bluuebunny/crossref_metadata_2025 huggingface dataset:
Difficult-to-treat rheumatoid arthritis: what have we learned and what do we still need to learn?
Authors: Hofman Zonne L M , Roodenrijs Nadia M T , Nikiphorou Elena , Kent Alison L , Nagy György , Welsing Paco M J , van Laar Jaap M
Published: October 2024

Difficult-to-treat RA (D2T RA) is an area of high unmet need. The prevalence reported in the first D2T RA cohort studies ranged from 5.5% to 27.5%. Key to the definition is a conviction by the patient and/or rheumatologist that disease management has become problematic and failure of at least two biological or targeted synthetic DMARDs. D2T RA is a multifactorial disease state which was reflected in data from D2T RA cohort studies: these pointed towards high prevalence of comorbidities and/or lower socioeconomic status in D2T RA subgroups, while others had persistent symptoms without these factors being present. A holistic approach is necessary to identify the root problems underlying D2T RA in individual patients. In this review, biological and non-biological drivers that should be considered to be optimized will be discussed in view of what we have learned from patient data emerging from the first D2T RA cohort studies.
Risk Factors for Late-Onset Psychosis: A Case-Control Study
Authors: Skinner Joseph P , Shinn Ann K , Moran Lauren V
Published: October 2024

Background and Hypothesis

The onset of schizophrenia occurs after the age of 40 in up to 20% of cases. We aim to depict risk factors for first-episode psychosis after the age of 40 by comparing late-onset psychosis (LOP) patients to healthy age-matched controls.

Study Design

In this case-control study using electronic health records, 142 individuals aged 40–65 years with an encounter for a first episode of psychosis between 2013 and 2021 were included. Four controls (N = 568) were matched to each case on age, sex, race, and year of encounter. Potential risk factors for the primary analysis were captured via structured data and text-mining of medical notes. Conditional logistic regression models were used to assess the odds of LOP with potential risk factors.

Study Results

After adjusting for all variables in the main analysis, odds for LOP were increased by immigration (OR 3.30, 95% CI, 1.56–6.98), depression (OR 3.58, 95% CI, 2.01–6.38), anxiety (OR 2.12, 95% CI, 1.20–3.75), cannabis use (OR 3.00, 95% CI, 1.36–6.61), alcohol use disorder (OR 5.46, 95% CI, 2.41–12.36), polysubstance use (OR 4.22, 95% CI, 1.30–13.7), severe trauma (OR 2.29, 95% CI, 1.08–4.48), and caregiver burden (OR 15.26, 95% CI, 3.85–60.48).

Conclusions

Life stressors along with the effects of substance use and other psychiatric conditions may confer some risk to the development of LOP. Replication is required in independent prospective studies. Further research is necessary to truly parse out which of these factors belong on the causal pathway.
‘The Advice of a Gent Who Died from Neglecting it’: The Gentlemanly Pursuit of Knowledge Regarding Domestic Medicine in Kent c.1630–1800
Authors: Richards Francesca Elizabeth
Published: October 2024

English gentlemen in the early modern period held ultimate responsibility for the health of their households. Building on previous studies which have revealed how both men and women of the gentry participated in remedy-collecting and some forms of caring duties as necessity demanded, this article situates gentlemanly interest in domestic medicine within familial, social and professional networks of knowledge and reading practices. Employing a micro-historical approach, this study explores the interests of Sir Henry Oxinden of Barham and his great-grandson, Lee Warly of Canterbury, who developed their medical knowledge by consulting female relatives, local acquaintances and medical texts. They assessed the value of physicians’ advice and the appeal of new ingredients. This article thus contributes a significant case study to the historiography of domestic medicine, presenting the gentlemanly pursuit of medical knowledge for practical and academic purposes as an activity which enhanced male status within the family and community.
Biocontrol of Hemileia vastatrix, the Causal Agent of Coffee Leaf Rust, by Paenibacillus sp. NMA1017
Authors: Gómez-de la Cruz Irene , Martínez-Bolaños Misael , Chávez-Ramírez Belén , Estrada-de los Santos Paulina
Published: October 2024

Coffee leaf rust (CLR), caused by Hemileia vastatrix, is considered a highly important phytosanitary problem in Mexico. Currently, there are few microorganisms used as biocontrol alternatives to chemical control of CLR in organic coffee fields in Mexico. This study evaluates the use of Paenibacillus sp. NMA1017 as a biocontrol agent to inhibit the development of H. vastatrix in in vitro and in vivo (greenhouse) experiments. Hemileia vastatrix urediniospores were placed on water agar plates, and then Paenibacillus sp. NMA1017 was inoculated simultaneously or 8 h later. Urediniospores germination rate was reduced by 94% when the NMA1017 strain was inoculated simultaneously with the urediniospores and reduced by 38% when NMA1017 was inoculated 8 h later. Experiments with 8-month-old Bourbon coffee plants that were infected with H. vastatrix showed that disease incidence was reduced by 38, 90, and 50% when NMA1017 was applied 8 days before, simultaneously, or 8 days after the application of H. vastatrix, respectively. Paenibacillus sp. NMA1017 also reduced the severity of CLR on the leaves by up to 62%. The germination urediniospores of other rust pathogens such as Puccinia sorghi (maize leaf rust), Puccinia triticina (wheat leaf rust), Puccinia graminis f. sp. tritici (black stem rust of wheat), Uromyces striatus (alfalfa leaf rust), and Phragmidium sp. (rosebush leaf rust) were also inhibited. Use of the potential biocontrol agent Paenibacillus sp. NMA1017 might help reduce the application of chemical fungicides for the control of CLR, making coffee a more sustainable crop and providing management options for organic coffee growers.
Talocalcaneonavicular Realignment: The Foundation for Comprehensive Reconstruction of Severe, Resistant Neurologic Cavovarus, and Equinocavovarus Foot Deformities in Children and Adolescents
Authors: Galán-Olleros María , Chorbadjian-Alonso Gonzalo , Ramírez-Barragán Ana , Figueroa María Jesús , Fraga-Collarte Manuel , Martínez-González Carmen , Prato de Lima Carlos H. , Martínez-Caballero Ignacio
Published: October 2024

