bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Outcomes of Left Ventricular Assist Device Bleeding Complication
Authors: Imaoka Shusuke , Yoshioka Daisuke , Saito Shunsuke , Kawamura Takuji , Kawamura Ai , Toda Koichi , Miyagawa Shigeru
Published: September 2024

Bleeding complications have emerged as major causes of morbidity and mortality in patients with implantable left ventricular assist devices (LVAD). We hypothesized that the hemodynamics after LVAD implantation may influence the occurrence of bleeding complications after LVAD implantation. We retrospectively evaluated 78 patients who underwent continuous-flow LVAD implantation and hemodynamic ramp test after LVAD implantation between July 2017 and July 2023 at Osaka University. The bleeding complication occurred in 13 patients. The rates of freedom from bleeding complications at 1, 3, and 5 years were 94%, 85%, and 74%. Gastrointestinal bleeding, nose bleeding, and intraperitoneal hemorrhage occurred in six, three, and two patients, respectively. Preoperative average brachial-ankle pulse wave velocity (baPWV) was positively associated with bleeding complication (1,276 ± 280 vs. 1,098 ± 190 cm/s p = 0.04). In the hemodynamic ramp test, systemic vascular resistance (SVR) in patients with bleeding complications was higher than that in patients without bleeding complications (SVR: 1,359 ± 341 vs. 1,150 ± 217 dyne sec/cm5, p = 0.01). High preoperative baPWV and high SVR in the hemodynamic ramp test were significantly associated with bleeding complications after LVAD implantation. Arteriosclerosis is a risk factor for bleeding complications after LVAD implantation.
Active learning assisted piezoelectric materials synthesis on the basis of composite decision-making
Authors: Zhao En , Wang Tingyu , Wang Yutong , Zeng Fan , Chen Ling , Zhu Zhiyuan , Tang Wei
Published: September 2024

The synthesis and development of novel materials for soft electronics, health monitoring, etc, have become a research hotspot. Traditional laboratory synthesis is significantly time and resource consuming. Machine learning therefore becomes an ideal approach for expediting the experimental process, constructing a virtual and automated closed-loop material synthesis, and evaluation approach. In this work, we combined piezoelectric materials’ synthesis with machine learning to achieve automatic design optimization. A total of 300 samples with different material recipes were used to train the initial active learning model. Thereafter, more samples were fabricated based on the recommended feasible recipes for each learning loop and then proceeded to the next round of learning. Through 10 active learning loops, 105 piezoelectric samples were stage-wise fabricated. Moreover, a reverse design model based on Bayesian optimization is demonstrated, and Spearman rank correlation coefficient and P values revealed the rules for the synthesis of piezoelectric materials. Finally, according to the setup model, we fabricate optimized piezoelectric materials and demonstrate their application in cycling monitoring. We anticipate this work establishes an essential approach to accelerate the development of new materials.
Develop, Sustain, and Evaluate the Training of Simulation Educators
Authors: Paige Jane B. , Graham Leslie , Sittner Barbara
Published: September 2024

Background:

Developing the competency of simulation educators is critical for optimizing learner outcomes. Yet guidelines on how to sustain received simulation training and evaluate training programs are limited.

Purpose:

To examine the impact of a professional development workshop (PDW) aimed at individuals responsible for developing, sustaining, and evaluating simulation educator training programs.

Methods:

A longitudinal exploratory design was used, guided by the New World Kirkpatrick Model.

Results:

Seventy-seven participants from 6 countries and 5 professions participated at the outset of the study, with 56% completing the entire study at the 6-month mark. Significant changes in knowledge, confidence, and commitment were observed from pre-to-post PDW. Themes of personal capacity, supportive mechanisms, and embracing accountability were identified as facilitators to develop/evaluate training programs, whereas their absence acted as barriers.

Conclusions:

Develop a training program evaluation plan from the outset. Sustain the training of simulation leaders and educators through intentional processes that support, reinforce, monitor, and reward efforts.
Typing of Vulvar Squamous Cell Carcinoma: Why it is Important?
Authors: Alfaraidi Mona , Gilks C. Blake , Hoang Lynn
Published: September 2024

The classification of vulvar squamous cell carcinoma (VSCC), as in endometrial cancer, has shifted from the histology-based descriptors toward molecular-based identifiers. Recently, it has been reported that there are 3 genetically distinct and clinically significant subtypes of VSCC: HPV-associated VSCC, HPV-independent/p53 wild-type VSCC, and HPV-independent/p53-mutated VSCC. Each group has different prognostic implications as well as response to treatment, thus reinforcing the need for this 3-tier molecular classification. This molecular subtyping can easily be done on vulvar biopsies using p16 and p53 immunohistochemistry stains to further improve risk prediction and individualized treatment decisions, leading to better patient outcomes.
Expression of POU2F3 Transcription Factor and POU2AF2, POU2F3 Coactivator, in Tuft Cell-like Carcinoma and Other Tumors
Authors: Kaczorowski Maciej , Ylaya Kris , Chłopek Małgorzata , Lasota Jerzy , Miettinen Markku
Published: September 2024

