bluuebunny/crossref_metadata_2025 huggingface dataset:
Early Endoscopic Retrograde Cholangiopancreatography in Gallstone Pancreatitis Is Safe
Authors: Maloof Tassiana , Rodrigues Darren , Li Thomas , Rodrigues Terrance , Lancki Nicola , Keswani Rajesh N.
Published: May 2024

Objectives

There is concern that performing early endoscopic retrograde cholangiopancreatography (ERCP) in the setting of gallstone pancreatitis (GSP) with choledocholithiasis can worsen underlying pancreatitis. This study was designed to assess outcomes of early versus delayed ERCP in patients with GSP with choledocholithiasis in the absence of cholangitis.

Materials and Methods

In this single-center retrospective study, we identified 124 patients who underwent ERCP for choledocholithiasis in the setting of GSP without cholangitis between 2012 and 2022. Timing of ERCP was categorized as early (<48 hours after time of diagnosis) versus delayed (>48 hours). Data on patient demographics, complications, length of stay (LOS), and mortality were collected.

Results

Cannulation success rates were similar for early and delayed ERCP (97% vs 100%). The adverse event rate for early ERCP was 15% compared to 29% for delayed ERCP. LOS for patients with predicted mild pancreatitis was shorter for early versus delayed ERCP (4.2 vs 7.1 days, P = 0.007). There were no deaths in either group.

Conclusions

There was a trend toward fewer adverse events and there was a shorter LOS among patients with GSP with choledocholithiasis undergoing early versus delayed ERCP. Early ERCP should be considered, particularly in patients with predicted mild pancreatitis.
Quality of Life Following Total Pancreatectomy With Islet Autotransplantation
Authors: Barthold Laura , Smith Kerrington D. , Chaidarun Sushela S. , Fischer Dawn A. , Gardner Timothy B.
Published: May 2024

Objectives

Total pancreatectomy with islet autotransplantation (TPIAT) is performed to improve the quality of life (QOL) of patients with chronic pancreatitis. Few reports have documented QOL following TPIAT, with none using the pancreatitis-specific Pancreatitis Quality of Life Instrument (PANQOLI). We surveyed patients at our center who underwent TPIAT to document postoperative QOL.

Materials and Methods

We collected survey data from 18 adult patients who underwent TPIAT at our medical center from 2012 to 2020. Patients were asked questions assessing QOL following TPIAT and completed the Short-Form Health Survey and PANQOLI instruments.

Results

Forty-three patients who underwent TPIAT were mailed surveys, and 18 were returned. The mean age was 45 years, and 67% of respondents were female. Almost half (44%) had hereditary pancreatitis. Sixty-seven percent believed that their overall QOL had improved after surgery. The mean postoperative Short-Form Health Survey physical score was 38.9 and mean mental score was 44. The mean PANQOLI score was 66 (physical function 20, role function 16, emotional function 14, self-worth 15). Following surgery, 33% were using opiate medications and 67% were using antihyperglycemic medications.

Conclusions

TPIAT resulted in improved self-reported QOL in most patients, although postoperative physical and mental QOL are less compared to the average healthy United States adult.
Essential Fatty Acid Deficiency Is Common After Total Pancreatectomy and Islet Autotransplantation
Authors: Downs Elissa M. , Hodges James S. , Trikudanathan Guru , Freeman Martin L. , Chinnakotla Srinath , Kirchner Varvara , Pruett Timothy L. , Beilman Gregory , Schwarzenberg Sarah Jane , Bellin Melena D.
Published: May 2024

Objectives

Total pancreatectomy and islet autotransplantation (TPIAT) for pancreatitis may induce risk for essential fatty acid deficiency (EFAD) due to exocrine pancreatic insufficiency and intestinal alterations. The prevalence of EFAD post-TPIAT is currently unknown.

Methods

We abstracted essential fatty acid (EFA) profiles (n = 332 samples) for 197 TPIAT recipients (72% adult, 33% male). Statistical analyses determined the prevalence of, and associations with, EFAD post-operatively. EFAD was defined as a Triene-to-Tetraene ratio ≥0.05 if <18 years old, or ≥0.038 if ≥18 years old.

Results

Prevalence of EFAD was 33%, 49%, and 53.5% at 1, 2, and ≥3 years. At 1-year post-TPIAT, older age at transplant (P = 0.03), being an adult versus a child (P = 0.0024), and obstructive etiology (P = 0.0004) were significant predictors of EFAD. Only 6% of children had EFAD 1-year post-TPIAT versus 46% of adults. The alpha-linolenic acid levels were lower with lower body mass index at transplant (P = 0.011). EFAD was associated with the presence of other intestinal diseases (P < 0.0001).

