bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of eosinophil counts and megakaryocyte nuclei for distinction of acute and chronic immune thrombocytopenic purpura
Authors: Cilesiz Kubra , Kocak Ulker , Kaya Zuhre , Yenicesu Idil
Published: December 2024

Objective

Immune thrombocytopenic purpura (ITP), the most common cause of thrombocytopenia, is clinically classified as acute and chronic. This study aimed to distinguish between acute/chronic ITP parameters examined at diagnosis via complete blood count (CBC), peripheral blood (PB) and bone marrow aspirate (BMA) smears. It would also contribute to early treatment options, cost-effective policies, and the life quality of patients.

Methods

This study consisted of 304 ITP patients aged under 18 years diagnosed and followed up between 1982–2018. Differences between acute and chronic groups were compared by eosinophilia, megakaryocytes (MKs), and megakaryocyte nuclei. Diagnostic scales were created using simple parameters both to guide the distinction between acute and chronic ITP as well as for the prediction of the chronic progression of the patients at diagnosis.

Results

Of the patients in this study, 71% had acute and 29% had chronic ITP. In CBC and PB smears, eosinophil and lymphocyte counts were higher in acute whereas neutrophil counts were higher in chronic ITP patients. Eosinophil counts in the BMA were also significantly higher in acute ITP patients. There was no significant difference in MK counts. However, the mean number of MK nuclei was higher in acute ITP patients.

Conclusion

Comparison analyses between acute/chronic ITP with the methods developed for the first time are low-cost and promising. Using only eosinophil percentages in the CBC and PB smear, we could identify acute cases by 100%. Further studies including the integration of our study and clinical risk scoring models would contribute to the diagnosis and treatment process of ITP.
A case report on metastatic prostate cancer with normal PSA level diagnosed by immunohistochemistry and its management
Authors: Bhandari Kritick , Chothe Saili , Pandey Saujanya Jung , Karki Devendra , Shah Sanjit Kumar , Tandukar Shree Krishna , Jha Rahul
Published: December 2024

Introduction and importance:

Metastatic prostate cancer (mPCa) is an advanced form of cancer that spreads beyond the prostate to distant organs such as bones and lymph nodes. While prostate-specific antigen (PSA) testing is commonly used for diagnosis, rare cases with normal PSA levels complicate detection. This case highlights the crucial role of immunohistochemistry (IHC) in diagnosing mPCa with normal PSA and its management in resource-limited settings.

Case presentation:

A 63-year-old male presented with 2 months of persistent back pain without neurological deficits. Initial diagnostics, including PSA levels, CT, MRI, and TRUS guided prostate biopsy, revealed no prostate abnormalities. However, an MRI and Bone scan showed a suspicious vertebral lesion, and a subsequent biopsy confirmed malignancy. IHC demonstrated overexpression of alpha-methyl acyl-CoA racemase (AMACR), leading to the diagnosis of mPCa. The patient underwent bilateral subcapsular orchiectomy and received external beam radiotherapy (EBRT) to manage symptoms and control disease progression.

Clinical discussion:

This case highlights the diagnostic challenges of mPCa in patients with normal PSA levels. Standard diagnostics, including imaging and biopsy, may fail to detect prostate cancer, making IHC, specifically AMACR, an essential tool for diagnosis. Early surgical intervention followed by EBRT offered significant symptomatic relief and disease control.

Conclusion:

This case demonstrates the importance of IHC in diagnosing atypical presentations of mPCa with normal PSA. A multidisciplinary approach combining surgery and radiotherapy can improve outcomes and quality of life, even in resource-limited settings
Extensive surveillance of mosquitoes and molecular investigation of arboviruses in Central Iran
Authors: Abedi-Astaneh Fatemeh , Rad Hedaiatollah R. , Izanlou Hassan , Hosseinalipour Seied A. , Hamta Amir , Eshaghieh Mohammad , Ebrahimi Mahdi , Ansari-Cheshmeh Mohammad A. , Pouriayevali Mohammad H. , Salehi-Vaziri Mostafa , Jalali Tahmineh , Talbalaghi Asghar , Abbasi Ebrahim
Published: December 2024

Background:

Arboviruses are one of the greatest threats to animal and public health. Culicidae family is one of the most important vectors for the transmission of arboviruses in the world. According to the geographical, demographic, and climatic features of Qom city in Iran, it can be a suitable region for vectors and therefore transmission of arboviruses.

Methods:

In this study, which was conducted between 2019 and 2020 in different parts of Qom city, 83 414 mosquitoes were collected, and after evaluating the species of mosquitoes based on morphological and molecular detection, the presence of alphaviruses, flaviviruses, and phleboviruses were evaluated using genus-specific Reverse transcription polymerase chain reaction (RT-PCR) assays.

Results:

In this study, Culex tarsalis, Culex theileri, and Culex quinquefasciatus were detected, including the first recorded presence of Culex tarsalis in Iran. No infections with alphavirus, flavivirus, or phlebovirus were identified in the collected mosquitoes.