Epithelial chemosensory cells in hollow organs, also known as tuft cells, were implicated in tumorigenesis, including a tuft cell-like small cell lung carcinoma. Expression of the POU2F3 transcription factor is a marker of tuft cell lineage. However, tuft cell development, differentiation, and proliferation are controlled by the expression of the complex formed by POU2F3 and POU2AF2 or POU2AF3 transcriptional coactivators. A cohort of epithelial (n=6064) and mesenchymal/neuroectodermal (n=2730) tumors was screened for POU2F3 expression by immunohistochemistry. Variable immunoreactivity ranging from diffuse to scattered positive cells was found in ∼12.4% of epithelial and 4.6% of mesenchymal/neuroectodermal tumors. Cases with predominantly diffuse or patchy POU2F3 positivity representing various types of malignant tumors (n=43) were selected for further study, including POU2AF2 immunohistochemistry. Thirteen of 15 tumors with neuroendocrine differentiation originating from the lung, colon, head and neck, skin, and bladder revealed diffuse POU2F3 positivity. Most of those tumors (n=9) co-expressed POU2AF2, usually extensively. Seven squamous and basal cell carcinomas from the oral cavity, skin, lung, and thymus with diffuse POU2F3 immunostaining except one, lacked POU2AF2 expression. Other variably POU2F3-positive carcinomas (n=13) from the colon, pancreas, liver, kidney, testis, endometrium, ovary, and breast lacked POU2AF2 immunoreactivity. All POU2F3-positive mesenchymal and neuroectodermal tumors (n=8), including synovial sarcoma, solitary fibrous tumor, glioblastoma, Wilms tumor, and melanoma were POU2AF2-negative. POU2F3 expression is a highly sensitive but nonspecific indicator of tuft cell differentiation. Co-expression of POU2F3 and POU2AF2 appears to be a more specific marker, although it may not pinpoint tumors driven by the POU2F3-POU2AF3 complex.
The Influence of State Restrictions on Opioid Prescribing: 2006–2018
Authors: Cosler Leon E. , Midence Luis , Hayes Jacob J. , Gondeck Justin-Theodore , Moy Kaitlin , Chen Mei-Hsiu , Hogan John D.
Published: September 2024

Objective

To measure the longitudinal effect of opioid restrictions on prescribing patterns at the state and regional levels.

Design

Health policy evaluation using a Poisson regression of opioid metrics from federal repositories to model what the estimated opioid counts are for the next fiscal year.

Setting

State-specific prescribed opioid counts between 2006 and 2018 from CDC reports; population data were obtained from the U.S. Census Bureau for 2006-2018; and opioid prescribing restrictions were extracted from published reports and state regulatory databases.

Intervention

Poisson regression models were fitted to assess the relationship of statewide restrictions on opioid prescribing counts adjusting for states’ population.

Main Outcome Measure

Estimated opioid counts provided by the Poisson regression model.

Results

Per capita rates of prescribed opioids peaked in 2012 at 86.2 per 100 population. Prescribing restrictions are associated with statistically significant decreases in opioid prescribing. Controlling for population and year, we found for every 100 opioid prescriptions in a state without restrictions, only 98 opioid prescriptions are expected for every additional year in a state with restrictions in place.

Conclusions

Contrary to other research conducted over a shorter study period, we found that restrictions do reduce opioid prescribing; however, a statistically significant change in rates may not be detectable in the early years after restrictions are enacted.
Improving ICD Coding in the Emergency Department: Factors Related to Use of “Unspecified” Codes for Head and Brain Injury
Authors: Wharton Tracy , Costello Emily Hunt , Peterson Alexis , Bleser Julia A. , Sarmiento Kelly , Bailey Morgan
Published: September 2024

Context

International Classification of Diseases (ICD) codes are used for billing but also for surveillance for injuries such as traumatic brain injuries (TBI). While specificity is possible in the ICD-10-CM scheme, use of the code for unspecified injury of head (SO9.9) remains high.

Objectives

This process evaluation sought to understand medical ICD-10-CM coding behaviors for TBI in emergency department (ED) settings.

Design

Semi-structured interviews explored the processes that facilitate or hinder ED physicians from selecting specific ICD codes for TBI and potential points of intervention for increased coding specificity and reducing the use of unspecified codes.

Setting

Video interviews were conducted with a nationwide sample in the United States.

Participants

A purposive snowball sampling strategy was used to recruit 26 ED physicians with experience diagnosing TBI.

Intervention

Semi-structured interviews identified factors related to the selection of specific ICD codes for head injury.

Main Outcome Measure

Thematic analysis of transcribed data.

Results

Four main themes emerged from the data: the impact of training and expertise, factors related to diagnosis, unclear connections with medical coders, and actionable recommendations. Interviews underscored the context surrounding “unspecified” codes for TBI, including demands from patient care, time pressures, issues around how a diagnosis may impact patient management decisions, and considerations related to mapping within the electronic medical record (EMR) where options may default to an unspecified code.

Conclusions

Findings from this analysis indicate that ED providers may benefit from more robust training on how documentation can better support ICD-10-CM coding for this type of trauma. Revised EMR structures could support efficient coding specificity and clarity.
Development of a Definition to Identify Severe Opioid Overdoses Treated in Emergency Departments, 2019-2022
Authors: Liu Stephen J. , Smith Herschel , Krishnasamy Vikram , Gladden R. Matthew
Published: September 2024

Background:

Existing surveillance systems monitor nonfatal and fatal opioid overdoses but do not monitor severe nonfatal overdoses that require intensive medical interventions.