Conclusions

One-third of individuals had EFAD 1-year post-TPIAT, highlighting the need for systematic monitoring. Older age at transplant increased risk and adults were more affected than children. Other diagnoses affecting intestinal health may further increase risk for EFAD.
The International System for Reporting Serous Fluid Cytopathology: A Systematic Review and Meta-Analysis of Diagnostic Test Accuracy Studies
Authors: Jamal Fatima E. , Vey Johannes A. , Proctor Tanja , Ishak Angela , Schmitt Fernando C. , Nikas Ilias P.
Published: May 2024

This is the first systematic review and meta-analysis of The International System (TIS) for reporting serous fluid cytopathology. Our aims were to present the pooled malignancy rate of each TIS reporting category and the diagnostic accuracy of cytology using this system. Database search using a predefined strategy was followed by study selection, data extraction, study quality assessment, and statistical analysis. Data derived from 16 eligible studies were pooled. The pooled rates of malignancy were as follows: 27% (95% CI; 16%-41%) for “nondiagnostic” (ND), 11% (95% CI; 7%-18%) for negative for malignancy” (NFM), 49% (95% CI; 37%-61%) for “atypia of undetermined significance” (AUS), 90% (95% CI; 81%-95%) for “suspicious for malignancy” (SFM), and 100% (95% CI; 98%-100%) for “positive for malignancy” (MAL). Studies performed exclusively in cancer hospitals showed higher pooled malignancy rates, compared with academic and community hospitals serving the general population, in the ND [40% (95% CI; 21%-62%) vs. 22% (95% CI; 11%-39%)], NFM [20% (95% CI; 13%-30%) vs. 9% (95% CI; 5%-17%)], and AUS categories [55% (95% CI; 47%-63%) vs. 46% (95% CI; 31%-62%)]. Notably, the difference was significant in the NFM category (P=0.04). When both SFM and MAL cytology interpretations were considered as malignant outcomes, the pooled sensitivity and specificity were 68.74% (95% CI; 59.90%-76.39%) and 98.81% (95% CI; 98.18%-99.22%), respectively. In addition, the diagnostic odds ratio (DOR) was found to be 170.7 (95% CI; 96.2-303.3). Despite its strengths, our study also had some limitations. Therefore, future large-scale longitudinal studies could strengthen the findings of this review.
Development of the Split-Bolus Pulmonary Arteriovenous Separating Computed Tomography Angiography Protocol Based on Time Enhancement Curve for Lung Cancer Surgery
Authors: Kiriki Masato , Koizumi Masashi , Maeda Katsuhiko , Sakai Toshiyuki , Kotoura Noriko
Published: May 2024

Objective

We devised a split-bolus injection and imaging protocol for pulmonary artery and vein separation computed tomography (CT) angiography based on time enhancement curve characterization. Furthermore, we aimed to evaluate the contrast enhancement effect and success rate of blood vessel separation between the pulmonary artery and vein of this proposed protocol.

Methods

In this study, 102 patients (45 patients with the standard protocol and 57 patients with the proposed protocol) who underwent pulmonary arteriovenous computed tomography angiography were included. The CT values of various vessels, CT value difference between the pulmonary trunk and left atrium, and coefficient of variation in pulmonary arteries and veins were obtained from images of the standard and proposed protocols.

Results

The CT values in the proposed protocol for the pulmonary trunk were significantly higher than those in the standard protocol (487.3 [415.5–546.9] HU vs. 293.0 [259.0–350.0] HU, P < 0.01). The CT value difference between the pulmonary trunk and left atrium in the proposed protocol was significantly higher than that in the conventional protocol (211.3 [158.0–265.7] HU vs. 32 [−30.0–55.0] HU, P < 0.01). The coefficient of variation in the proposed protocol was 0.08 (0.06–0.10) and 0.09 (0.08–0.11) in pulmonary arteries and 0.08 (0.06–0.09) and 0.09 (0.07–0.12) in pulmonary veins, respectively.

Conclusions

The proposed protocol achieved separation between the pulmonary artery and vein in many patients, making it useful for the preoperative assessment of individual thoracic anatomy.
Negative 18F-Piflufolastat PET/CT, But Positive 18F-Fluciclovine PET/CT, in a Patient With Biochemically Recurrent Prostate Cancer
Authors: Ulaner Gary A.
Published: May 2024

An 83-year-old man with prostate cancer post external beam radiotherapy presented with biochemical recurrence (PSA, 29.7 ng/mL). PSMA-targeted 18F-Piflufolastat PET/CT was performed, but no avid lesions were identified. Given the high PSA and high suspicion for recurrence, an 18F-Fluciclovine PET/CT was performed. Fifteen 18F-fluciclovine–avid pelvic, abdominal, retrocrural, and left supraclavicular nodal metastases were then identified. Although the majority of prostate cancer metastases are avid on PSMA-targeted PET, some metastases are not. This case demonstrates the ability of metabolic tracers such as 18F-Fluciclovine PET to localize and quantitate disease extent in a patient whose metastases are not avid on PSMA-targeted PET.
Microbacterium salsuginis sp. nov., a halotolerant actinobacterium with antimicrobial activity
Authors: Su Qingyang , Liu Yuwei , Xia Tingting , Wei Shuanglong , Cui Caixia , Zhang Zhao , Liu Xudong , Nie Guoxing , Ming Hong
Published: May 2024