Conclusion:

Climatic and weather changes are the basis for the growth and spread of vectors and, consequently, the spread of arboviral diseases, and this issue seems to be very important to the necessity of increasing and continuing entomological and virological studies.
FDG PET/CT and MRI of IgG4-Related Disease Presenting as a Hepatic Solitary Solid Mass
Authors: Ma Wanjun , Luo Yongjun , Wang Furong , Liu Jiangyan
Published: December 2024

A hepatic solitary solid mass mimicking malignancy was discovered through MRI and FDG PET/CT in a 76-year-old woman with abdominal pain and no abnormal tumor markers in the blood. She underwent surgery to remove the lesion. Histopathology with biopsy was highly suspicious for IgG4-related disease, although immunohistochemical staining demonstrated non–IgG4-positive plasma cells. Finally, intrahepatic IgG4-related disease was supported by elevated serum IgG4 of 141 mg/dL. IgG4-related disease could manifest as hepatic solitary solid mass without any other organ involvement, and the immunohistochemical staining of IgG4 may be negative.
Retrospective cohort study of the economic value of providing microprocessor knees to the population of Medicare fee-for-service K2 beneficiaries with a knee disarticulation/above knee amputation
Authors: Dobson Al , Beins Michael , DaVanzo Joan , Kim Seung , McMahon Patrick , Haught Randall , Hasselbrink Roger , Gonzalez Sky , Kannenberg Andreas , Seidinger Susanne
Published: December 2024

Background:

Microprocessor knees (MPKs) improve the functional mobility, quality of life, and safety of individuals with a knee disarticulation or above knee amputation and are cost-effective when adjusting for quality-of-life years gained. However, few studies have been conducted on the K2 population, and to this point, the Centers for Medicare and Medicaid Services has not covered MPKs for the K2 population.

Objectives:

The aim of this study was to determine the extent to which MPK provision to the K2 population is cost effective at the person and population levels. A secondary objective was to determine the effectiveness of MPKs at reducing injurious falls within the K2 population.

Study design:

A retrospective cohort study using Medicare fee-for-service claims data from the Centers for Medicare and Medicaid Services.

Methods:

Propensity score weighting using inverse probability treatment weights was used to balance beneficiary characteristics and a generalized linear regression with log-link function and Gamma distribution was run to determine per-member-per-month cost and prosthetic device cost. A 10-year Congressional Budget Office-style score was conducted. A logistic regression was run for the fallers analysis.

Results:

Microprocessor knee provision to K2 beneficiaries reduced injured fallers by 18.5% and resulted in medical savings of $1,351 per-member-per-month, amortizing the $25,075 difference between the MPK and nonmicroprocessor knee in 19 months. Providing MPKs to K2 users resulted in cumulative Medicare savings of $410.3 million over 10 years.

Conclusion:

The MPK prosthetic device could provide meaningful safety benefits to the K2 population and result in fiscal savings to Medicare at both the person and population levels.
Liver Allograft Cirrhosis, Retransplant, and Mortality Secondary to Recurrent Disease After Transplant for MASH: A Systematic Review and Meta-analysis
Authors: Jatana Sukhdeep , Krys Daniel , Verhoeff Kevin , Kung Janice Y. , Jogiat Uzair , Montano-Loza Aldo J. , Shapiro A.M. James , Dajani Khaled , Anderson Blaire , Bigam David L.
Published: December 2024

Background.

Recurrent disease after liver transplant is well recognized for many diseases. Metabolic dysfunction–associated steatotic liver disease (MASLD) and steatohepatitis (MASH) are leading indications for liver transplant, and there is scarce knowledge about recurrence-related end outcomes such as retransplant and mortality. This project aims to assess the proportion of patients transplanted for MASH who develop recurrent disease and adverse clinical outcomes.

Methods.

A systematic review and pooled proportions meta-analysis was performed by searching the following databases: MEDLINE, Embase, Scopus, Web of Science Core Collection, and Cochrane Library. Inclusion criteria were studies discussing adult patients with liver transplants secondary to MASH or presumed MASH with recurrent disease-related outcomes. Outcomes were assessed in time frames from <6 mo to ≥5 y.

Results.

Of 5859 records, 40 were included (16 157 patients). Recurrent MASLD and MASH (28 studies each) occurred in frequencies of 35%–49% and 11%–24%, respectively. Fibrosis occurred in 4%–25% (13 studies). Recurrent disease-related cirrhosis (13 studies), graft failure (8 studies), and retransplant (9 studies) occurred in 0%–2%, 3%–9%, and 0%–1%, respectively. Recurrent disease-related hepatocellular carcinoma (1 study) and mortality (17 studies) both had a prevalence of 0%. Studies were of moderate or high quality using the Methodological Index for Non-Randomized Studies tool.

Conclusions.

Recurrent MASLD and MASH after liver transplant occur frequently, but adverse clinical outcomes due to disease recurrence are infrequent, maybe due to insufficient data on long-term follow-up. Long-term outcomes after transplantation for MASLD appear favorable; however, identifying those more likely to have progressive recurrent disease leading to adverse clinical outcomes may allow for pre- and posttransplant interventions to improve outcomes further.
Diminishing Returns: An Analysis of Surgeon Compensation in the Setting of Ever-Increasing Student Debt
Authors: Sickels Angela D , McElroy Katherine , Robinson Joshua , Chen Herbert , Rose J Bart
Published: December 2024

Background:

The knowledge required to manage surgical patients has expanded considerably over the past 40 years. Simultaneously, the cost of medical education has increased substantially. Surgical trainees are at particular disadvantage due to the time demands of training. We aim to determine whether surgeon compensation over time has adequately accounted for increasing student debt burden.

Study Design:

We conducted a retrospective review of data on surgeon salaries and medical education debt from the Medical Group Management Association and Association of American Medical Colleges (2014-2019). Inflation adjustment was performed using the consumer price index calculator from the United States Bureau of Labor and Statistics. Outcomes of interest included trends in debt, salaries, and the debt:income ratio.