Methods:

The Centers for Disease Control and Prevention’s Drug Overdose Surveillance and Epidemiology system was used to query emergency department data from local syndromic systems and the National Syndromic Surveillance Program from January 2019 to August 2022. Opioid overdoses were classified as not severe or severe using a definition from the patient’s chief complaint terms and discharge diagnosis codes. The percentage of opioid overdoses treated in emergency departments classified as severe was described by patient demographics, US Census region, and month.

Results:

Among 503 156 opioid overdoses in 29 states and Washington, DC, from January 2019 to August 2022, 17.4% were classified as severe. Common key terms found among severe opioid overdoses were hypoxia (34.8%), unresponsive (32.9%), and naloxone/Narcan (20.9%). The largest severity percentage was in the South Census region (19.6%). The trends of severe opioid overdoses remained stable during the study period.

Discussion:

Based on the severe opioid overdose definition, there was minimal change in the severity of opioid overdoses during the study period. This definition can help monitor trends of severe opioid overdoses, guiding public health action such as focusing on naloxone and fentanyl test strip distribution to areas of need.
Partnering for Vaccine Equity: A Public Health-Community Action Model to Advance Delivery of Essential Health Services
Authors: Nadkarni Geetika , Nair Shalini , Seels Lillie
Published: September 2024

As part of CDC’s Partnering for Vaccine Equity Program, the Association of State and Territorial Health Officials worked with the National Community Action Partnership and five community action agencies (CAAs) to address disparities in adult immunization among racial and ethnic minority populations. CAAs leveraged partnerships with public health, healthcare, and other local entities to increase uptake of COVID-19 and other vaccines, while simultaneously addressing related social determinants of health. With over 1000 agencies across the United States, including state associations, CAAs are accessible partners to nearly all state and local health departments. Collaboration between public health and community action is a promising model that can be used to cultivate trust, build and support resiliency, and address systemic disparities to advance health equity within communities.
The Impact of Blood Glucose Levels on the Prognosis of Diabetic Patients With Successful Recanalization After Mechanical Thrombectomy: A Single-Center Retrospective Study
Authors: Wang Yubo , Ren Hecheng , Ma Lin , Xiang Yi , Zhang Xiqiang , Luo Bin
Published: September 2024

Objective:

To investigate the impact of postoperative fasting blood glucose monitoring on the prognosis of patients with acute intracranial large vessel occlusion (ALVO) after mechanical thrombectomy.

Methods:

A retrospective study was conducted on 328 diabetic patients diagnosed with acute ischemic stroke through MRI, confirmed to have intracranial large vessel occlusion through MRA or DSA, and treated with mechanical thrombectomy between June 2021 and June 2023 at Tianjin Huanhu Hospital. Based on the 90-day postonset prognosis (modified Rankin scale, 90d-mRS), 148 patients were categorized into the favorable prognosis group (90d-mRS score 0–2) and 180 into the poor prognosis group (90d-mRS 3–6). Clinical data between the 2 groups were compared. Factors with P<0.1 in univariate analysis were included in multivariate Logistic regression analysis to evaluate their impact on prognosis.

Results:

A total of 328 diabetic patients were included in the study, with a median age of 63 (56, 69) years; 240 males aged 60.88 (55, 68.75) years and 88 females aged 65.16 (60, 72) years. There were significant differences between the 2 groups in terms of gender, preoperative mRS, and fasting blood glucose within the first 3 days postoperation. Multivariate Logistic regression analysis indicated that gender, preoperative mRS score, and fasting blood glucose on the first postoperative day were independent risk factors for poor prognosis. Female diabetic patients had a 56.7% higher rate of poor prognosis compared with males patients (OR: 0.567, 95% CI: 0.326–0.986, P=0.044); the poor prognosis rate in the preoperative mRS 3 to 6 group was 2.101 times that of the preoperative mRS 0 to 2 group (OR: 2.101, 95% CI: 1.027–4.300, P=0.042); for every 1 mmol/L increase in fasting blood glucose on the first day post-thrombectomy was associated with a 10.2% increase in the rate of poor prognosis at 90 days (OR: 1.102, 95% CI: 1.023–1.189, P=0.011). The predictive power of fasting blood glucose on the first postoperative day for 90d-mRS was greater than that of gender and preoperative mRS, with sensitivity and specificity of 68.2% and 60.6%, respectively. Combined prediction using fasting blood glucose, gender, and preoperative mRS had similar effectiveness. Maintaining fasting blood glucose levels below 11.5 mmol/L on the first day post-thrombectomy could reduce the rate of poor prognosis in patients.

Conclusion:

Fasting blood glucose levels on the first day post-thrombectomy can be used as a prognostic indicator for diabetic patients with acute intracranial large vessel occlusion. Effective blood glucose control can significantly reduce the rate of poor prognosis in these patients.
Conservative Versus Radical Treatment of Ameloblastoma: A 14-Year Study in Kedah, Malaysia
Authors: Ling Xiao Feng , Ismail Sumairi bin , Zainal Abidin Marzuki bin , bt Amran Nurfitri Atirah , bin Abd Samad Mohammad Azrin , Tew Mei Mei , Awang Hasyim Noratikah binti
Published: September 2024

Introduction:

Ameloblastoma is a slow-growing benign odontogenic tumor of the jaws. The objectives of this study were to evaluate the epidemiological data of ameloblastoma in Kedah, to identify the clinicopathological characteristics that predict the outcome of the treatment and recurrence rate.