A novel Gram-staining-positive actinobacterium with antimicrobial activity, designated CFH 90308T, was isolated from the sediment of a salt lake in Yuncheng, Shanxi, south-western China. The isolate exhibited the highest 16S rRNA gene sequence similarities to Microbacterium yannicii G72T, Microbacterium hominis NBRC 15708T and Microbacterium xylanilyticum S3-ET (98.5, 98.4 and 98.2 %, respectively), and formed a separate clade with M. xylanilyticum S3-ET in phylogenetic trees. The strain grew at 15–40 ºC, pH 6.0–8.0 and could tolerate NaCl up to a concentration of 15 % (w/v). The whole genome of strain CFH 90308T consisted of 4.33 Mbp and the DNA G+C content was 69.6 mol%. The acyl type of the peptidoglycan was glycolyl and the whole-cell sugars were galactose and mannose. The cell-wall peptidoglycan mainly contained alanine, glycine and lysine. The menaquinones of strain CFH 90308T were MK-12, MK-13 and MK-11. Strain CFH 90308T contained anteiso-C15:0, anteiso-C17:0, iso-C16:0 and iso-C15:0 as the predominant fatty acids. The average nucleotide identity (ANI) and digital DNA–DNA hybridization (dDDH) values between CFH 90308T and the other species of the genus Microbacterium were found to be low (ANIb <81.3 %, dDDH <25.6 %). The secondary metabolite produced by strain CFH 90308T showed antibacterial activities against Bacillus subtilis, Pseudomonas syringae, Aeromonas hydrophila and methicillin-resistant Staphylococcus aureus. Based on genotypic, phenotypic and chemotaxonomic results, the isolate is considered to represent a novel species of the genus Microbacterium, for which the name Microbacterium salsuginis sp. nov. is proposed. The type strain is CFH 90308T (=DSM 105964T=KCTC 49052T).
Glycine maxpolygalacturonase inhibiting protein 11 (GmPGIP11) functions in the root to suppressHeterodera glycinesparasitism
Authors: Acharya Sudha , Troell Hallie A. , Billingsley Rebecca L. , Lawrence Kathy S. , McKirgan Daniel S. , Alkharouf Nadim W. , Klink Vincent P.
Published: May 2024

Pathogen-secreted polygalacturonases (PGs) alter plant cell wall structure by cleaving the α- (1→4) linkages between D-galacturonic acid residues in homogalacturonan (HG), macerating the cell wall, facilitating infection. Plant PG inhibiting proteins (PGIPs) disengage pathogen PGs, impairing infection. The soybean cyst nematode,Heterodera glycines,obligate root parasite produces secretions, generating a multinucleate nurse cell called a syncytium, a byproduct of the merged cytoplasm of 200-250 root cells, occurring through cell wall maceration. The common cytoplasmic pool, surrounded by an intact plasma membrane, provides a source from whichH. glycinesderives nourishment but without killing the parasitized cell during a susceptible reaction. The syncytium is also the site of a naturally-occurring defense response that happens in specificG. maxgenotypes. Transcriptomic analyses of RNA isolated from the syncytium undergoing the process of defense have identified that one of the 11G. max PGIPs,GmPGIP11, is expressed during defense. Functional transgenic analyses show roots undergoingGmPGIP11overexpression (OE) experience an increase in its relative transcript abundance (RTA) as compared to theribosomal protein 21(GmRPS21) control, leading to a decrease inH. glycinesparasitism as compared to the overexpression control. TheGmPGIP11undergoing RNAi experiences a decrease in its RTA as compared to theGmRPS21control with transgenic roots experiencing an increase inH. glycinesparasitism as compared to the RNAi control. Pathogen associated molecular pattern (PAMP) triggered immunity (PTI) and effector triggered immunity (ETI) components are shown to influenceGmPGIP11expression while numerous agricultural crops are shown to have homologs.
Virtual Growing Child (VGC): A general normative comparative system via quantitative dynamic MRI for quantifying pediatric regional respiratory anomalies with application in thoracic insufficiency syndrome (TIS)
Authors: Tong Yubing , Udupa Jayaram K. , McDonough Joseph M. , Xie Lipeng , Hao You , Akhtar Yusuf , Wu Caiyun , Rajapakse Chamith S. , Gogel Samantha , Mayer Oscar H. , Anari Jason B. , Torigian Drew A. , Cahill Patrick J.
Published: May 2024

Background

A normative database of regional respiratory structure and function in healthy children does not exist.

Methods

VGC provides a database with four categories of regional respiratory measurement parameters including morphological, architectural, dynamic, and developmental. The database has 3,820 3D segmentations (around 100,000 2D slices with segmentations). Age and gender group analysis and comparisons for healthy children were performed using those parameters via two-sided t-testing to compare mean measurements, for left and right sides at end-inspiration (EI) and end-expiration (EE), for different age and gender specific groups. We also apply VGC measurements for comparison with TIS patients via an extrapolation approach to estimate the association between measurement and age via a linear model and to predict measurements for TIS patients. Furthermore, we check the Mahalanobis distance between TIS patients and healthy children of corresponding age.

Findings

The difference between male and female groups (10-12 years) behave differently from that in other age groups which is consistent with physiology/natural growth behavior related to adolescence with higher right lung and right diaphragm tidal volumes for females(p<0.05). The comparison of TIS patients before and after surgery show that the right and left components are not symmetrical, and the left side diaphragm height and tidal volume has been significantly improved after surgery (p <0.05). The left lung volume at EE, and left diaphragm height at EI of TIS patients after surgery are closer to the normal children with a significant smaller Mahalanobis distance (MD) after surgery (p<0.05).

Interpretation

The VGC system can serve as a reference standard to quantify regional respiratory abnormalities on dMRI in young patients with various respiratory conditions and facilitate treatment planning and response assessment.

Funding

The grant R01HL150147 from the National Institutes of Health (PI Udupa).
Importance of variables from different time frames for predicting self-harm using health system data
Authors: Wolock Charles J. , Williamson Brian D. , Shortreed Susan M. , Simon Gregory E. , Coleman Karen J. , Yeargans Rodney , Ahmedani Brian K. , Daida Yihe , Lynch Frances L. , Rossom Rebecca C. , Ziebell Rebecca A. , Cruz Maricela , Wellman Robert D. , Coley R. Yates
Published: May 2024

Objective

Self-harm risk prediction models developed using health system data (electronic health records and insurance claims information) often use patient information from up to several years prior to the index visit when the prediction is made. Measurements from some time periods may not be available for all patients. Using the framework of algorithm-agnostic variable importance, we study the predictive potential of variables corresponding to different time horizons prior to the index visit and demonstrate the application of variable importance techniques in the biomedical informatics setting.