Results:

The median salary for a general surgeon in 1984 was $111,287 and median medical school debt was $22,000, corresponding to a salary of $274,900 and $54,344 in 2019 dollars, respectively, representing a 147% increase. The reported median salary for a general surgeon in 2019 was $350,000 (214.5% increase) and medical school debt was $200,000 (809% increase). The debt:income ratio increased from 0.2 in 1984 to 0.57 in 2012 and has remained stable since that time. Direct comparison of loan burden and salary reveals that while medical school debt has increased by 268% in the past 40 years, surgeon salaries have increased as well, but not nearly to the same degree (27.3%).

Conclusions:

The rate of debt accumulation has outpaced the rate of salary growth for general surgeons to a significant degree.
Impact of ontogeny and spines on the hydrodynamic performance of the Cambrian arthropod
Isoxys
Authors: Pates Stephen , Ma Jiaxin , Wu Yu , Fu Dongjing
Published: December 2024

A metazoan-dominated biological pump was established early in the Phanerozoic, a time that saw the evolution of the first pelagic euarthropod zooplankton such as some species of the Cambrian bivalved euarthropod
Isoxys
. Pelagic groups evolved from benthic stock, in many cases through neoteny and retention of characteristics from planktic larval stages. However,
Isoxys
brooded eggs and did not have a planktic larval stage, precluding this route into the pelagic realm. Computational fluid dynamics was used to quantify hydrodynamic performance through the ontogeny of two hyperbenthic species of
Isoxys, Isoxys auritus
and
Isoxys minor
. Coefficients were used to quantify forces for different carapace shapes over a range of biologically relevant sizes and swimming speeds. Streamlining and lift generation were greater for later growth stages, a consequence of carapace asymmetry and elongated anterior and posterior spines. Simulations performed with anterior spines artificially removed demonstrate the importance of this feature for lift generation, with a minimal impact on drag. Elongated spines and faster swimming can also be considered anti-predatory, and the reduction of drag would have reduced the detectability of
Isoxys
to predators. Taken together, it is likely that pelagic
Isoxys
species evolved from benthic stock through the co-option of anti-predatory features.
The role of spatial dimension in the emergence of localized radial patterns from a Turing instability
Authors: Hill Dan J.
Published: December 2024

The emergence of localized radial patterns from a Turing instability has been well studied in two- and three-dimensional settings and predicted for higher spatial dimensions. We prove the existence of localized

(
n
+
1
)

-dimensional radial patterns in general two-component reaction–diffusion systems near a Turing instability, where

n
>
0

is taken to be a continuous parameter. We determine the explicit dependence of each pattern’s radial profile on the dimension

n

through the introduction of

(
n
+
1
)

-dimensional Bessel functions, revealing a deep connection between the formation of localized radial patterns in different spatial dimensions.
Psychoactive pollutant alters movement dynamics of fish in a natural lake system
Authors: Brand Jack A. , Bertram Michael G. , Cerveny Daniel , McCallum Erin S. , Hellström Gustav , Michelangeli Marcus , Palm Daniel , Brodin Tomas
Published: December 2024

Pharmaceutical pollution poses an increasing threat to global wildlife populations. Psychoactive pharmaceutical pollutants (e.g. antidepressants, anxiolytics) are a distinctive concern owing to their ability to act on neural pathways that mediate fitness-related behavioural traits. However, despite increasing research efforts, very little is known about how these drugs might influence the behaviour and survival of species in the wild. Here, we capitalize on the development of novel slow-release pharmaceutical implants and acoustic telemetry tracking tools to reveal that exposure to environmentally relevant concentrations of the benzodiazepine pollutant temazepam alters movement dynamics and decreases the migration success of brown trout (
Salmo trutta
) smolts in a natural lake system. This effect was potentially owing to temazepam-exposed fish suffering increased predation compared with unexposed conspecifics, particularly at the river–lake confluence. These findings underscore the ability of pharmaceutical pollution to alter key fitness-related behavioural traits under natural conditions, with likely negative impacts on the health and persistence of wildlife populations.
The global diet diversity spectrum in avian apex predators
Authors: DeLong John P. , Coblentz Kyle E. , La Sorte Frank A. , Uiterwaal Stella F.
Published: December 2024

Some predators depend heavily on one or a few prey types, and others have exceptionally broad diets. It is unclear how this diet variation arises. Here, we demonstrate a strong link between diet species richness and Shannon entropy of prey frequencies (a diet diversity spectrum) for a globally distributed group of apex predators–raptors. For many raptors, diet entropy is consistent with random sampling expectations given a lognormal distribution of abundances among prey species. Yet most species-rich diets often approach the maximum possible diet entropy, indicating an unexpected level of diet evenness that is not predicted by theory. Positioning along this diet diversity spectrum is linked to evolutionary history, the types of prey that are acceptable and the role of raptors as food web integrators through cross-habitat sampling. These results suggest that raptors may have a highly stabilizing effect on terrestrial food webs and play an important role in maintaining biodiversity.
Decline in diversity of tropical soil fauna under experimental warming
Authors: Szczygieł Hubert A. , Butler Orpheus M. , Nottingham Andrew T.
Published: December 2024