Introduction:

The progression of neurologic cavovarus (NCV) and equinocavovarus (NECV) foot deformities during growth can eventually lead to non-reducible severe talonavicular (TN) and subtalar (ST) joint rotational malalignments. This study aimed to describe a technique to correct severe, resistant inversion deformity of the ST joint complex as the foundational procedure in comprehensive reconstruction of multi-segmental NCV and NECV deformities in pediatric patients and to analyze mid-term radiologic, functional, and satisfaction outcomes.

Methods:

This prospective study included children with severe NCV and NECV foot deformities who underwent TCNR between 2019 and 2022, with a minimum follow-up of 2 years. Talocalcaneal angle, talus-1 metatarsal angles, and TN coverage angle were measured in preoperative and postoperative weight-bearing foot radiographs. The foot and ankle disability index, foot function index, and Maryland foot score evaluated functionality. Qualitative questions assessed perceived improvement, satisfaction, and expectations of patients/caregivers. Descriptive, comparative pre-post, subgroup, correlation, and satisfaction analysis were performed.

Results:

Twenty-six patients (36 feet: 16 unilateral and 10 bilateral) were included; 50% were female, median age was 12.1 years (IQR, 3.21) and median follow-up was 32.9 months (IQR, 18.7). Fifty-four percent had cerebral palsy, and 23% had charcot-marie-tooth disease; 84.6% were ambulatory. Significant improvements were found in radiologic parameters and functional outcomes (P<0.01), with no relevant differences between unilateral or bilateral procedures, pathology, functional level, or ambulatory capacity (P>0.05). Correlations between radiologic parameters or functional scales with age were generally low. Most reported significant functional improvements, outcomes exceeding expectations, and high satisfaction; they would recommend the surgery and undergo the procedure again. There were 3 minor complications: hypersensitivity, partial recurrence, and undercorrection.

Conclusions:

The TCNR technique enables realignment of severe, resistant inversion deformity of the ST joint complex in NCV and NECV foot deformities. When combined with procedures to correct the other foot deformities and muscle imbalances, functional outcomes are enhanced, high patient/caregiver satisfaction is achieved, and low complication rates are possible. This approach represents an important modification and extension of an already described technique, the deep plantar-medial release.

Level of Evidence

Level III, therapeutic prospective cohort study.
Branch retinal vein occlusion and peripheral nonperfusion associated with astrocytic hamartoma of the optic nerve head in a patient with tuberous sclerosis
Authors: Bulas Sabrina Y. , Hanif Adam M. , Thomas Merina
Published: October 2024

Purpose:

To report a case of branch retinal vein occlusion (BRVO) causing retinal neovascularization (NV) and vitreous hemorrhage associated with astrocytic hamartoma (AH) involving the optic nerve head in a patient with tuberous sclerosis complex (TSC). We review the natural history of the clinical presentation and posit its etiology.

Methods:

Electronic health records were reviewed for patient history and demographics and multimodal ophthalmic imaging including fundus photography, fluorescein angiography, and optical coherence tomography (OCT).

Results:

Neovascularization emanating superiorly and inferiorly from a large AH of the optic nerve head was identified as the cause of a longstanding vitreous hemorrhage. Retinal nonperfusion was also found in superior peripheral quadrants, most notably distal to the superior NV. OCT was useful in visualizing small retinal AH in the fellow eye that was otherwise undetected on prior dilated fundus examinations. The patient was treated with intravitreal anti-VEGF and superior sectoral PRP in the involved eye.

Conclusion:

BRVO and associated NV may represent rare vision-threatening sequela of AH in TSC and manifested in this case with diffuse peripheral retinal nonperfusion secondary to BRVO-induced ischemia. OCT is a valuable resource in identifying and monitoring AH of the retina.
Invasive Candidiasis in Pediatric Hematologic Malignancy: Increased Risk of Dissemination With Candida tropicalis
Authors: Said Amira M. , Afridi Faraz , Redell Michele S. , Vrana Chelsea , O’Farrell Candelaria , Scheurer Michael E. , Dailey Garnes Natalie J. , Gramatges Maria Monica , Dutta Ankhi
Published: October 2024

Background:

Candida species are the most common cause of invasive fungal disease, and children with hematologic malignancy are at increased risk. Non-albicans Candida (NAC) now account for more than half of all invasive candidiasis (IC) and carry a worse prognosis. We aimed to compare the epidemiology, risk factors, organ dissemination, biomarkers and outcomes in IC based on the species implicated and evaluate trends in antifungal resistance over time.