Materials and Methods

We use variable importance to quantify the potential of recent (up to three months before the index visit) and distant (more than one year before the index visit) patient mental health information for predicting self-harm risk using data from seven health systems. We quantify importance as the decrease in predictiveness when the variable set of interest is excluded from the prediction task. We define predictiveness using discriminative metrics: area under the receiver operating characteristic curve (AUC), sensitivity, and positive predictive value.

Results

Mental health predictors corresponding to the three months prior to the index visit show strong signal of importance; in one setting, excluding these variables decreased AUC from 0.85 to 0.77. Predictors corresponding to more distant information were less important.

Discussion

Predictors from the months immediately preceding the index visit are highly important. Implementation of self-harm prediction models may be challenging in settings where recent data are not completely available (e.g., due to lags in insurance claims processing) at the time a prediction is made.

Conclusion

Clinically derived variables from different time frames exhibit varying levels of importance for predicting self-harm. Variable importance analyses can inform whether and how to implement risk prediction models into clinical practice given real-world data limitations. These analyses be applied more broadly in biomedical informatics research to provide insight into general clinical risk prediction tasks.
Poor Sleep Quality is associated with Decreased Brain Glucose Metabolism in Healthy Middle-aged Adults
Authors: Shin Seunghyeon , Seok Ju Won , Kim Keunyoung , Kim Jihyun , Nam Hyun-Yeol , Pak Kyoungjune
Published: May 2024

Sleep disturbance is associated with the development of neurodegenerative disease. We aimed to address the effects of sleep quality on brain glucose metabolism measured by18F-Fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) in healthy middle-aged adults. A total of 378 healthy men (mean age: 42.8±3.6 years) were included in this study. Participants underwent brain18F-FDG PET and completed the Korean version of the Pittsburgh Sleep Quality Index (PSQI-K). Additionally, anthropometric measurements were obtained. PETs were spatially normalized to MNI space using PET templates from SPM5 with PMOD. The Automated Anatomical Labeling 2 atlas was used to define regions of interest (ROIs). The mean uptake of each ROI was scaled to the mean of the global cortical uptake of each individual and defined as the standardized uptake value ratio (SUVR). After the logarithmic transformation of the regional SUVR, the effects of the PSQI-K on the regional SUVR were investigated using Bayesian hierarchical modeling. Brain glucose metabolism of the posterior cingulate, precuneus, and thalamus showed a negative association with total PSQI-K scores in the Bayesian model ROI-based analysis. Voxel-based analysis using statistical parametric mapping revealed a negative association between the total PSQI-K scores and brain glucose metabolism of the precuneus, postcentral gyrus, posterior cingulate, and thalamus. Poor sleep quality is negatively associated with brain glucose metabolism in the precuneus, posterior cingulate, and thalamus. This finding may provide a link between sleep quality and the risk of neurodegenerative disease. Therefore, the importance of sleep should not be overlooked, even in healthy middle-aged adults.
Hypothalamic integrity is associated with age, sex and cognitive function across lifespan: A comparative analysis of two large population-based cohort studies
Authors: Xu Peng , Estrada Santiago , Etteldorf Rika , Liu Dan , Shahid Mohammad , Zeng Weiyi , Früh Deborah , Reuter Martin , Breteler Monique M.B. , Aziz N. Ahmad
Published: May 2024

Background

The hypothalamus is the body’s principal homeostatic center. Emerging findings from animal studies suggest that the hypothalamus could also play a crucial role in the modulation of cognition. However, detailed assessments of age and sex effects on hypothalamic structural integrity and its cognitive correlates across the lifespan are still lacking. Therefore, we aimed to investigate hypothalamic structural integrity in relation to age, sex and cognitive performance across lifespan in the general population.

Methods

We used cross-sectional data from the Rhineland Study (RS) (N=5812, 55.2 ± 13.6 years, 58% women) and the UK Biobank Imaging Study (UKB) (N=45076, 64.2 ± 7.7 years, 53% women), two large-scale population-based cohort studies. Volumes of hypothalamic structures were obtained from 3T structural magnetic resonance images through application of a recently developed automatic parcellation procedure (FastSurfer-HypVINN). The standardized cognitive domain scores were derived from extensive neuropsychological test batteries. We employed multivariable linear regressions to assess age and sex effects on volumes of hypothalamic structures, and to evaluate the associations of these volumes with domain-specific cognitive function.

Findings

Mean (standard deviation) volumes of the total hypothalamus were 1124.2 mm3(104.8) in RS and 1102.1 mm3(119.9) in UKB. With increasing age, the volumes of the total, anterior and posterior hypothalamus, and mammillary bodies decreased (between -1.20 to -0.14 mm3/year in RS and between -3.82 to -0.49 mm3/year in UKB), and of the medial hypothalamus and tuberal region increased (between 0.33 to 0.65 mm3/year in RS and between 0.21 to 0.68 mm3/year in UKB). Volumes of all hypothalamic structures were larger in men compared to women. Larger total hypothalamus volumes were associated with better global cognition (β ± standard error (SE): 0.025 ± 0.017 [RS] and 0.026 ± 0.007 [UKB], both p<0.005), and total memory (0.030 ± 0.022 [RS] and 0.021 ± 0.009 [UKB], both p<0.007), while larger posterior hypothalamus volumes were associated with better global cognition (0.036 ± 0.014 [RS] and 0.028 ± 0.006 [UKB], both p<0.001), and total memory (0.038 ± 0.018 [RS] and 0.020 ± 0.008 [UKB], both p<0·001).