Climate change is exacerbating a global decline in biodiversity. Numerous observational studies link rising temperatures to declining biological abundance, richness and diversity in terrestrial ecosystems, yet few studies have considered the highly diverse and functionally significant communities of tropical forest soil and leaf litter fauna. Here, we report major declines in the order-level richness and diversity of soil and leaf litter fauna following three years of experimental whole-profile soil warming in a tropical forest. These declines were greatest during the dry season, suggesting that warming effects could be exacerbated by drought. Contrary to findings from higher latitudes, total faunal abundance increased under warming, and these effects were paralleled by major shifts in community composition. These responses were driven by increased dominance of a relatively small number of thermophilic taxa, and of oribatid mites in particular. Our study provides direct experimental evidence that warming causes diversity declines and compositional shifts for tropical forest soil and leaf litter fauna, a result with potential consequences for soil functions and biogeochemical cycles, and that highlights the vulnerability of tropical biodiversity to climate change.
Nutrient-rich spatial refuges buffer against extinction and promote evolutionary rescue in evolving microbial populations
Authors: Kelbrick Matthew , Fenton Andrew , Parratt Stephen , Hall James P. J. , O'Brien Siobhan
Published: December 2024

Microbial populations are often exposed to long-term abiotic disturbances, which can reduce population viability and cause local extinction. Eco-evolutionary theory suggests that spatial refuges can facilitate persistence and evolutionary rescue. However, one drawback of spatial refuges is reduced exposure to nutrients such as carbon and oxygen, suggesting the protective effect of refuges depends on the interplay between environmental conditions and the degree of stress. Here, we test this general idea using mathematical modelling, and experimental evolution of the model bacterium
Pseudomonas fluorescens
SBW25 under salinity stress. As our model predicted, we find that the ability of spatial refuges to rescue evolving populations from extinction crucially depends on nutrient availability. Populations evolving under salinity stress where nutrient-rich spatial refuges were available, harboured clones that displayed enhanced salt resistance, indicating that nutrient-rich spatial refuges can facilitate evolutionary rescue. Furthermore, while control-salinity-evolved populations adapted to spatial structure by evolving enhanced motility (likely through parallel mutations in
PFLU_4551
, a predicted aerotaxis response regulator), this phenotype was constrained under high salinity, because increased motility negates the benefits of a spatial refuge. Our results reveal a general interplay between spatial refuges and nutrient availability that could be leveraged to reduce extinction risk in natural populations.
Antimicrobial Effect of Blue Light on Antibiotic-Sensitive and Drug-Resistant E. coli: A Novel Isotropic Optical Fiber
Authors: Goh Megan H. , Connolly Joseph J. , Chen Antonia F. , Rabiner Robert A. , Calderon Santiago Lozano
Published: December 2024

BACKGROUND

Orthopaedic oncologic pelvic reconstructions have an elevated risk of infection with gram-negative bacteria. This study evaluates the bactericidal ability of a novel antimicrobial blue light (ABL)-emitting optical fiber on antibiotic-sensitive E. coli (AS-Ec) and ESBL-producing E. coli (ESBL-Ec).

MATERIALS AND METHODS

Time-to-kill assays used a 10 mL NaCl solution with a starting inocula of 1x105 CFU/mL for AS-Ec or ESBL-Ec; assays were repeated a minimum of 3 times per strain. Experimental tubes had either 1 optical fiber (20.1 mW/mm; low power [LP]) or 2 optical fibers (40.3 mW/mm; high power [HP]), which delivered 5 wavelengths of ABL over 60 minutes. Control tubes had no optical fibers. 50µL samples taken from each tube at 0, 10, 20, 30 and 60 min were streaked onto agar plates and incubated. CFU/mL was determined. Bactericidal reduction was defined as a 99.9% (≥3 log10) reduction in CFU/mL. One-way ANOVA were conducted.

RESULTS

Bactericidal effects were seen for AS-Ec under both LP-ABL and HP-ABL with a log10CFU/mL±SD difference of 3.44±0.35 (p=0.043) and 3.74±0.21 (p=0.048) at 30 min and 20 min, respectively. For ESBL-Ec, while there was a significant reduction in bacterial colony formation, the bactericidal threshold was not reached with a log10CFU/mL±SD difference of only 1.02±0.41 (p=0.034) and 2.53±0.22 (p=0.037) at 60 min for LP-ABL and HP-ABL, respectively.

CONCLUSIONS

A novel ABL-emitting optical fiber exhibited bactericidal effects in AS-Ec and a clinically meaningful reduction of ESBL-Ec, providing a promising avenue for the use of ABL as a potential therapy for gram-negative infections.
Single-nucleus RNA sequencing of human periventricular white matter in vascular dementia
Authors: Díaz-Pérez Sebastián , DeLong Jonathan H. , Rivier Cyprien A. , Lee Chia-Yi , Askenase Michael H. , Zhu Biqing , Zhang Le , Brennand Kristen J. , Martins Andrew J. , Sansing Lauren H.
Published: December 2024