Methods:

Patients 0–18 years of age with hematologic malignancy and IC at 2 centers were included. Fifty-three patients from 2011 to 2022 were identified. Information related to demographics, host and risk factors, Candida species and antifungal susceptibilities, treatment and outcomes was collected via retrospective chart review. Data were analyzed at the species level.

Results:

The incidence rate of IC was 29 per 1000 patients with leukemia and lymphoma. The median time to infection from diagnosis of malignancy was 38 days. Candida tropicalis (n = 17; 30%) was the most identified species followed by Candida albicans (n = 14; 25%). Patients with C. tropicalis infection were more likely to have dissemination to the eyes (P = 0.035), spleen (P = 0.001) and skin (P = 0.003) than patients with C. albicans or other NAC. Of the 34 patients who underwent dilated retinal examination, 24% (n = 8) had evidence of intraocular candidiasis. Seven of the 8 patients with intraocular disease had prolonged candidemia (3 or more days; P = 0.003). The 12-week crude mortality rate was 16.9%.

Conclusions:

NAC, specifically C. tropicalis, accounted for most of the IC in children with hematological malignancies. Screening for intraocular candidiasis continues to play an important role in patients with IC, and future studies are needed to determine if screening can be limited to patients with select risk factors.
A Composite Score Reflecting an Initiative to Reduce Harm, Protect Patients, and Promote Safety
Authors: Smith Katelynd , McAvoy Julia , Six John D. , Goss Lisa
Published: October 2024

Since 2011, hospitals in the United States have used the Total Harm Rate as a metric to address and enhance patient safety by mitigating harmful events. However, upon evaluation, it was concluded that this tool had lost its validity and was not widely used as an effective measure to prevent harm to patients. There are no similar comparative data in the literature to which we can compare our results with others. The Quality Management Performance Improvement team began to develop a composite safety score that would be used to reflect the environment of patient safety and promote improvement opportunities.
Crista Fenestra Heights Measured by HRCT Predicts the Necessity for Extended Round Window Approach for Slim Modiolar Electrode
Authors: Teramura Atsumu , Kashio Akinori , Sahara Toshihito , Koyama Hajime , Kamogashira Teru , Urata Shinji , Ueha Rumi , Yamasoba Tatsuya
Published: October 2024

Objective

To evaluate the morphology of the crista fenestra (CF) using three-dimensional reconstruction based on high-resolution computed tomography (HRCT) and to examine the influence of CF height on the insertion approach used for CI632/532 implants.

Study design

Retrospective study

Setting

Tertiary referral center

Patients

Forty-five ears of 37 patients who received CI632/532 implants were included.

Interventions

HRCT images were reconstructed into three-dimensional images, and CF structures were identified. The patients were divided into two group based on the insertion approach: round window approach (RW; n = 27) and extended round window approach (eRW; n = 18). To evaluate CF interference, 10 cases in the eRW group in which the sheath or electrode did not pass through the RW before widening the RW niche (nRW group) were specifically included in the analysis.

Main outcome measure

The identified CF cross-sections were confirmed by HRCT axial sectioning, and CF heights were measured.

Results

The mean CF height was significantly greater in the nRW group than in the RW group (0.97 vs. 0.78 mm).

Conclusion

CF was identified using three-dimensional computer graphics (3DCG) and the CF height on the HRCT axial sections. Thus, measuring the CF height using 3DCG reconstruction can facilitate the preoperative selection of the electrode insertion approach.
The A to Z of Peroral Endoscopic Myotomy
Authors: Norton Benjamin Charles , Papaefthymiou Apostolis , Telese Andrea , Murray Charles , Murino Alberto , Johnson Gavin , Bisschops Raf , Haidry Rehan
Published: October 2024

Peroral endoscopic myotomy (POEM) is a novel technique within the field of third space endoscopy. The overarching principal is creation of a mucosal incision, careful dissection of the submucosal space using an electrosurgical knife to reach the muscularis (ie, tunneling), performing a controlled myotomy, and finally, closure of the mucosal incision. POEM was first developed for the management of achalasia, and now a decade of evidence shows the procedure is safe, effective, and highly reproducible. Since then, the indications for POEM have expanded to a range of benign upper gastrointestinal (GI) pathologies including cricopharyngeal bar (C-POEM), Zenker’s diverticulum (Z-POEM), esophageal diverticula (D-POEM), and gastroparesis (G-POEM). POEM offers the benefit of a minimally invasive alternative to surgical intervention with high clinical success and low rate of adverse events. As the field expands, there is need for more high-quality prospective evidence for the use of POEM within the upper GI tract akin to the ground-breaking work that has been achieved in achalasia. Within this review, we discuss the 5 main indications for POEM, the technical aspects of each corresponding procedure, and analyze the current evidence supporting their use in clinical practice.
Medical therapy for male infertility
Authors: Pozzi Edoardo , Corsini Christian , Salonia Andrea
Published: October 2024

Purpose of review

To provide up-to-date evidence and clinical guidance on the role of medical therapy in the context of hormonal imbalances affecting human spermatogenesis.

Recent findings

Compelling evidence has accumulated over the years regarding the role of gonadotropins, selective estrogen modulators, and aromatase inhibitors to either improve or restore spermatogenesis in men with hormonal abnormalities (e.g. hypogonadotropic/hypergonadotropic hypogonadism, hyperprolactinemia) or supraphysiologic levels (e.g. exogenous testosterone/anabolic steroid use). Despite the increasing number of studies being performed, most of the available evidence relies on small nonrandomized studies, mainly in men with hypergonadotropic hypogonadism or with history of exogenous testosterone/anabolic steroid use. As such, the efficacy of medical therapy is highly variable emphasizing the necessity of randomized clinical trials and individualized approaches.