Conclusion

We found strong age and sex effects on hypothalamic structures, as well as robust associations between these structures and domain-specific cognitive functions. Overall, these findings thus implicate specific hypothalamic subregions as potential therapeutic targets against age-associated cognitive decline.
Benchmarking Large Language Models for Extraction of International Classification of Diseases Codes from Clinical Documentation
Authors: Simmons Ashley , Takkavatakarn Kullaya , McDougal Megan , Dilcher Brian , Pincavitch Jami , Meadows Lukas , Kauffman Justin , Klang Eyal , Wig Rebecca , Smith Gordon , Soroush Ali , Freeman Robert , Apakama Donald J , Charney Alexander W , Kohli-Seth Roopa , Nadkarni Girish N , Sakhuja Ankit
Published: May 2024

Background

Healthcare reimbursement and coding is dependent on accurate extraction of International Classification of Diseases-tenth revision – clinical modification (ICD-10-CM) codes from clinical documentation. Attempts to automate this task have had limited success. This study aimed to evaluate the performance of large language models (LLMs) in extracting ICD-10-CM codes from unstructured inpatient notes and benchmark them against human coder.

Methods

This study compared performance of GPT-3.5, GPT4, Claude 2.1, Claude 3, Gemini Advanced, and Llama 2-70b in extracting ICD-10-CM codes from unstructured inpatient notes against a human coder. We presented deidentified inpatient notes from American Health Information Management Association Vlab authentic patient cases to LLMs and human coder for extraction of ICD-10-CM codes. We used a standard prompt for extracting ICD-10-CM codes. The human coder analyzed the same notes using 3M Encoder, adhering to the 2022-ICD-10-CM Coding Guidelines.

Results

In this study, we analyzed 50 inpatient notes, comprising of 23 history and physicals and 27 progress notes. The human coder identified 165 unique codes with a median of 4 codes per note. The LLMs extracted varying numbers of median codes per note: GPT 3.5: 7, GPT4: 6, Claude 2.1: 6, Claude 3: 8, Gemini Advanced: 5, and Llama 2-70b:11. GPT 4 had the best performance though the agreement with human coder was poor at 15.2% for overall extraction of ICD-10-CM codes and 26.4% for extraction of category ICD-10-CM codes.

Conclusion

Current LLMs have poor performance in extraction of ICD-10-CM codes from inpatient notes when compared against a human coder.
Global associations of maternal hypertensive disorders and offspring allergic disease burden
Authors: Ni Duan , Nanan Ralph
Published: May 2024

Objectives

Maternal hypertensive disorders (MHD) are widespread globally, modifying maternal and fetal immunity, and have been linked to increased allergic diseases in offsprings. Nevertheless, so far, most studies in this field are small-scale and results remain inconclusive.

Methods

Harnessing unprecedented global allergic disease and pregnancy data covering more than 150 countries from 1990 to 2019 as proxies, we leveraged the state-of-the-art generalized additive model (GAM) to interrogate the potential link between MHD and common offspring allergic diseases, exemplified by atopic dermatitis (AD) and asthma.

Results

A model considering the main effects from MHD, socioeconomic factor like GDP and time, as well as their interactions was favoured, suggesting their interactive effects on offspring allergic diseases. Generally, MHD in pregnancies were associated with increased AD and asthma in offsprings early in life, and a more pronounced effect was found for AD relative to asthma.

Conclusions

Globally, MHD in pregnancies are linked to increased offspring allergic disease burden, which, with further in-depth investigations, would inform allergic disease preventions in clinic. Our analyses also support the Developmental Origins of Health and Disease (DOHAD) concept and showcase a novel methodology for DOHAD-related research.
Associations Between Stroke Type, Ischemic Stroke Subtypes, and Post-Stroke Cognitive Trajectories
Authors: Levine Deborah A. , Whitney Rachael T. , Ye Wen , Briceño Emily M. , Gross Alden L. , Giordani Bruno J. , Sussman Jeremy B. , Lazar Ronald M. , Howard Virginia J. , Aparicio Hugo J. , Beiser Alexa S. , Elkind Mitchell S. V. , Gottesman Rebecca F. , Koton Silvia , Pendlebury Sarah T. , Kollipara Adam S. , Springer Mellanie V. , Seshadri Sudha , Romero Jose R. , Fitzpatrick Annette L. , Longstreth William T. , Hayward Rodney A.
Published: May 2024

Background

It is unclear how post-stroke cognitive trajectories differ by stroke type and ischemic stroke subtype. We studied associations between stroke types (ischemic, hemorrhagic), ischemic stroke subtypes (cardioembolic, large artery atherosclerotic, lacunar/small vessel, cryptogenic/other determined etiology), and post-stroke cognitive decline.