Methodology:

A retrospective cohort study was conducted for patients who underwent treatment for ameloblastoma from 2007 to 2021. All patients with histopathologically proven ameloblastoma and underwent at least 2 years of follow-up were included in the study.

Results:

Fifty-one patients met the study’s inclusion criteria. The mean age was 39.8 +/− 18.8 years old, and the mean follow-up period was 80 +/− 51 months. A recurrence was observed in 10 patients out of 51 patients (19.6%). There was significant association between histologic pattern and tumor recurrence (P<0.05). Most of the recurrence cases showed mixed histologic subtypes with the predominant variant lead by acanthomatous-follicular subtypes.

Discussion:

The recurrence rate in our study, 19.6% was in line with other studies. (17.2%–24.0%) Conventional ameloblastoma with mixed acanthomatous and follicular subtypes were the most common histologic variant in recurrence cases of our study. In our study, the recurrence rate for enucleation with peripheral ostectomy was 26.7% in conventional ameloblastoma, which was lower than the reported rates, 33.3%.

Conclusions

Our data indicate that the conservative treatment can preserve the appearance and function well, at the same time keeping the risk of recurrence lower than currently published figures.
The Difference in Cognitive Profiles Between Patients With Alzheimer Dementia With and Without Psychosis
Authors: Carmel Jean-François , Clerc Doris , Couture Vincent , Reid Isabelle , Filali Ali , Villalpando Juan Manuel
Published: September 2024

Background:

Psychosis in Alzheimer disease (AD) is a major burden for patients and their family. Identifying the characteristics of delusions and hallucinations in the AD population is key to understanding the interconnection between the psychiatric and cognitive symptoms in neurocognitive disorders. The aim of this study is to compare the cognitive profiles of AD patients with and without psychosis.

Methods:

We conducted a rapid review to explore the relationship between psychotic symptoms and cognitive performances in patients with AD. We used MEDLINE, Embase, and PsychINFO literature databases between January 2015 and January 2023. This rapid review was guided by the Cochrane Rapid Reviews Methods Group.

Results:

We identified 2909 records from the initial searches. After reviewing the titles, abstracts, and full texts, we selected 8 cross-sectional and 5 cohort studies for the qualitative analysis. Among them, 6 studies were included in the final quantitative analysis. Most studies suggested a correlation between general cognitive decline and the risk of presenting psychotic symptoms. Three studies found an association between hallucinations and deficits in the visuocognitive domains (visuospatial, visuoperceptual, and visuoconstructive skills). Two studies found a relationship between psychotic symptoms and executive dysfunction. Two studies also found a correlation between psychotic symptoms and language. Our results are in line with previous data in the literature, especially regarding the outcome of psychosis on executive function and visuocognitive abilities.

Conclusions:

There appears to be an association between cognitive deficits and psychotic symptoms in AD, but the direction of causality is still unclear, and further studies using longitudinal designs would give more insight into the pathophysiological process of psychosis in AD.
Fruit resources shape sexual selection processes in a lek mating system
Authors: Anderson H. Luke , Cabo Jairo , Karubian Jordan
Published: September 2024

The degree to which within-population variation in sexual trait expression relates to resource heterogeneity remains poorly explored. This is particularly true in lek-mating species, where genetic explanations for male phenotypic variance and mating success are dominant. Here, we demonstrate a link between fine-scale fruit resource availability and indices of male mating success in the white-bearded manakin (
Manacus manacus
), a lek-mating frugivorous bird that produces energetically costly courtship displays. We used motion-activated camera traps to monitor male display behaviour and female visitation at male courts while concurrently conducting twice-monthly fruit surveys around courts. We observed significant variability in ripe fruit biomass among display courts and leks, and mean fruit biomass at courts significantly predicted male display rates. In turn, male display rate was the strongest predictor of female visitation to courts. Causal modelling supported the hypothesis that hyper-local fruit availability indirectly affects female visitation via its direct effects on male display rate. The demonstration that resource availability at fine spatial scales predicts display rate in a lekking organism—for which resource-related variables are typically not considered to play important roles in shaping male reproductive variance—has implications for the expression, honesty and maintenance of sexually selected traits under fluctuating ecological conditions.
Hematological Abnormalities as Diagnostic Indicators of Malaria in Returning Travelers: A Retrospective Study at Mohamed V Military Instruction Hospital
Authors: Zniber nabil Mohamed , Laatiris Hamid , Siyar Hamza , Erraji Abdelouahab , Labrouzi Ismail , Jnah Mohamed , Talbi Mehdi , Iken Maryem , Lmimouni Badreddine , Naoui Hafida
Published: September 2024

Introduction

Malaria remains a significant global health concern, particularly in travelers returning from endemic regions. Hematological abnormalities are often associated with malaria and can serve as diagnostic indicators, especially when clinical symptoms are nonspecific.

Objective

This study aims to identify the most relevant hematological parameters for diagnosing malaria in travelers returning from endemic areas, who sought care at the Mohamed V Military Instruction Hospital in Rabat.

Methods

We conducted a retrospective comparative study involving 829 patients who returned from malaria-endemic regions between January 2017 and December 2023. Data collected included demographic information, parasitological test results, and comprehensive hematological profiles. Statistical analysis was performed to determine the sensitivity and specificity of various hematological parameters in diagnosing malaria.