This narrative review provides clinical guidance on medical therapies for male factor infertility based on the most up-to-date evidence, focusing on treatments for hormonal abnormalities (either hypogonadotropic or hypergonadotropic hypogonadism and hyperprolactinemia) and supraphysiologic levels (and exogenous testosterone/anabolic steroid use) to improve spermatogenesis.
Retention of Nursing Educators
Authors: Bahari Ghareeb , Alghamdi Alya
Published: October 2024

Background:

Limited support for nurse educators can hinder their professional development, as they may struggle to apply best practices and innovative teaching strategies.

Purpose:

This study aimed to identify the personal and work environment aspects that influence nursing faculty members’ ability to remain in academia.

Methods:

This qualitative descriptive study was conducted with 18 faculty members working at 2 public universities in Saudi Arabia. Four focus group sessions were conducted, and a thematic analysis approach was used for the data analysis.

Results:

The following themes emerged: appreciation and sense of security, individual and personal characteristics, work environment factors, cultural influences and responsibilities, and recommendations for individuals and organizations.

Conclusions:

Based on these themes, future research should implement appreciation initiatives such as recognition programs, mentorship opportunities, and regular feedback sessions, as well as evaluate their impact on educators’ sense of appreciation and recognition.
Altered orbitofrontal cortex neural variability underlies idiosyncratic experiences during aging
Authors: Majumdar Gargi , Yazin Fahd , Banerjee Arpan , Roy Dipanjan
Published: October 2024

Moment-to-moment neural variability plays a crucial role in learning and behavioral flexibility. This variability has been linked to age-associated differences in task performances and resting-state activity. However, its directional effects – whether increased or decreased neural variability is beneficial – remain context-dependent and unclear. Here, we demonstrate that changes to cortical neural variability during naturalistic experience serve as a readout of changes to region-specific computations, distinct from resting-state variability and mean neural activity. During the affective experience, older adults exhibited a bi-directional neural variability shift within the medial and lateral orbitofrontal cortex. By employing a Bayesian learning model, we revealed that this corresponded to heightened uncertainty in the computational estimates of evolving valence in older adults. This was reflected in frequent state switching in neural response and temporally distorted representations within the lOFC in older adults, compared to stable, coherent representations in the young. Crucially, these representational changes mirrored the arousal responses of the two groups. These results advance our understanding of how neural variability might carry unique information in aging, particularly to their changing and possibly idiosyncratic affective experiences.

Significance Statement

With an increase in average lifespan, older individuals will be required to take greater responsibility for their physical and emotional wellbeing. However, the nature and neural underpinnings of age-associated emotional changes still remain a paradox. Without a well-grounded theoretical principle, the neurocognitive theories that ensued to explain these alterations have yielded significant inconsistencies especially in relation to emotion processing under naturalistic real-world scenarios. Combining evidence from large-scale behavioral and neuroimaging data on both simple and naturalistic emotional tasks, we demonstrated that these idiosyncratic emotional responses with aging, stems from their suboptimal computation of uncertainty during hierarchical inference, manifested as increased neural variability and distorted latent state representations in lateral orbitofrontal cortex. Together, our findings illustrate that age-associated emotional changes can be unified under a singular framework of misestimation of uncertainty, within a Bayesian brain purview, without the need for bespoke theories to explain disjunctive evidence.
Enhanced proteome profiling of human cerebrospinal fluid using a commercial plasma enrichment strategy
Authors: Borràs Eva , Anastasi Federica , Pastor Olga , Suárez-Calvet Marc , Sabidó Eduard
Published: October 2024

Cerebrospinal fluid (CSF) is a valuable liquid biopsy for identifying protein biomarkers in neurological diseases, yet its proteome profiling faces challenges due to the large dynamic range of protein abundances. In this study, we assessed the effectiveness of a commercial enrichment strategy, initially developed for plasma samples, in enhancing the detection of low-abundance proteins in human CSF. We demonstrate significant improvements in protein identification and coverage depth while maintaining high reproducibility and low coefficients of variation. These findings underscore the potential of this enrichment strategy to facilitate rapid and sensitive CSF analysis, advancing biomarker discovery in neurological research.
TheEscherichia colireplication initiator DnaA is titrated on the chromosome
Authors: Olivi Lorenzo , Köstlbacher Stephan , Langendoen Mees , Claassens Nico J. , Ettema Thijs J.G. , van der Oost John , Wolde Pieter Rein ten , Hohlbein Johannes , Staals Raymond H. J.
Published: October 2024