Methods

This pooled cohort analysis from four US cohort studies (1971-2019) identified 1,143 dementia-free individuals with acute stroke during follow-up: 1,061 (92.8%) ischemic, 82 (7.2%) hemorrhagic, 49.9% female, 30.8% Black. Median age at stroke was 74.1 (IQR, 68.6, 79.3) years. Outcomes were change in global cognition (primary) and changes in executive function and memory (secondary). Outcomes were standardized as T-scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition. Median follow-up for the primary outcome was 6.0 (IQR, 3.2, 9.2) years. Linear mixed-effects models estimated changes in cognition after stroke.

Results

On average, the initial post-stroke global cognition score was 50.78 points (95% CI, 49.52, 52.03) in ischemic stroke survivors and did not differ in hemorrhagic stroke survivors (difference, -0.17 points [95% CI, -1.64, 1.30];P=0.82) after adjusting for demographics and pre-stroke cognition. On average, ischemic stroke survivors showed declines in global cognition, executive function, and memory. Post-stroke declines in global cognition, executive function, and memory did not differ between hemorrhagic and ischemic stroke survivors. 955 ischemic strokes had subtypes: 200 (20.9%) cardioembolic, 77 (8.1%) large artery atherosclerotic, 207 (21.7%) lacunar/small vessel, 471 (49.3%) cryptogenic/other determined etiology. On average, small vessel stroke survivors showed declines in global cognition and memory, but not executive function. Initial post-stroke cognitive scores and cognitive declines did not differ between small vessel survivors and survivors of other ischemic stroke subtypes. Post-stroke vascular risk factor levels did not attenuate associations.

Conclusion

Stroke survivors had cognitive decline in multiple domains. Declines did not differ by stroke type or ischemic stroke subtype.
Library-based single-cell analysis of CAR signaling reveals drivers ofin vivopersistence
Authors: Perez Caleb R. , Garmilla Andrea , Nilsson Avlant , Baghdassarian Hratch M. , Gordon Khloe S. , Lima Louise G. , Smith Blake E. , Maus Marcela V. , Lauffenburger Douglas A. , Birnbaum Michael E.
Published: May 2024

The anti-tumor function of engineered T cells expressing chimeric antigen receptors (CARs) is dependent on signals transduced through intracellular signaling domains (ICDs). Different ICDs are known to drive distinct phenotypes, but systematic investigations into how ICD architectures direct T cell function—particularly at the molecular level—are lacking. Here, we use single-cell sequencing to map diverse signaling inputs to transcriptional outputs, focusing on a defined library of clinically relevant ICD architectures. Informed by these observations, we functionally characterize transcriptionally distinct ICD variants across various contexts to build comprehensive maps from ICD composition to phenotypic output. We identify a unique tonic signaling signature associated with a subset of ICD architectures that drives durablein vivopersistence and efficacy in liquid, but not solid, tumors. Our findings work toward decoding CAR signaling design principles, with implications for the rational design of next-generation ICD architectures optimized forin vivofunction.
Molecular and neural mechanisms of behavioural integration in the extended-amygdala
Authors: Chang Simon , Fermani Federica , Huang Lianyun , Schneider Steffen , Mathis Mackenzie W. , Deussing Jan M. , Cai Na
Published: May 2024

Integration of diverse stimuli is crucial for organisms to adapt and communicate effectively, enabling overall homeostasis and survival. Studies have been performed on identifying specific neuronal encoding of individual behaviours, but how neurons integrate diverse behaviours across contexts remains elusive. Here we use Ca2+imaging in freely moving mice to identify neural ensembles in the extended amygdala encoding behaviours across six distinct contexts. We found extensive flexibility in these ensemble encodings that may act as reserves for behavioural integration, with those encoding aversive stimuli showing greater specificity. Finally, we identified differential gene expression profiles between ensembles that are enriched in associations with human psychiatric and neurodegenerative disorders. Overall, our results demonstrate the molecular mechanisms behind behavioural integration, and their potential implications in health and disease.
RNA sequencing variants are enriched for eQTL in cattle tissues
Authors: Leonard Alexander S. , Mapel Xena M. , Pausch Hubert
Published: May 2024

Association testing between molecular phenotypes and genomic variants can help to understand how genotype affects phenotype. RNA sequencing provides access to molecular phenotypes such as gene expression and alternative splicing while DNA sequencing or microarray genotyping are the prevailing options to obtain genomic variants. Here we genotype variants for 74 male Braunvieh cattle from both DNA and deep total RNA sequencing from three tissues. We show that RNA sequencing calls approximately 40% of variants (7-10 million) called from DNA sequencing, with over 80% precision, rising to over 92% of variants called with nearly 98% precision in highly expressed coding regions. Allele-specific expression and putative post-transcriptional modifications negatively impact variant genotyping accuracy from RNA sequencing and contribute to RNA-DNA differences. Variants called from RNA sequencing detect roughly 75% of eGenes identified using variants called from DNA sequencing, demonstrating a nearly 2-fold enrichment of eQTL variants. We observe a moderate-to-strong correlation in nominal association p-values (Spearman ρ2∼0.6), although only 9% of eGenes have the same top associated variant. We also find several highly significant RNA variant-only eQTL, demonstrating that caution must be exercised beyond filtering for variant quality or imputation accuracy when analysing or imputing variants called from RNA sequencing.
Spatiotemporal Orchestration of Mitosis by Cyclin-Dependent Kinase
Authors: Kapadia Nitin , Nurse Paul
Published: May 2024

