DCM genes. FDRs had normal LV size and LVEF. Negative FDRs of probands with pathogenic or likely pathogenic (P/LP) variants (n=28) were a reference group to which negative FDRs of probands without P/LP variants (n=30), FDRs with only VUSs (n=27), and FDRs with P/LP variants (n=39) were compared. In an analysis accounting for age-dependent penetrance, FDRs below the median age showed minimal differences in LV GLS across groups while those above it with P/LP variants or VUSs had lower absolute values than the reference group (−3.9 [95% CI: −5.7, −2.1] or −3.1 [−4.8, −1.4] %-units) and negative FDRs of probands without P/LP variants (−2.6 [−4.0, −1.2] or −1.8 [−3.1, −0.6]).

Conclusions

Older FDRs with normal LV size and LVEF who harbored P/LP variants or VUSs had lower absolute LV GLS values, indicating that some DCM-related VUSs are clinically relevant. LV GLS may have utility for defining a pre-DCM phenotype.

Clinical Trial Registration

clinicaltrials.gov,NCT03037632

Graphical Abstract

Differences in Cardiac Mechanics among Genetically At-Risk First-Degree Relatives: The DCM Precision Medicine Study.DCM = dilated cardiomyopathy, FDR = first-degree relative, GLS = global longitudinal strain, HF = heart failure, LP = likely pathogenic, LV = left ventricular, LVEF = left ventricular ejection fraction, P = pathogenic, VUS = variant of uncertain significance.
Economic Evaluation of State Control, Low Price, and Research-Based Policy for Eating Disorders Treatment in Sweden
Authors: Södersten Per , Brodin Ulf , Bergh Cecilia
Published: June 2023

Introduction

Porter and Olmsted Teisberg suggested that the value of healthcare should be measured by treatment outcomes related to costs. Policy should financially reward treatment effects and in an outline of value-based healthcare, they predicted:

State control policy yields variable effects, increasing costs

Low price policy decreases effects, increasing costs

Research and Development (R&D) policy increases effects, decreasing costs

Methods

The treatment of eating disorders in Region Stockholm, Sweden, in years 2012-2016 makes it possible to test these predictions because a State control, a Low price, and an R&D provider were contracted and the effects and costs of their treatments are publically available from Region Stockholm.

Results

The State control provider was contracted to provide more care services than the other providers. The average yearly number of patients treated to remission/patients treated was 164/714 (23%) at the State control provider, 41/170 (24) at the Low price provider, and 152/192 (79%) at the R&D provider. The average yearly budget was 73 million Swedish crowns (MSEK) compared to 49 MSEK at the R&D provider and 32 MSEK at the Low price provider (on average 30% lower per care service than the two other providers). The average cost to treat a patient to remission/patients treated was highest at the Low price provider (859 KSEK), followed by the State control provider (464 KSEK) and the R&D provider (327 KSEK).

Conclusions

The results confirm Porter and Olmsted Teisberg’s three predictions and suggest that an R&D policy increases the value of healthcare.