DNA replication initiation is orchestrated in many prokaryotes by the replication initiator DnaA. Two models for regulation of DnaA activity inEscherichia colihave been proposed: the switch between an active and inactive form of DnaA, and the titration of DnaA on theE. colichromosome. Although proposed decades ago, experimental evidence of a titration-based control mechanism is still lacking. Here, we first identified a conserved high-density region of binding motifs near the origin of replication, an advantageous trait for titration of DnaA. We then investigated the mobility of DnaA by single-particle tracking microscopy in wild-type and deletion mutantsE. colistrains, while monitoring cellular size and DNA content. Our results indicate that the chromosome ofE. colicontrols the free amount of DnaA in a growth rate-dependent fashion. Finally, we provide insights on the relevance of DnaA titration in stabilising DNA replication by preventing re-initiation events during slow growth.
Direct mitochondrial import of lactate supports resilient carbohydrate oxidation
Authors: Cluntun Ahmad A. , Visker Joseph R. , Velasco-Silva Jesse N. , Lang Marisa J. , Cedeño-Rosario Luis , Shankar Thirupura S. , Hamouche Rana , Ling Jing , Kim Ji Eon , Toshniwal Ashish G. , Low Hayden K. , Cunningham Corey N. , Carrington James , Catrow Jonathan Leon , Pearce Quentinn , Jeong Mi-Young , Bott Alex J. , Narbona-Pérez Álvaro J. , Stanley Claire E. , Li Qing , Eberhardt David R. , Morgan Jeffrey T. , Yadav Tarun , Wells Chloe E. , Ramadurai Dinesh K. A. , Swiatek Wojciech I. , Chaudhuri Dipayan , Rothstein Jeffery D. , Muoio Deborah M. , Paulo Joao A. , Gygi Steven P. , Baker Steven A. , Navankasattusas Sutip , Cox James E. , Funai Katsuhiko , Drakos Stavros G. , Rutter Jared , Ducker Gregory S.
Published: October 2024

Lactate is the highest turnover circulating metabolite in mammals. While traditionally viewed as a waste product, lactate is an important energy source for many organs, but first must be oxidized to pyruvate for entry into the tricarboxylic acid cycle (TCA cycle). This reaction is thought to occur in the cytosol, with pyruvate subsequently transported into mitochondria via the mitochondrial pyruvate carrier (MPC). Using13C stable isotope tracing, we demonstrated that lactate is oxidized in the myocardial tissue of mice even when the MPC is genetically deleted. This MPC-independent lactate import and mitochondrial oxidation is dependent upon the monocarboxylate transporter 1 (MCT1/Slc16a1). Mitochondria isolated from the myocardium without MCT1 exhibit a specific defect in mitochondrial lactate, but not pyruvate, metabolism. The import and subsequent mitochondrial oxidation of lactate by mitochondrial lactate dehydrogenase (LDH) acts as an electron shuttle, generating sufficient NADH to support respiration even when the TCA cycle is disrupted. In response to diverse cardiac insults, animals with hearts lacking MCT1 undergo rapid progression to heart failure with reduced ejection fraction. Thus, the mitochondrial import and oxidation of lactate enables carbohydrate entry into the TCA cycle to sustain cardiac energetics and maintain myocardial structure and function under stress conditions.
Environment and diet shape the geography-specificDrosophila melanogastermicrobiota composition
Authors: Gale Joseph T. , Kreutz Rebecca , Gottfredson Morgan Sarah J. , Davis Emma K. , Hough Connor , Cisneros Cancino Wendy A. , Burnside Brittany , Barney Ryan , Hunsaker Reese , Hoyt Ashton Tanner , Cluff Aubrey , Nosker Maggie , Sefcik Chandler , Beales Eliza , Beltz Jack , Frandsen Paul B. , Schmidt Paul , Chaston John M.
Published: October 2024

Geographic and environmental variation in the animal microbiota can be directly linked to the evolution and wild fitness of their hosts but often appears to be disordered. Here, we sought to better understand patterns that underlie wild variation in the microbiota composition ofDrosophila melanogaster. First, environmental temperature predicted geographic variation in fly microbial communities better than latitude did. The microbiota also differed between wild flies and their diets, supporting previous conclusions that the fly microbiota is not merely a reflection of diet. Flies feeding on different diets varied significantly in their microbiota composition, and flies sampled from individual apples were exceptionally depauperate for the Lactic Acid Bacteria (LAB), a major bacterial group in wild and laboratory flies. However, flies bore significantly more LAB when sampled from other fruits or compost piles. Follow-up analyses revealed that LAB abundance in the flies uniquely responds to fruit decomposition, whereas other microbiota members better indicate temporal seasonal progression. Finally, we show that diet-dependent variation in the fly microbiota is associated with phenotypic differentiation of fly lines collected in a single orchard. These last findings link covariation between the flies’ dietary history, microbiota composition, and genetic variation across relatively small (single-orchard) landscapes, reinforcing the critical role that environment-dependent variation in microbiota composition can play in local adaptation and genomic differentiation of a model animal host.

SIGNIFICANCE STATEMENT

The microbial communities of animals influence their hosts’ evolution and wild fitness, but it is hard to predict and explain how the microbiota varies in wild animals. Here, we describe that the microbiota composition of wildDrosophila melanogastercan be ordered by temperature, humidity, geographic distance, diet decomposition, and diet type. We show how these determinants of microbiota variation can help explain lactic acid bacteria (LAB) abundance in the flies, including the rarity of LAB in some previous studies. Finally, we show that wild fly phenotypes segregate with the flies’ diet and microbiota composition, illuminating links between the microbiota and host evolution. Together, these findings help explain how variation in microbiota compositions can shape an animal’s life history.
Automated stenosis estimation of coronary angiographies using end-to-end learning
Authors: Eschen Christian Kim , Banasik Karina , Dahl Anders Bjorholm , Chmura Piotr Jaroslaw , Bruun-Rasmussen Peter , Pedersen Frants , Køber Lars , Engstrøm Thomas , Bøttcher Morten , Winther Simon , Christensen Alex Hørby , Bundgaard Henning , Brunak Søren
Published: October 2024

Background

The initial evaluation of coronary stenosis during coronary angiography is typically performed by visual assessment. The visual assessment of coronary angiographies has limited accuracy compared to quantitative methods like fractional flow reserve and quantitative coronary angiography. Quantitative methods are also more time-consuming and costly.