Vascular dementia (VaD) refers to a variety of dementias driven by cerebrovascular disease and is the second leading cause of dementia globally. VaD may be caused by ischemic strokes, intracerebral hemorrhage, and/or cerebral small vessel disease, commonly identified as white matter hyperintensities on MRI. The mechanisms underlying these white matter lesions in the periventricular brain are poorly understood. In this study we perform an extensive transcriptomic analysis on human postmortem periventricular white matter lesions in patients with VaD with the goal of identifying molecular pathways in the disease. We find increased cellular stress responses in astrocytes, oligodendrocytes, and oligodendrocyte precursor cells as well as transcriptional and translational repression in microglia in our dataset. We show that several genes identified by GWAS as being associated with white matter disease are differentially expressed in cells in VaD. Finally, we compare our dataset to an independent snRNAseq dataset of PVWM in VaD and a scRNAseq dataset on human iPSC-derived microglia exposed to oxygen glucose deprivation (OGD). We identify the increase of the heat shock protein response as a conserved feature of VaD across celltypes and show that this increase is not linked to OGD exposure. Overall, our study is the first to show that increased heat shock protein responses are a common feature of lesioned PVWM in VaD and may represent a potential therapeutic target.
Element partitioning, element localisation and transcriptome responses of date palms exposed to NaCl
Authors: Pongrac Paula , Fischer Sina , Wright Gladys , Thompson Jacqueline A. , Kelemen Mitja , Neugebauer Konrad , Brown Lawrie K. , Vogel-Mikuš Katarina , Šala Martin , El-Serehy Hamed A. , White Philip J.
Published: December 2024

Date palm (Phoenix dactyliferaL.) is an economically important fruit crop in many (semi)arid regions. Large intra-species variation in susceptibility to NaCl has been reported. Controlled experiments were conducted to evaluate sodium (Na) and chlorine (Cl) partitioning in two-year old plants of six date palm varieties and to determine tissue location of Na and Cl and transcriptome responses to NaCl of two varieties. The largest Na concentrations were found in secondary roots, especially under NaCl treatment. By contrast, only small differences in within-plant partitioning of Cl were observed with less differences between varieties than for Na. Variety Sultana had the largest Na translocation factor. The variety Khalas exhibited better restriction of Na mobility, which may be a consequence of Na hotspots in roots, presumably immobilising Na in roots, which were absent in Sultana. In the root, shoot base and lower part of leaves, Cl accumulated in fibre bands and sclerenchyma sheaths of vascular bundles. RNAseq analysis revealed that Sultana and Khalas respond very differently to NaCl: Khalas modified expression of NaCl-specific genes in both roots and leaves, while Sultana responded manly in leaves. Gene ontology analysis showed that the expression changes for genes linked with photosynthesis and carbohydrate metabolism predominated as a response to NaCl. In Khalas, differentially expressed genes encoding for metal transporters and those reported to be involved in heat, salt and osmotic stress response were found. Large variability in Na and Cl accumulation in different date palm varieties may have practical agronomical consequences.
ASSOCIATION BETWEEN CIRCADIAN RHYTHMS, SLEEP, AND DEPRESSION: A BIDIRECTIONAL MENDELIAN RANDOMISATION STUDY IN THE UK BIOBANK
Authors: Paz Valentina , Williams Dylan M , Richards Marcus , Tassino Bettina , Silva Ana , Garfield Victoria
Published: December 2024

Increasing evidence links circadian and sleep disruptions with depression, though whether they are causally related remains unclear. This study used Mendelian randomization (MR) with exposures instrumented using genome-wide genetic variants and data from the UK Biobank (n=408 480; mean age=56.9 years) to explore causal associations between circadian and sleep traits, and depression. We conducted bidirectional MR analyses between morningness, sleep duration, insomnia symptoms, and depression, and secondary unidirectional analyses with circadian and sleep traits as exposures and mixed anxiety-depressive symptoms and anxiety disorders as outcomes. Using inverse-variance weighting and sensitivity analyses for horizontal pleiotropy (MR-Egger and Weighted Median Estimator), we found suggestive associations between morningness and lower odds of depression (diagnosis and treatment: OR=0.89, 95%CI=0.80, 0.98), and depression and shorter sleep duration (β=-4.67 minutes, 95%CI=-7.44; -1.89). Depression showed an effect on insomnia (any symptoms: OR=1.22, 95%CI=1.11; 1.34; frequent symptoms: OR=1.30, 95%CI=1.19; 1.42), while frequent insomnia was associated with increased odds of depression (diagnosis: OR=1.14, 95%CI=1.10; 1.19; diagnosis and treatment: OR=1.10, 95%CI=1.06; 1.14). Insomnia also had an effect on mixed anxiety-depressive symptoms (any symptoms: OR=1.19, 95%CI=1.08, 1.32; frequent symptoms: OR=1.20, 95%CI=1.17, 1.23), but no associations were found between the exposures and anxiety disorders. These findings shed light on the causal links between the circadian system and depression.
The Combination of Neuropsychiatric Symptoms and Blood-based biomarkers for Early Detection of Cognitive Disorders
Authors: Leow Yi Jin , Ismail Zahinoor , Saffari Seyed Ehsan , Sandhu Gurveen Kaur , Tanoto Pricilia , Hui En Lee Faith Phemie , Ghildiyal Smriti , Liew Shan Yao , Bhalla Gursimar , Ying Sim Xin , Mohammed Adnan Azam , Vipin Ashwati , Dang Chao , Kandiah Nagaendran
Published: December 2024

Background

Integrating behavioural assessments with blood-based biomarkers (BBM) could improve diagnostic accuracy for Mild Cognitive Impairment (MCI) linked to early-stage neurodegenerative disease (NDD). This study investigates the potential of combining neuropsychiatric symptoms (NPS) with BBM to enhance the differentiation between older adults with MCI and those with Normal Cognition (NC) in a multi-ethnic Southeast Asian cohort.