Results

Thrombocytopenia, lymphocytopenia, and anemia were the most significant hematological abnormalities associated with malaria. Thrombocytopenia, defined as a platelet count below 150 x 103/µL, demonstrated a sensitivity of 75.91% and a specificity of 84.11%. Lymphocytopenia, with a threshold of less than 1.5 x 103/µL, showed a sensitivity of 69.47% and a specificity of 78.39%. Anemia, defined by hemoglobin levels below 13 g/dL in men and 12 g/dL in women, also significantly correlated with malaria diagnosis.

Discussion

This study highlights the significance of hematological abnormalities as key diagnostic markers for imported malaria cases. By analyzing retrospective data, we observed that these abnormalities, especially thrombocytopenia and anemia, are common among returning travelers with confirmed malaria. These findings suggest that clinicians can use such markers as a valuable tool for early malaria diagnosis, potentially improving patient outcomes. Additionally, the study reinforces the need for heightened awareness among healthcare providers in non-endemic regions regarding the presentation of malaria in travelers.

Conclusion

Hematological parameters such as thrombocytopenia, lymphocytopenia, and anemia are valuable diagnostic tools for malaria in returning travelers. These findings suggest that these parameters should be integrated into diagnostic protocols to improve the accuracy and timeliness of malaria diagnosis, particularly in clinical settings with limited access to advanced diagnostic tools.
Unique dental arrangement in a new species ofGroenlandaspis(Placodermi, Arthrodire) from the Middle Devonian of Mount Howitt, Victoria, Australia
Authors: Fitzpatrick Austin N. , Clement Alice M. , Long John A.
Published: September 2024

Well-preserved specimens of an undescribed species of arthrodiran placoderm,Groenlandaspis howittensissp. nov. (Middle Devonian of Victoria, Australia), reveals previously unknown information on the dermal skeleton, body-shape and tooth arcade of the wide-spread genusGroenlandaspis. The new material includes, dual pineal plates, extrascapular plates, and cheek bones cheek bones showing the presence of cutaneous sensory organs. The anterior supragnathal, usually a paired element in arthrodires, is a fused medial bone inG. howittensissp. nov. It is positioned anterior to the occlusion of the mouth between the lower jaw (infragnathals) and upper jaw (posterior supragnathals) bones, indicating a specialised feeding mechanism and broadening the known diversity of placoderm dental morphologies.G. howittensissp. nov. differs from all other groenlandaspidids by a less pronounced posterior expansion of the nuchal plate; the shape of the posterior dorsolateral plate and the presence of a short accessory canal on the anterior dorsolateral plate. A new phylogenetic analysis positions Groenlandaspididae in a monophyly with the phlyctaeniid families Arctolepidae and Arctaspdidae, however, the specific intrarelationships of groenlandaspidids remain poorly resolved.
Associations of Genetic Variants in the Dopamine Transporter with Problematic Sexual Behavior and Reward Deficiency Syndrome
Authors: Jiang Shui , Foo Jerome C , Hu Xiuying , Green Bradley , Arnau Randolph , Carnes Pennie J ,   Behavioral Addictions Studies and Insights Consortium, Isenberg Rick , Wishart David , Carnes Patrick J , Fujiwara Esther , Aitchison Katherine J
Published: September 2024

Objectives Problematic sexual behavior (PSB) is defined by recurrent sexual behaviors that are difficult to control, causing social and functional impairments. PSB can co-occur with reward deficiency syndrome (RDS), but this relationship remains unclear. RDS has been associated with the 10/10 genotype of 3 ′ variable number tandem repeat (VNTR) in the dopamine transporter gene SLC6A3, which is implicated in the reward pathway. This study investigates the genetic relationship between PSB and RDS, testing their association with SLC6A3 3′ VNTR genotype. Methods PSB patients from addiction treatment facilities (n=454), and comparison participants (with PSB=82; without PSB, n=888) were recruited. PSB was measured by the Sexual Addiction Screening Test-Revised (SAST-R) Core and RDS was measured using a composite variable from a custom test battery. DNA was collected from saliva and buccal swabs. Genotyping was performed using polymerase chain reaction (PCR), and regression analyses were conducted to investigate the association of SLC6A3 3′ VNTR genotype with PSB and RDS. Results The 10/10 genotype of SLC6A3 3′ VNTR was associated with RDS in a combined analysis of all groups, and with PSB only in comparison participants. In patients, rare SLC6A3 3′ VNTR genotypes (3-, 6-, 8-, 11-repeat alleles) were associated with PSB. No genotype showed relationships to RDS in only PSB patients. Conclusions The link of the 10/10 genotype to RDS indicates that PSB could be a manifestation of RDS in non-clinical populations; rare genotypes might be associated with clinical forms of PSB, together with comorbid psychopathology.
Transcriptome profiling of dopaminergic neurons derived from an ADHD induced pluripotent stem cell (iPSC) model
Authors: Namipashaki Atefeh , Arnatkeviciute Aurina , Hellyer Shane D. , Nowell Cameron J , Walsh Kevin , Polo Jose M. , Gregory Karen J , Bellgrove Mark A. , Hawi Ziarih
Published: September 2024