Objectives

To test whether applying deep-learning-based image analysis to coronary angiographies might yield a faster and more accurate stenosis estimation than visual assessment.

Methods

We developed deep learning models for predicting coronary artery stenosis using 332,582 multi-frame x-ray images (cine loops) from 19,414 patients undergoing coronary angiography. The curated dataset for model development included 13,840 patients, with 62,165 cine loops of the left coronary artery and 31,161 cine loops of the right coronary artery.

Results

For identification of significant coronary stenosis (visual assessment of diameter stenosis >70%), our model obtained a receiver operator characteristic (ROC) area under the curve (ROC-AUC) of 0.903 (95% CI: 0.900-0.906) on the internal test set with 5,056 patients. The performance was evaluated on an external test set with 608 patients against visual assessment, 3D quantitative coronary angiography, and fractional flow reserve (≤ 0.80), obtaining ROC AUC values of 0.833 (95% CI: 0.814-0.852), 0.798 (95% CI: 0.741-0.842, and 0.780 (95% CI: 0.743-0.817), respectively.

Conclusion

For assessment of coronary stenosis during invasive coronary angiography a deep-learning-based model showed promising results for predicting visual assessment (ROC AUC of 0.903). Compared to previous work, our approach demonstrates performance increase, includes all 16 segments, does not exclude revascularized patients, is externally tested, and is simpler using fewer steps and fewer models.
Transferability and accuracy of electronic health record-based predictors compared to polygenic scores
Authors: Detrois Kira E. , Hartonen Tuomo , Teder-Laving Maris , Jermy Bradley , Läll Kristi , Yang Zhiyu ,   Estonian Biobank research team, FinnGen, Mägi Reedik , Ripatti Samuli , Ganna Andrea
Published: October 2024

Electronic health record (EHR)-based phenotype risk scores (PheRS) leverage individuals’ health trajectories to infer disease risk. Similarly, polygenic scores (PGS) use genetic information to estimate disease risk. While PGS generalizability has been previously studied, less is known about PheRS transferability across healthcare systems and whether PheRS provide complementary risk information to PGS.

We trained PheRS to predict the onset of 13 common diseases with high health burden in a total of 845,929 individuals (age 32-70) from 3 biobank-based studies from Finland (FinnGen), the UK (UKB) and Estonia (EstB). The PheRS were based on elastic-net models, incorporating up to 242 diagnoses captured in the EHR up to 10 years before baseline. Individuals were followed up for a maximum of 8 years, during which disease incidence was observed. PGS were calculated for each disease using recent publicly available results from genome-wide association studies.

All 13 PheRS were significantly associated with the diseases of interest. The PheRS trained in different biobanks utilized partially distinct diagnoses, reflecting differences in medical code usage across the countries. Even with the large variability in the prevalence of various diagnoses, most PheRS trained in the UKB or EstB transferred well to FinnGen without re-training. PheRS and PGS were only moderately correlated (Pearson’srranging from 0.00 to 0.08), and models including both PheRS and PGS improved onset prediction compared to PGS alone for 8/13 diseases. PheRS was able to identify a subset of individuals at high-risk better than PGS for 8/13 disease.

Our results indicate that EHR-based risk scores and PGS capture largely independent information and provide additive benefits for disease risk prediction. Furthermore, for many diseases the PheRS models transfer well between different EHRs. Given the large availability of EHR, PheRS can provide a complementary tool to PGS for risk stratification.
Establishing laboratory reference ranges for adults and children in Kilifi, Kenya
Authors: Downs Louise O , Orindi Benedict , Hamaluba Mainga , Bejon Philip , Ochola-Oyier Lynette Isabella , Ngetsa Caroline
Published: October 2024

Accurate laboratory reference ranges (RR) are essential for diagnosis and management of patients in routine clinical care and clinical trials. RRs vary between geographical location due to differences in population demographics and blood analysis equipment, so locally derived RRs are essential. Here we establish adult and paediatric RRs for a rural population in Kilifi, Kenya using clinical trial data from KEMRI-Wellcome Trust Research Programme (KWTRP).

Data from healthy, non-pregnant participants from six clinical trials conducted between 2016 and 2020 were used. Coulter ACT 5 Diff and Ilab Aries were used for haematological and biochemical analysis respectively. Quality control was undertaken daily prior to sample analysis. Derived RRs were compared with RRs from other African countries and further afield. All analyses were performed using R version 3.6.1 (Reference Intervals package).

2338 adults and 2054 children were included, 52% of adults and 51% of children were male, median adult age was 32.5 years. Haemoglobin range was lower in women compared to men (9.5–14.2g/dL and 11.5–16.6g/dL respectively), platelet upper limit of normal (ULN) was higher in women compared to men (397 × 103/μL vs 358 × 103/ μL). Biochemistry values were higher in men (ALT ULN 57 U/L in men and 35 U/L in women, creatinine ULN 113umol/L in men and 91umol/L in women). Paediatric RRs showed differences in multiple parameters depending on the age of the child.

In both adults and children, many parameters in 2023 Kilifi RRs differed from those in other countries. There was however little difference between 2023 and 2017 Kilifi paediatric RRs.