Methods

This cross-sectional study analyzed baseline data from the Biomarkers and Cognition Study, Singapore(BIOCIS). Data from 678 participants (mean[SD]age 59.16[11.02]years, 39.50% males) with NC and MCI were included. Behavioral symptoms were assessed using the Mild Behavioral Impairment Checklist (MBI-C) and Depression, Anxiety, and Stress Scales (DASS). Blood samples were analyzed for amyloid-beta (Aβ40, Aβ42), phosphorylated Tau (p-tau181), neurofilament light (NfL) and glial fibrillary acidic protein (GFAP). Regression models adjusted for age, education, gender, cognitive status (CS) and APOE-ε4 status were used. Discriminative power was evaluated using the area under the curve (AUC) to assess the combined predictive accuracy of behavioral and biological markers for CS, i.e., MCI status over CN.

Results

The study included MBI-C scores (total, interest, mood, control) and BBM levels (Aβ40, NfL, GFAP) were significantly higher in MCI group, compared to CN group. Elevated GFAP (OR:3.636, 95% CI:1.959, 6.751, p<0.001) and higher MBI-C-Mood scores (OR:2.614, 95% CI:1.538, 4.441, p<0.001) significantly increased the likelihood of MCI. The combined model, integrating NPS and BBM markers, showed strong discriminative ability for MCI (AUC = 0.786), with 64.7% sensitivity and 84.9% specificity at a threshold of 0.616, compared to NPS markers (AUC: 0.593) or BBM (AUC: 0.697) alone.

Conclusions and Relevance

The combined use of BBM and NPS achieved optimal accuracy in distinguishing MCI from NC, with strong associations between GFAP, MBI-C Mood scores, and CS. These findings underscore neuroinflammation and mood disturbances as critical factors in early NDD, supporting the importance of dual-dimension screening strategies. Integrating NPS and BBM represents a novel and effective diagnostic approach for detection of MCI due to AD or other dementias. The integrated framework, leveraging both pathophysiological and neuropsychiatric markers, facilitates earlier diagnosis, potentially improving clinical decision-making and enabling targeted disease-modifying therapies for individuals with neurodegenerative disorders.
EXTRA-seq: a genome-integrated extended massively parallel reporter assay to quantify enhancer-promoter communication
Authors: Kribelbauer-Swietek Judith F. , Gardeux Vincent , Llimos-Aubach Gerard , Faltejskova Katerina , Russeil Julie , Grenningloh Nadia , Levassor Lucas , Steiner Clémence , Vondrasek Jiri , Deplancke Bart
Published: December 2024

Precise control of gene expression is essential for cellular function, but the mechanisms by which enhancers communicate with promoters to coordinate this process are not fully understood. While sequence-based deep learning models show promise in predicting enhancer-driven gene expression, experimental validation and human-interpretable mechanistic insights lag behind.

Here, we presentEXTRA-seq, a novelEXTendedReporterAssay followed bysequencing designed to quantify enhancer activity in endogenous contexts over kilobase-scale distances. We demonstrate that EXTRA-seq can be targeted to disease-relevant loci and captures expression changes at the resolution of individual transcription factor binding sites, enabling mechanistic discovery. Using engineered synthetic enhancer-promoter combinations, we reveal that the TATA-box acts as a dynamic range amplifier, modulating expression levels in function of enhancer strength. Importantly, we find that integrating state-of-the-art deep learning models with plasmid-based enhancer assays improves the prediction of gene expression as measured by EXTRA-seq. These findings open new avenues for predictive modeling and therapeutic applications.

Overall, our work provides a powerful experimental platform to interrogate the complex interplay between enhancers and promoters, bridging the gap betweenin silicopredictions and human-interpretable biological mechanisms.
Storage and transport of labile iron is mediated by lysosomes in axons and dendrites of hippocampal neurons
Authors: Kittilukkana Aiyarin , Carmona Asuncion , Somogyi Andrea , Pilapong Chalermchai , Ortega Richard
Published: December 2024

Iron dyshomeostasis in neurons, involving iron accumulation and abnormal redox balance, is implicated in neurodegeneration. In particular, labile iron, a highly reactive pool of intracellular iron, plays a prominent role in iron-induced neurological damage. However, the mechanisms governing the detoxification and transport of labile iron within neurons are not fully understood. This study investigates the storage and transport of labile ferrous iron Fe(II) in cultured primary rat hippocampal neurons. Iron distribution was studied using live cell confocal microscopy with a selective labile Fe(II) fluorescent dye, and synchrotron X-ray fluorescence microscopy (SXRF) for total iron distribution. Fluorescent labelling of the axon initial segment and of lysosomes allowed iron distribution to be correlated with these subcellular compartments. The results show that labile Fe(II) is stored in lysosomes within somas, axons and dendrites and that lysosomal labile Fe(II) is transported retrogradely and anterogradely along axons and dendrites. In addition, we have developed a methodological workflow to quantify labile Fe(II) relative to total iron in neurites. This method is based on correlative imaging of fluorescence microscopy of labile Fe(II) combined with quantitative elemental mapping of total iron by SXRF. Quantitative analysis revealed that after Fe(II) exposure, lysosomal Fe(II) accounts for a small but significant percentage of the total iron content in neurites. These result suggest that after exposure to labile Fe(II), iron is mainly present in a non-reactive form in neurons, while the smaller fraction of reactive labile Fe(II) is stored in lysosomes and can be transported along dendrites and axons.
GWAS significance thresholds in large cohorts
Authors: Cheruiyot Evans K , Yang Tingyan , McRae Allan F
Published: December 2024