The most recent ADHD–GWAS meta–analysis highlighted the potential role of 76 genes enriched among genes expressed in early brain development and associated with midbrain dopaminergic neurons. However, the precise functional importance of the GWAS-identified single nucleotide polymorphisms (SNPs) remain unknown. In contrast to GWAS, transcriptome analysis directly investigates gene products by assessing the transcribed RNA. This allows one to gain functional insights into gene expression paving the way for a better understanding of the molecular risk mechanisms of conditions, such as ADHD. In this study, we performed transcriptome profiling of highly homogeneous dopamine neurons developed from induced pluripotent cells (iPSCs) that were derived from an individual with ADHD and a neurotypical comparison individual. Comparative gene expression analysis between the examined lines revealed that the top differentially expressed genes (DEGs) were predominantly associated with nervous system functions related to neuronal development and dopaminergic regulation. Notably, 29 of the DEGs overlapped with those identified by ADHD–GWAS meta- analysis. These genes are overrepresented in biological processes including developmental growth regulation, axonogenesis, and nervous system development. In addition, gene set analysis revealed significant enrichment for meta categories such as ion channel activity, synaptic function and assembly, neuronal development and cell differentiation. Further, we observed significantly reduced projections in the ADHD dopamine neurons at the mid–differentiation stage (day 14 in vitro), providing preliminary support for the delayed neuronal maturation hypotheses of ADHD. This study underscores the potential of using iPSC–derived cell type–specific models that integrate genome and transcriptome analyses for biological discovery in ADHD.
Dissecting the Reduced Penetrance of Putative Loss-of-Function Variants in Population-Scale Biobanks
Authors: Blair David R. , Risch Neil
Published: September 2024

Loss-of-function variants (LoFs) disrupt the activity of their impacted gene. They are often associated with clinical phenotypes, including autosomal dominant diseases driven by haploinsufficiency. Recent analyses using biobanks have suggested that LoF penetrance for some haploinsufficient disorders may be low, an observation that has important implications for population genomic screening. However, biobanks are also rife with missing data, and the reliability of these findings remains uncertain. Here, we examine the penetrance of putative LoFs (pLoFs) using a cohort of ≈24,000 carriers derived from two population-scale biobanks: the UK Biobank and the All of Us Research Program. We investigate several possible etiologies for reduced pLoF penetrance, including biobank recruitment biases, annotation artifacts, missed diagnoses, and incomplete clinical records. Systematically accounting for these factors increased penetrance, but widespread reduced penetrance remained. Therefore, we hypothesized that other factors must be driving this phenomenon. To test this, we trained machine learning models to identify pLoFs with high penetrance using the genomic features specific to each variant. These models were predictive of penetrance across a range of diseases and pLoF types, including those with prior evidence for pathogenicity. This suggests that reduced pLoF penetrance is in fact common, and care should be taken when counseling asymptomatic carriers.
Framing Major Depressive Disorder as a Condition of Network Imbalance at the Compartment Level: A Proof-of-Concept Study
Authors: Lee Tien-Wen
Published: September 2024

Background: Hypoactivity in the frontoparietal (FP) system and hyperactivity in the limbic system have been observed in major depressive disorder (MDD). Among the neuropathological theories of MDD, the cortico-limbic dysregulation model has been prominent, and it was recently extended and refined by the framework of imbalanced reciprocal suppression between the FP and limbic compartments. This research aims to examine this refined theory. Methods: Sixty MDD and sixty healthy control datasets, including structural magnetic resonance imaging and resting-state functional MRI (rsfMRI), were selected from the CAN-BIND database. The cerebral cortex in rsfMRI was parcellated by MOSI (modular analysis and similarity measurements). For each parcellated node, the mean amplitude of low-frequency fluctuation (mALFF) was computed. Correlation analyses were employed to construct an adjacency matrix between partitioned nodes and to examine the relationship between nodal power and nodal degree. Results: Two-sample t-tests revealed that the limbic system in MDD was associated with a higher partition number and mALFF (p < 0.005). A negative correlation between nodal degree and nodal power was replicated (p < 1E-10), indicating that higher functional input may more effectively suppress regional neural activity. For FP nodal power and Limbic-FP connectivity, the MDD group exhibited a more negative correlation (stronger suppression), while for limbic nodal power and FP-Limbic connectivity, the MDD group showed a less negative correlation (weaker suppression). Conclusions: Consistent with the inter-compartmental network imbalance framework, MDD is characterized by abnormal cortical signal organization and aberrant reciprocal suppression between the FP and limbic systems.
Longitudinal analysis of genetic and environmental interplay in human metabolic profiles and the implication for metabolic health
Authors: Wang Jing , Zenere Alberto , Wang Xingyue , Bergström Göran , Edfors Fredrik , Uhlén Mathias , Zhong Wen
Published: September 2024

Background

Understanding how genetics and environmental factors shape human metabolic profiles is crucial for advancing metabolic health. Variability in metabolic profiles, influenced by genetic makeup, lifestyle, and environmental exposures, plays a critical role in disease susceptibility and progression.

Methods

We conducted a two-year longitudinal study involving 101 clinically healthy individuals aged 50 to 65, integrating genomics, metabolomics, lipidomics, proteomics, clinical measurements, and lifestyle questionnaire data from repeat sampling. We evaluated the influence of both external and internal factors, including genetic predispositions, lifestyle factors, and physiological conditions, on individual metabolic profiles. Additionally, we developed an integrative metabolite-protein network to analyze protein-metabolite associations under both genetic and environmental regulations.