This study provides RRs for adults and children in Kilifi, and the most extensive RRs available for much of East and Southern Africa. We show the need for locally derived reference ranges, highlighting differences between sex, age and geographical location.
Glycemic Fluctuations, Fatigue, and Sleep Disturbances in Type 2 Diabetes During Ramadan Fasting: A Cross-Sectional Study
Authors: Pratama Satwika Arya , Kurniawan Rudy , Chiu Hsiao-Yean , Kuo Hsuan-Ju , Ekpor Emmanuel , Al-Baqi Safiruddin , Hasan Faizul , Romadlon Debby Syahru
Published: October 2024

Background

This study aimed to assess the prevalence of glycemic fluctuations, fatigue, and sleep disturbances during Ramadan, and to identify factors associated with hypoglycemia and hyperglycemia events in this period.

Methods

A cross-sectional study of 88 individuals with type 2 diabetes during Ramadan fasting (March-April 2024) was conducted. HbA1c levels before Ramadan were obtained from medical records. Participants monitored blood glucose twice daily (during the day and two hours after breaking fast). Blood glucose under 70 mg/dl was considered hypoglycemia, and over 200 mg/dl was hyperglycemia. Fatigue and sleep quality were assessed using the Indonesian Multidimensional Fatigue Inventory-20 (IMFI-20) and the Pittsburgh Sleep Quality Index (PSQI).

Results

A total of 88 patients with type 2 diabetes (mean age, 52.7 years) participated, predominantly female (68.2%) and married (63.6%). The study found a prevalence of 21.6% for hypoglycemia and 30.6% for hyperglycemia. Additionally, 30.7% of participants experienced fatigue, and 40.9% reported poor sleep quality. HbA1c levels before Ramadan and fatigue were significantly associated with both hypoglycemia and hyperglycemia (p < 0.05). Sleep quality was also significantly associated with hyperglycemia events (p < 0.05).

Conclusion

The study found that hypoglycemia and hyperglycemia are common in individuals with type 2 diabetes during Ramadan. Fatigue and poor sleep quality were also prevalent.

Significant factors linked to both glycemic events included pre-Ramadan HbA1c levels and fatigue, while sleep quality was associated with hyperglycemia. These findings emphasize the need for targeted interventions and personalized management to reduce glycemic fluctuations and improve well-being during Ramadan fasting.
The acceptability of being trained to deliver online, group-based Acceptance and Commitment Therapy to stroke survivors: the experience of third-sector practitioners
Authors: Foote Hannah , Bowen Audrey , Cotterill Sarah , Patchwood Emma
Published: October 2024

Purpose

The Wellbeing After Stroke study (WAterS) co-developed a nine-week, online, group-based intervention for stroke survivors, informed by Acceptance and Commitment Therapy (ACT), to be delivered by third sector practitioners. This study explored practitioners’ perceptions of the acceptability of the training and their views on delivering the intervention.

Materials and methods

Semi-structured interviews completed with practitioners after training, but before intervention delivery had begun. Interview schedule guided by the Theoretical Framework of Acceptability. Template Analysis used to inductively and deductively interpret the data.

Results

All eight WAterS-trained practitioners were interviewed. Five main themes were generated. Practitioners were motivated to deliver a stroke-specific therapy. Practitioners reported that training was understandable and that experiencing ACT during training benefitted practitioners’ own wellbeing and increased their preparedness for intervention delivery. Previous experience affected their confidence to deliver. Practitioners expected the therapy to be acceptable to many stroke survivors. The online group context was expected to be beneficial, although they foresaw challenges in remotely facilitating groups with diverse accessibility needs.

Conclusion

It is acceptable to upskill a third-sector workforce to deliver a protocolised ACT-informed intervention to stroke survivors, potentially enabling greater reach of much needed psychological support.
A dataset for evaluating clinical research claims in large language models
Authors: Zhang Boya , Yazdani Anthony , Bornet Alban , Khlebnikov Philipp , Milutinovic Marija , Rouhizadeh Hossein , Amini Poorya , Teodoro Douglas
Published: October 2024

Large language models (LLMs) have the potential to enhance the verification of health claims. However, issues with hallucination and comprehension of logical statements require these models to be closely scrutinized in healthcare applications. We introduce CliniFact, a scientific claim dataset created from hypothesis testing results in clinical research, covering 992 unique interventions for 22 disease categories. The dataset used study arms and interventions, primary outcome measures, and results from clinical trials to derive and label clinical research claims. These claims were then linked to supporting information describing clinical trial results in scientific publications. CliniFact contains 1,970 scientific claims from 992 unique clinical trials related to 1,540 unique publications. Intrinsic evaluation yields a Cohen’s Kappa score of 0.83, indicating strong inter-annotator agreement. In extrinsic evaluations, discriminative LLMs, such as PubMedBERT, achieved 81% accuracy and 79% F1-score, outperforming generative LLMs, such as Llama3-70B, which reached 52% accuracy and 39% F1-score. Our results demonstrate the potential of CliniFact as a benchmark for evaluating LLM performance in clinical research claim verification.
Spatial mutual nearest neighbors for spatial transcriptomics data
Authors: Zhou Haowen , Panwar Pratibha , Guo Boyi , Hallinan Caleb , Ghazanfar Shila , Hicks Stephanie C.
Published: October 2024