Mitotic onset is a critical transition for eukaryotic cell proliferation. The prevailing view for its control is that cyclin-dependent kinase (CDK) is activated first in the cytoplasm, at the centrosome, which then initiates mitosis1–3. Bistability in CDK activation ensures the transition is irreversible but how this unfolds in a spatially compartmentalized cell is unknown4–8. Here using fission yeast, we show that CDK is actually activated in the nucleus first, not the cytoplasm, and that the bistable responses dramatically differ within the nucleus and cytoplasm. There is a stronger response in the nucleus permitting mitotic signal propagation from there to the cytoplasm. Abolishing cyclin-CDK localization to the yeast centrosome led to activation occurring only in the nucleus, spatially uncoupling the nucleus and cytoplasm mitotically, suggesting centrosomal cyclin-CDK acts as a “signal relayer”. We propose that the key mitotic regulatory system operates in the nucleus in proximity to DNA, allowing incomplete DNA replication and DNA damage to be effectively monitored to preserve genome integrity and for integration of ploidy within the CDK control network. This spatiotemporal regulatory framework establishes core principles for control of the onset of mitosisin vivo, which will help inform how CDK controls mitotic onset in other eukaryotes.
The European Neolithic Expansion: A Model Revealing Intense Assortative Mating and Restricted Cultural Transmission
Authors: LaPolice Troy M. , Williams Matthew P. , Huber Christian D.
Published: May 2024

The Neolithic revolution initiated a pivotal change in human society, marking the shift from foraging to farming. The underlying mechanisms of agricultural expansion are debated, primarily between cultural diffusion (knowledge and practices transfer) and demic diffusion, or people migration and replacement. Ancient DNA analyses reveal significant ancestry changes during Europe’s Neolithic transition, suggesting primarily demic expansion. However, the presence of 10-15% hunter-gatherer ancestry in modern Europeans indicates cultural transmission and non-assortative mating were additional contributing factors. We integrate mathematical models, agent-based simulations, and ancient DNA analysis to dissect and quantify the roles of cultural diffusion and assortative mating in farming’s expansion. Our findings indicate limited cultural transmission and predominantly within-group mating. Additionally, we challenge the assumption that demic spread always leads to ancestry turnover. This underscores the need to reassess prehistoric cultural expansions and offers new insights into early agricultural society through the integration of ancient DNA with archaeological models.
Human CD29+/CD56+ myogenic progenitors display tenogenic differentiation potential and facilitate tendon regeneration
Authors: Shao Xiexiang , Lin Xingzuan , Zhou Hao , Wang Minhui , Han Lili , Fu Xin , Li Sheng , Zhu Siyuan , Zhou Shenao , Yang Wenjun , Wang Jianhua , Hu Ping
Published: May 2024

Tendon injury occurs at high frequency and is difficult to repair. Identification of human stem cells being able to regenerate tendon will greatly facilitate the development of regenerative medicine for tendon injury. We identified human CD29+/CD56+ myogenic progenitors having tendon differentiation potential both in vitro and in vivo. Transplantation of human CD29+/CD56+ myogenic progenitors contributes to injured tendon repair and thus improves locomotor function. Interestingly, the tendon differentiation potential in mouse muscle stem cells is minimal and the higher TGFβ signaling level may be the key for the distinct feature of human CD29+/CD56+ myogenic progenitors. These findings reveal that human CD29+/CD56+ myogenic progenitors are bi-potential adult stem cells and can serve as a new source for tendon regeneration.
Distinct anatomical and functional corticospinal inputs innervate different spinal neuron types
Authors: Fageiry Samaher , Warriner Claire L. , Loper Jackson , Pianski Liam , Reardon Thomas , Jessell Thomas M. , Costa Rui M. , Miri Andrew
Published: May 2024

The corticospinal tract exerts its influence on movement through spinal neurons, which can be divided into types that exhibit distinct functions. However, it remains unknown whether these functional distinctions are reflected in the corticospinal inputs that different types of spinal neurons receive. Using rabies monosynaptic tracing from individual neuron types in the cervical cord and 3D histological reconstruction in mice, we discovered that different types receive inputs distinctly distributed across cortex, and aligned with cell type function. This included a distinct, sparse distribution of direct inputs from cortex onto motor neurons. Coupling rabies tracing with activity measurement during motor behavior revealed different interneuron types receive different input activity patterns, primarily due to the topographical distribution of the corticospinal neurons contacting them. Our results establish that different spinal neuron types get distinct anatomical and functional inputs from the cortex, and reveal functionally relevant homology to primate corticospinal organization.
High-plex Digital Spatial Profiling Identifies Subregion-Dependent Directed Proteome Changes Across Multiple Variants of Dementia
Authors: Bolen MacKenzie L. , Menees Kelly B. , Merchak Andrea R. , Gearing Marla , Gong Jingjing , Ren Yuqi , Murray Melissa , McEachin Zachary T. , Tansey Malú Gámez
Published: May 2024