Results

Our findings highlighted the significant role of genetics in determining metabolic variability, identifying 22 plasma metabolites as genetically predetermined. Environmental factors such as seasonal variation, weight management, smoking, and stress also significantly influenced metabolite levels. The integrative metabolite-protein network comprised 5,649 significant protein-metabolite pairs and identified 87 causal metabolite-protein associations under genetic regulation, validated by showing a high replication rate in an independent cohort. This network revealed stable and unique protein-metabolite profiles for each individual, emphasizing metabolic individuality. Notably, our results demonstrated the importance of plasma proteins in capturing individualized metabolic variabilities. Key proteins representing individual metabolic profiles were identified and validated in the UK Biobank, showing great potential for predicting metabolic diseases and metabolic risk assessment.

Conclusions

Our study provides longitudinal insights into how genetic and environmental factors shape human metabolic profiles, revealing unique and stable individual metabolic profiles. Plasma proteins emerged as key indicators for capturing the variability in human metabolism and assessing metabolic risks. These findings offer valuable tools for personalized medicine and the development of diagnostics for metabolic diseases.
Beneficial vs harmful effects of pharmacological treatment of patent ductus arteriosus: A Bayesian meta-analysis
Authors: Villamor Eduardo , Galán-Henríquez Gloria , Bartoš František , Gonzalez-Luis Gema E
Published: September 2024

Background

Randomized controlled trials (RCTs) have failed to demonstrate beneficial effects of the pharmacological treatment of patent ductus arteriosus (PDA) in preterm infants. We conducted a Bayesian model averaged (BMA) meta-analysis of RCTs comparing pharmacological treatment of PDA with placebo or expectant treatment.

Methods

We searched for RCTs including infants with gestational age (GA) ≤32 weeks and with a rate of open-label treatment of less than 25% in the control arm. Primary outcome was mortality and secondary outcomes included bronchopulmonary dysplasia (BPD). We calculated Bayes factors (BFs). The BF+/-is the ratio of the probability of the data under H+(pharmacological treatment is beneficial) over the probability of the data under H-(pharmacological treatment is harmful).

Results

Five RCTs were included (1341 infants). BMA showed strong evidence in favor of a harmful effect of medication for BPD (BF+/-=0.02) and BPD or death (BF+/-=0.03). When the two largest trials, which used early (<72 h) ibuprofen in infants with GA ≤28 weeks, were pooled, the BMA demonstrated moderate evidence in favor of higher mortality in the medication group (BF+/-=0.24).

Conclusions

Early ibuprofen treatment of a PDA in extremely preterm infants may result in more complications than clinical benefit.
Enhancing the Diagnostic Efficacy of Right-to-Left Shunt Using Robot-Assisted Transcranial Doppler: A Quality Improvement Project
Authors: Shah Ruchir , Devlin Christian , Gao Lan. , Ledford Samuel , Ramjee Vimal , Madan Vinay , Patterson Jennifer , Walden Lauren , Devlin Thomas
Published: September 2024

Background

Stroke is the leading cause of adult disability worldwide, with approximately 30% of strokes remaining cryptogenic. One potential etiology is a patent foramen ovale (PFO), which may contribute to stroke through paradoxical thrombo-embolism or in situ thrombo-embolus formation. Recent advancements in robot-assisted transcranial Doppler (raTCD) have shown increased sensitivity in detecting right-to-left shunt (RLS) compared to transthoracic echocardiography (TTE), particularly in detecting large shunts, which are associated with a higher risk of stroke.

Methods

We conducted a retrospective quality improvement project at our regional stroke center to compare the performance of TTE and raTCD in identifying RLS in ischemic stroke patients. The study involved 148 patients admitted between February 2021 and February 2023. All patients underwent TTE and raTCD with agitated saline bubble contrast, with additional transesophageal echocardiography (TEE) at the treatment team’s discretion. The primary metrics analyzed included differences in overall RLS detection and large RLS detection rates for raTCD, TTE and TEE.

Results

raTCD detected RLS in 60.1% of patients compared to 37.2% with TTE (p = 0.00012), with a 42.6% detection rate for large shunts on raTCD versus 23.0% on TTE (p = 0.00053). The sensitivity and specificity of raTCD were 92% and 87.5%, respectively, compared to 78.57% and 71.43% for TTE, using TEE as the gold standard. Nine patients underwent PFO closure, all correctly identified with large shunts by raTCD, while TTE missed or underestimated the PFO size in 44% of the cases.

Conclusion

raTCD significantly outperforms TTE in detecting RLS and large shunts, suggesting its integration into standard PFO workup protocols may enhance secondary stroke prevention. These findings support the adoption of raTCD as a complementary diagnostic tool alongside TTE and TEE for more accurate PFO detection and risk stratification.
Hepatic mitochondrial respiration is crucial for euthermia in complex III-deficient mice with impaired brown adipose tissue thermogenesis
Authors: Banerjee Rishi , Upadhyay Divya , Zarybnický Tomáš , Kietz Christa , Kuure Satu , Fellman Vineta , Purhonen Janne , Kallijärvi Jukka
Published: September 2024