While the p-value threshold of 5.0 × 10−8remains the standard for genome-wide association studies (GWAS) in humans and other species, it still needs to be updated to reflect the current era of large-scale GWAS, where tens of thousands of sample sizes are used to discover genetic associations at loci with smaller minor allele frequencies. In this study, we used a dataset of 348,501 individuals of European ancestry from the UK Biobank to determine the GWAS thresholds required for multiple testing corrections when considering rare and common variants in additive and dominant GWAS models. Additionally, we employed conditional and joint (COJO) analysis to quantify the proportion of false significant hits in the GWAS results for 72 traits in the UK Biobank when applying the traditional GWAS cut-off versus our newly proposed p-value thresholds. Overall, the results indicate that the conventional GWAS significance threshold of 5.0 × 10−8yields a false positive rate of between 20% and 30% in GWAS studies that utilize large sample sizes and less common variants. Instead, a more stringent GWAS p-value threshold of 5.0 × 10−9is needed when rare variants (with minor allele frequency > 0.1%) are included in the association test for both additive and dominance models within the European ancestry population.
Differences in the serum metabolomic profile of progressive alcohol-related liver disease in comparison to non-progressive alcohol-related liver disease: a cross sectional metabolomics study
Authors: Puhakka Eemeli , Ahmed Hany , Haikonen Retu , Leclercq Sophie , Hanhineva Kati , Maccioni Luca , Amadieu Camille , Lehtonen Marko , Männistö Ville , Rysä Jaana , Stärkel Peter , Kärkkäinen Olli
Published: December 2024

Alcohol-related liver disease (ALD) is a major cause of mortality and disability adjusted life years. It is not fully understood why a small proportion of patients develop progressive forms of ALD (e.g. fibrosis, cirrhosis). Differences in the metabolic processes could be behind the individual progression of ALD. Our aim was to examine differences in serum metabolome between patients with non-progressive ALD and patients with an early form of progressive ALD.

The study had three study groups: progressive ALD (alcohol-related steatohepatitis or early-stage fibrosis, n=50), non-progressive ALD (simple steatosis, n=50) and healthy controls (n=32). Both ALD groups took part in a voluntary alcohol rehabilitation program. A non-targeted metabolomics analysis and targeted analysis of short chain fatty acids was done to the serum samples taken on the day of admission.

We found 111 significantly (p<0.0005) altered identified metabolites between the study groups. Our main finding was that levels of glycine conjugated bile acids, glutamic acid, 7-methylguanine and several phosphatidylcholines were elevated in the progressive ALD group in comparison to both the non-progressive ALD group and the controls. Glycine conjugated bile acid, glutamic acid and 7-methylguanine also positively correlated with increased levels of aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, cell death biomarker M65, and liver stiffness.

Our results indicate that the enterohepatic cycle of glycine conjugated bile acids as well as lipid and energy metabolism are altered in early forms of progressive ALD. These metabolic processes could be a target for preventing progression of ALD.
Identifying causal genotype-phenotype relationships for population-sampled parent-child trios
Authors: Tang Yushi , Cabreros Irineo , Storey John D.
Published: December 2024

The process by which genes are transmitted from parent to child provides a source of randomization preceding all other factors that may causally influence any particular child phenotype. Because of this, it is natural to consider genetic transmission as a source of experimental randomization. In this work, we show how parent-child trio data can be leveraged to identify causal genetic loci by modeling the randomization during genetic transmission. We develop a new test, the transmission mean test (TMT), together with its unbiased estimator of the average causal effect, and derive its causal properties within the potential outcomes framework. We also prove that the transmission disequilibrium test (TDT) is a test of causality as a complementary case of the TMT for the affected-only design. The TMT and the TDT differ in the types of traits that they can handle and the study designs for which they are appropriate. The TMT handles arbitrarily distributed traits and is appropriate when trios are randomly sampled; the TDT handles dichotomous traits and is appropriate when sampling is based on a child’s trait status. We compare the transmission-based methods with established approaches for genotype-phenotype analyses to clarify conditions appropriate for each method, what conclusions can be drawn by each one, and how these methods can be used together.
Intrinsic electronic phase separation and competition between
G
-type,
C
-type, and
CE
-type charge and orbital ordering modes in
Hg1−xNaxMn3Mn4O12
Authors: Tragheim Ben R. M. , Simpson Struan , Liu En-Pei , Senn Mark S. , Chen Wei-Tin
Published: December 2024

The novel series of hole-doped quadruple manganite perovskites Hg1−xNaxMn3Mn4O12 (HNMO) has been synthesized and its charge and orbital order behavior investigated through high-resolution synchrotron powder x-ray diffraction techniques. Through careful Rietveld refinements of structural models via symmetry-motivated approaches, we show that the ground state of HNMO compositions adopts a polar G-type charge and orbital ordered state, which is rare in manganite perovskites, and is robust as a sole phase up to a critical doping level. Upon this critical doping, coincident with that in which colossal magnetoresistance (CMR) is maximal in canonical manganite perovskites, electronic phase separation occurs between G-type and orbital order with charge disorder-type states. The latter state has recently been identified in Ca1−xNaxMn3Mn4O12 perovskites, and proposed to be the competing insulating state from which CMR phenomena emerge. We show that the mechanism for the formation of the G-type state is due to charge transfer processes which may occur through a coupling of distortions involving structural and charge and orbital degrees of freedom, ultimately driving the polar ground state through an improper-like ferroelectric polarization mechanism. These results will act as an important recipe for designing novel ferroelectric-active materials, in addition to expanding the richness of charge and orbital ordered states in manganite perovskites.