Frontotemporal lobar degeneration (FTLD) is the leading cause of dementia in patients under the age of 65. Even in a single anatomical region, there is variance within pathological protein deposition as a result of FTLD. This spectrum of pathology leads to difficulty in identification of the disease during its progression and consequential varied post mortem clinicopathological diagnoses. NanoString GeoMx™ Digital Spatial Profiling (DSP) is a novel method that leverages the ability to spatially multiplex protein biomarkers of interest. We utilized NanoString DSP to investigate the proteome geography at two levels of the cortex and the subcortical white matter in patients with various types of dementia (Alzheimer’s disease, FTLD-c9ALS, FTLD-17, FTLD-TDP, FTLD-GRN; n=6 per syndrome) and neurologically healthy controls (NHC). Analysis of 75 different protein biomarkers of interest revealed both a disease and cortical subregion specific biomarker profile. Layers II-V of the cortex from diseased individuals displayed the greatest protein dysregulation as compared to NHC. Additionally, out of all disease groups within cortical layer 1, II-V and white matter, the FTLD-17 group had the most significant protein dysregulation as compared to NHC--specifically associated with immune cell pathways. Traditional biomarkers of dementia, such as various phosphorylated tau proteins and amyloid-β 42 displayed dysregulation, however our data suggest spatial enrichment in distinct to cortical sublayers. In conclusion, we observed that depending on the variant of disease, specific protein deposits either span multiple levels of cortical geography or only a single layer. Thus, the specific localization of these deposits could potentially be used to elucidate region-specific pathologic biomarkers unique to individual variants of dementia.
Layer-specific control of inhibition by NDNF interneurons
Authors: Naumann Laura Bella , Hertäg Loreen , Müller Jennifer , Letzkus Johannes J. , Sprekeler Henning
Published: May 2024

Neuronal processing of external sensory input is shaped by internally-generated top-down information. In the neocortex, top-down projections predominantly target layer 1, which contains NDNF-expressing interneurons, nestled between the dendrites of pyramidal cells (PCs). Here, we propose that NDNF interneurons shape cortical computations by presynap-tically inhibiting the outputs of somatostatin-expressing (SOM) interneurons via GABAergic volume transmission in layer 1. Whole-cell patch clamp recordings from genetically identified NDNF INs in layer 1 of the auditory cortex show that SOM-to-NDNF synapses are indeed modulated by ambient GABA. In a cortical microcircuit model, we then demonstrate that this mechanism can control inhibition in a layer-specific way and introduces a competition for dendritic inhibition between NDNF and SOM interneurons. This competition is mediated by a unique mutual inhibition motif between NDNF interneurons and the synaptic outputs of SOM interneurons, which can dynamically prioritise different inhibitory signals to the PC dendrite. NDNF interneurons can thereby control information flow in pyramidal cells by redistributing dendritic inhibition from fast to slow timescales and by gating different sources of dendritic inhibition, as exemplified in a predictive coding application. This work corroborates that NDNF interneurons are ideally suited to control information flow within cortical layer 1.
SOP-MULTI: A self-organized polymer based coarse-grained model for multi-domain and intrinsically disordered proteins with conformation ensemble consistent with experimental scattering data
Authors: Baratam Krishnakanth , Srivastava Anand
Published: May 2024

Multidomain proteins with long flexible linkers and full-length intrinsically disordered proteins (IDPs) are best defined as an ensemble of conformations rather than a single structure. Determining high-resolution ensemble structures of such proteins poses various challenges using tools from experimental structural biophysics. Integrative approaches combining available low-resolution ensemble-averaged experimental data andin silicobiomolecular reconstructions are now often used for the purpose. However, an exhaustive Boltzmann weighted conformation sampling for large proteins, especially for ones where both the folded and disordered domains exist in the same polypeptide chain, remains a challenge. In this work, we present a 2-site per amino-acid resolution SOP-MULTI force field for simulating coarse-grained models of multidomain proteins. SOP-MULTI combines two well-established self-organized polymer (SOP) models —: (i) SOP-SC models for folded systems and (ii) SOP-IDP for IDPs. For the SOP-MULTI, we train the cross-interaction terms between the beads belonging to the folded and disordered regions to generate experimentally-consistent conformation ensembles for full-length multi-domain proteins such as hnRNPA1, TDP-43, G3BP1, hGHR-ECD, TIA1, HIV-1 Gag, Poly-Ubiquitin and FUS. When back-mapped to all-atom resolution, SOP-MULTI trajectories faithfully recapitulate the scattering data over the range of the reciprocal space. We also show that individual folded domains preserve native contacts with respect to solved folded structures, and root mean square fluctuations of residues in folded domains match those obtained from all-atom molecular dynamics simulations trajectories of the same folded systems. SOP-MULTI Force Field is made available as a LAMMPS-compatible user package along with setup codes for generating the required files for any full-length protein with folded and disordered regions.
Perinatal development of structural thalamocortical connectivity
Authors: Oldham Stuart , Mansour L. Sina , Ball Gareth
Published: May 2024

Thalamocortical connections are crucial for relaying sensory information in the brain and facilitate essential functions including motor skills, emotion, and cognition. Emerging evidence suggests that thalamocortical connections are organised along spatial gradients that may reflect their sequential formation during early brain development. However, this has not been extensively characterised in humans. To examine early thalamocortical development, we analysed diffusion MRI data from 345 infants, scanned between 29-45 weeks gestational age. Using diffusion tractography, we mapped thalamocortical connectivity in each neonate and used Principal Component Analysis to extract shared spatial patterns of connectivity. We identified a primary axis of connectivity that varied along an anterior/medial to posterior/lateral gradient within the thalamus, with corresponding projections to cortical areas varying along a rostral-caudal direction. The primary patterns of thalamocortical connectivity were present at 30 weeks’ gestational age and gradually refined during gestation. This refinement was largely driven by the maturation of connections between the thalamus and cortical association areas. Differences in thalamocortical connectivity between preterm and term neonates were only weakly related to primary thalamocortical gradients, suggesting a relative preservation of these features following premature birth. Overall, our results indicate that the organisation of structural thalamocortical connections are highly conserved across individuals, develop early in gestation and gradually mature with age.