Mutual nearest neighbors (MNN) is a widely used computational tool to perform batch correction for single-cell RNA-sequencing data. However, in applications such as spatial transcriptomics, it fails to take into account the 2D spatial information. Here, we presentspatialMNN, an algorithm that integrates multiple spatial transcriptomic samples and identifies spatial domains. Our approach begins by building ak-Nearest Neighbors (kNN) graph based on the spatial coordinates, prunes noisy edges, and identifies niches to act as anchor points for each sample. Next, we construct a MNN graph across the samples to identify similar niches. Finally, the spatialMNN graph can be partitioned using existing algorithms, such as the Louvain algorithm to predict spatial domains across the tissue samples. We demonstrate the performance of spatialMNN using large datasets, including one withN=36 10x Genomics Visium samples. We also evaluate the computing performance of spatialMNN to other popular spatial clustering methods. Our software package is available at (https://github.com/Pixel-Dream/spatialMNN).
Automated model-free analysis of cryo-EM volume ensembles with SIREn
Authors: Kinman Laurel F. , Carreira Maria V. , Powell Barrett M. , Davis Joseph H.
Published: October 2024

Cryogenic electron microscopy (cryo-EM) has the potential to capture snapshots of proteins in motion and generate hypotheses linking conformational states to biological function. This potential has been increasingly realized by the advent of machine learning models that allow 100s-1,000s of 3D density maps to be generated from a single dataset. How to identify distinct structural states within these volume ensembles and quantify their relative occupancies remain open questions. Here, we present an approach to inferring variable regions directly from a volume ensemble based on the statistical co-occupancy of voxels, as well as a 3D-convolutional neural network that predicts binarization thresholds for volumes in an unbiased and automated manner. We show that these tools recapitulate known heterogeneity in a variety of simulated and real cryo-EM datasets, and highlight how integrating these tools with existing data processing pipelines enables improved particle curation and the construction of quantitative conformational landscapes.
Transcriptomic and Biochemical analysis ofProcambarus clarkiiupon exposure to Pesticides: Population-Specific responses as a sign of pollutant resistance?
Authors: Diana Martínez-Alarcón , Reisser Celine , Solé Montserrat , Lignot Jehan-Hervé , Rivera-Ingraham Georgina
Published: October 2024

The effects that anthropogenic stressors may have on modulating species plasticity has been relatively unexplored; however, it represents a scientific frontier that may offer insights into their ability to colonize new habitats. To explore the advantage that inhabiting polluted environments may offer to invasive species, we selected the crayfishProcambarus clarkii, a species that can colonize and thrive in a wide range of aquatic environments, including heavily polluted ones. Here, we studied the molecular and physiological responses of crayfish when experimentally exposed to a pesticide mix of azoxystrobin and oxadiazon at sublethal concentrations. We compared these responses in three isolated crayfish populations in Southern France that are established in areas with different pollution levels: a) Camargue, seasonally affected by pesticide pollution; b) Bages-Sigean, impacted all year-round by domestic effluents and; c) Salagou, a more pristine site. Gene expression analyses revealed that the response to the pesticide mix was the strongest in the Camargue crayfish. In this population, a total of 88 differentially expressed genes (DEGs) were identified in hepatopancreas and 78 in gills between exposed and control laboratory groups. Among genes that were differentially expressed and successfully annotated, those involved in stress, DNA repair, immune response, and translation and transcription processes stand out. Interestingly, the hepatopancreas responded mainly with upregulation, but with downregulation in the gills. This suggests that compared to naïve individuals, when exposed to these biocides in their natural habitat crayfish respond with different mechanistic strategies that may confer them adaptability at the population level. Responses in terms of antioxidant and detoxification enzymes also corroborate differences to biocide inputs according to the origin of the crayfish.
Annulate Lamellae biogenesis is essential for nuclear pore function
Authors: Lin Junyan , Agote-Arán Arantxa , Liao Yongrong , Schoch Rafael , Ronchi Paolo , Cochard Victor , Zhu Rui , Kleiss Charlotte , Ruff Marc , Chevreux Guillaume , Schwab Yannick , Klaholz Bruno P. , Sumara Izabela
Published: October 2024

Nuclear pore complexes (NPCs), large protein assemblies embedded into the nuclear envelope (NE), are crucial for bidirectional transport between the nucleus and cytoplasm, a process often disrupted in human diseases. Besides their presence within the NE, NPCs are also found in stacked cytoplasmic endoplasmic reticulum (ER) membranes called annulate lamellae (AL)1,2. Despite being discovered in the mid-20th century3, the function and biogenesis mechanisms of AL have remained largely mysterious. While AL were thought to be restricted to germ, embryonic and malignant cells4–12, we find that AL also exist in the cytoplasm of somatic cells under normal physiological conditions and that they can expand upon specific stimuli. We show that AL merge with the NE, supplying the nucleus with new pores which maintains nuclear pore function and nuclear growth during early interphase. NPC protein RanBP2 (Nup358) and ER-associated Climp63 (CKAP4) trigger AL assembly and their NE-integration. The N-terminal phenylalanine-glycine (FG) repeats of RanBP2 drive the oligomerization of Y-complexes (the NPC outer ring units), and AL-NPCs formation and Climp63 ensures the localization of AL-NPCs to ER sheets and their fusion with the nucleus. These findings uncover a fundamental mechanism of AL biogenesis and highlight the critical role of cytosolic NPCs in the nuclear function and mammalian cellular homeostasis.