Published by the American Physical Society
2024
Cogenesis of baryon and dark matter with PBHs and the QCD axion
Authors: Borah Debasish , Das Nayan , Das Suruj Jyoti , Samanta Rome
Published: December 2024

With entropy injection, an early matter-dominated epoch (EMD) impels the axion decay constant fa toward larger values to produce correct axion dark matter (DM) abundance, thereby unfolding the low-mass axion (ma≲10−5  eV) parameter space to be searched for in axion experiments. We implement this proposition in a scenario where fa and the leptogenesis scale in a seesaw mechanism are equivalent. We show that if, instead, the EMD is provided by evaporating ultralight primordial black holes (PBHs), the scenario becomes strikingly testable with gravitational wave (GW) background alongside the axion searches. In particular, while being consistent with correct axion DM abundance, the scale fa≳1012  GeV, corresponding to the unflavored regime of leptogenesis with hierarchical right-handed neutrinos, can be probed with GW and axion experiments, which is otherwise not testable at neutrino or collider experiments. Additionally, axions produced from PBH evaporation can give rise to dark radiation within reach of future cosmic microwave background experiments.

Published by the American Physical Society
2024
Extracting error thresholds through the framework of approximate quantum error correction condition
Authors: Zhao Yuanchen , Liu Dong E.
Published: December 2024

The robustness of quantum memory against physical noises is measured by two methods: the exact and approximate quantum error correction (QEC) conditions for error recoverability and the decoder-dependent error threshold which assesses if the logical error rate diminishes with system size. Here we unravel their relations and propose a unified framework to extract an intrinsic error threshold from the approximate QEC condition, which could upper bound other decoder-dependent error thresholds. Our proof establishes that relative entropy, effectively measuring deviations from exact QEC conditions, serves as the order parameter delineating the transition from asymptotic recoverability to unrecoverability. Consequently, we establish a unified framework for determining the error threshold across both exact and approximate QEC codes, addressing errors originating from noise channels as well as those from code space imperfections. This result sharpens our comprehension of error thresholds across diverse QEC codes and error models.

Published by the American Physical Society
2024
How does CEO personality affect new product development performance? The partial mediating role of strategic schema change
Authors: Ding Xiaozhou
Published: December 2024

Purpose

This study aims to explore the direct impact of various personality traits of the CEO on new product development (NPD) performance, as well as the mediating role of strategic schema changes in the relation among these key variables.

Design/methodology/approach

The research focuses on Chinese science and technology enterprises. A total of 659 valid responses from CEOs and senior managers have been analyzed to test the hypotheses.

Findings

The results reveal that CEO’s conscientiousness and agreeableness negatively correlate with NPD performance and strategic schema changes. CEO traits such as extroversion, openness to experience and emotional stability are positively associated with both variables. Furthermore, the study confirms that strategic schema changes partially mediate the relation between CEO personality traits and NPD performance.

Research limitations/implications

This study focuses only on the relation between CEOs’ Big Five personality traits and NPD performance. However, other personality traits such as narcissism or dark personality traits may also influence NPD performance. Future research should explore the effect of a broader range of CEO personality traits on corporate performance. And, this paper primarily investigates the mediating role of strategic schema change between CEO personality and NPD performance, drawing on personality psychology and strategic cognition. However, other important theoretical perspectives, such as organizational resources and binary learning, may offer additional insights into the relation between CEO personality and NPD performance. Future research could delve deeper into these perspectives at multiple levels for a more comprehensive understanding.

Originality/value

The findings broaden the application of personality psychology within innovation management, offering valuable practical insights and new perspectives for technology enterprises seeking to enhance new product performance.
Educate Northwest Helvetia: a Delphi study on public schooling in Switzerland
Authors: Quesel Carsten , Mittag Michael , Moeser Guido
Published: December 2024

Purpose

The Delphi study Educate Northwest Helvetia is part of a multi-stakeholder approach to define common challenges and priorities for public schooling in a federal setting. This paper aims to take stock of the outcome of expert ratings and group discussions.

Design

Based on a literature review of megatrends, 21st century skills and sustainable development goals, the study focused on four domains: digital change, economic change, sociocultural change and ecological change. Opinions of teachers, principals and other experts were collected in the first wave via an online survey (n = 707). In the second wave, findings of the survey were discussed in ten online workshops, and participants refined priorities for schooling 2030 via real-time online scoring. Quantitative data were analyzed using exploratory and confirmatory factor analysis.

Findings

Analysis of quantitative data shows an emphasis on soft skills, self-organization, equity and transversal competencies. The enhancement of computational thinking and teaching on sciences, technology, engineering and mathematics are important minority concerns.

Practical implications

The study delivers a manageable set of 12 priorities addressed to cantonal ministries of education, teacher unions, associations of principals and other stakeholders.

Research limitations/implications

Since these priorities are rather abstract, qualitative in-depth research concerning uptake and impact is needed.

Originality/value

This study provides new perspectives for the dialogue on evidence-based policymaking in settings of consensus democracy. It also provides valuable pointers for school improvement and teacher education that can be further explored.