Liver is the key hub of systemic energy metabolism and growth regulation, yet its roles in mitochondrial disease pathophysiology remain relatively understudied.Bcs1lp.S78Gknock-in mice, carrying a patient mutation causing respiratory complex III (CIII)-deficiency, present juvenile-onset liver and kidney disease, growth restriction, lipodystrophy, and early death. We restored CIII function in the hepatocytes of these mice using recombinant adeno-associated viral vectors (rAAVs) expressing wild-typeBcs1l. A single intraperitoneal injection of rAAVs into presymptomatic juvenile mice prevented liver disease, improved hypoglycemia and growth, normalized hepatic fuel utilization, and doubled the survival. The mutant mice showed hypothermia and brown adipose tissue (BAT) inflammation, and lacked BAT activation basally and upon acute cold challenge. Disrupted foot pad innervation suggested sensory neuropathy and impaired thermosensation as a contributor to the BAT inactivity. Surprisingly, the rAAV-treated mice maintained near-normal body temperature without significant effect on BAT. Increasing cellular respiration via transgenic alternative oxidase (AOX) was sufficient to prevent the hypothermia. The CIII-deficient mice did not reach euthermia until at an ambient temperature of 35°C, housing at which relieved metabolic stress and ameliorated hepatocyte senescence. We conclude that mitochondrial respiration in hepatocytes is essential for euthermia in mice. Our findings highlight the crucial role of the liver in thermoregulation, hypothermia as a consequence of mitochondrial dysfunction, and the therapeutic potential of rAAV-based gene delivery in a preclinical model of a multiorgan mitochondrial disease.

Graphical abstract
dScaff – an automatic bioinformatics framework for scaffolding draftde novoassemblies based on reference genome data
Authors: Constantin Nicoleta-Denisa , Ionascu Adrian , Ratiu Attila Cristian
Published: September 2024

Rapid evolution of long-read sequencing technologies requires accurate, fast and user-friendly genome assembly and scaffolding tools. In this article we present Digital Scaffolding (dScaff), a bioinformatics tool that performs scaffolding ofde novogenome assemblies based on reference scaffolds or chromosomes. dScaff makes use of a series of bash and R scripts in order to create a minimal complete scaffold from a genome assembly, with future features to be implemented. Herein, we demonstrate the functionality of dScaff on a novel genome assembly pertaining to a recently sequenced local strain ofDrosophila suzukii.
Watch-breaker: establishment of a microwell array-based miniaturized thymic organoid model suitable for high throughput applications
Authors: Major Viktoria , Palmer Sam , Rouse Paul , Henderson Timothy , Hübscher Tania , Sweetman Joanna , Morys Jan , Bacon Andrea , Chengrui An , Guiyun Qiu , Wang Yu , Corsinotti Andrea , Cholewa-Waclaw Justyna , Chapman S. Jon , Lütolf Matthias P. , Anderson Graham , Blackburn C. Clare
Published: September 2024

T-cell development depends critically on the thymic stroma, in particular the diverse array of functionally distinct thymic epithelial cell (TEC) types. However, a robustin vitrothymus model mimicking the native thymus and compatible with medium/high-throughput analyses is currently lacking. Here, we demonstrate a novel high-density microwell array-based miniaturized thymus organoid (mTO) model, that supports T-cell commitment and development, possesses key organizational characteristics of the native thymus and is compatible with live-imaging and medium/high-throughput applications. We establish the minimum cellular input required for functional mTO and show that mTO TEC phenotype and complexity closely mirrors the native thymus. Finally, we use mTO to probe the role of fetal thymic mesenchyme, revealing a requirement beyond maintenance ofFoxn1in differentiation/maintenance of mature TEC subpopulations. Collectively, mTO present a newin vitromodel of the native thymus adaptable to medium/high-throughput applications and validated for exploration of thymus- and thymus organoid-biology.
Patterns of landscape partitioning indicate low levels of resource competition among neighbouring Guinea baboon (Papio papio) parties
Authors: Ohrndorf Lisa , Mundry Roger , Beckmann Jörg , Fischer Julia , Zinner Dietmar
Published: September 2024

Background

Access to critical resources, including food, water, or shelter, significantly determines individual fitness. As these resources are limited in most habitats, animals may employ strategies of landscape partitioning to mitigate the impact of direct resource competition. Territoriality may be regarded as an aggressive form of landscape partitioning but in non-territorial species, other forms exist. Animals living in groups with greater flexibility in their association patterns, such as multilevel societies with fission-fusion dynamics, may adjust their grouping and space use patterns to short-term variations in ecological conditions such as food availability, predation pressure, or the presence of conspecific groups. This flexibility may allow them to balance the costs of competition while reaping the benefits of better predator detection and defence.

Methods

We explored patterns of landscape partitioning among neighbouring Guinea baboon (Papio papio) parties in the Niokolo-Koba National Park, Senegal. Guinea baboons live in a multilevel society in which parties predictably form higher-level associations (“gangs”). We used four years of locational data from individuals equipped with GPS collars to estimate annual home ranges, home range overlap, and minimum distances between parties. We examined whether food availability and predator presence levels affected the cohesion between parties in 2022.

Results

We found substantial home range and core area overlap among parties (33 to 100%). We found no effect of food availability or predator presence on the distance to the closest neighbouring party; the minimum distance between parties was less than 100 m on average.

Conclusions

Our results suggest a low level of feeding competition between our study parties. Whether this is a general feature of Guinea baboons or particular to the situation in the Niokolo-Koba National Park remains to be investigated.