bluuebunny/crossref_metadata_2025 huggingface dataset:
Prompt matters: evaluation of large language model chatbot responses related to Peyronie’s disease
Authors: Warren Christopher J , Edmonds Victoria S , Payne Nicolette G , Voletti Sandeep , Wu Sarah Y , Colquitt JennaKay , Sadeghi-Nejad Hossein , Punjani Nahid
Published: September 2024

Introduction

Despite direct access to clinicians through the electronic health record, patients are increasingly turning to the internet for information related to their health, especially with sensitive urologic conditions such as Peyronie’s disease (PD). Large language model (LLM) chatbots are a form of artificial intelligence that rely on user prompts to mimic conversation, and they have shown remarkable capabilities. The conversational nature of these chatbots has the potential to answer patient questions related to PD; however, the accuracy, comprehensiveness, and readability of these LLMs related to PD remain unknown.

Aims

To assess the quality and readability of information generated from 4 LLMs with searches related to PD; to see if users could improve responses; and to assess the accuracy, completeness, and readability of responses to artificial preoperative patient questions sent through the electronic health record prior to undergoing PD surgery.

Methods

The National Institutes of Health’s frequently asked questions related to PD were entered into 4 LLMs, unprompted and prompted. The responses were evaluated for overall quality by the previously validated DISCERN questionnaire. Accuracy and completeness of LLM responses to 11 presurgical patient messages were evaluated with previously accepted Likert scales. All evaluations were performed by 3 independent reviewers in October 2023, and all reviews were repeated in April 2024. Descriptive statistics and analysis were performed.

Results

Without prompting, the quality of information was moderate across all LLMs but improved to high quality with prompting. LLMs were accurate and complete, with an average score of 5.5 of 6.0 (SD, 0.8) and 2.8 of 3.0 (SD, 0.4), respectively. The average Flesch-Kincaid reading level was grade 12.9 (SD, 2.1). Chatbots were unable to communicate at a grade 8 reading level when prompted, and their citations were appropriate only 42.5% of the time.

Conclusion

LLMs may become a valuable tool for patient education for PD, but they currently rely on clinical context and appropriate prompting by humans to be useful. Unfortunately, their prerequisite reading level remains higher than that of the average patient, and their citations cannot be trusted. However, given their increasing uptake and accessibility, patients and physicians should be educated on how to interact with these LLMs to elicit the most appropriate responses. In the future, LLMs may reduce burnout by helping physicians respond to patient messages.
Retrospective analysis of the efficacy of low-intensity extracorporeal shock wave therapy on young and middle-aged patients with erectile dysfunction responsive to PDE5Is: reducing the use of PDE5Is
Authors: Yao Rui-Jie , Wang Mao-Yuan , Chen Qiang , Xiao Hong , Yang Peng , Ding Yi-Lang , Chen Xi , Tang Song-Xi , Zhou Hui-Liang
Published: September 2024

Background

Low-intensity extracorporeal shock wave therapy (Li-ESWT) is a new method for treating erectile dysfunction (ED), but there are no standards yet for its indications.

Aim

The study aimed to suggest the early clinical efficacy of Li-ESWT and explore its related factors in young and middle-aged patients with ED who responded to phosphodiesterase type 5 Inhibitors (PDE5Is).

Methods

Data from 61 patients with ED who had previously responded to oral PDE5Is and subsequently underwent Li-ESWT were collected. This included information on age, body mass index, total testicular volume, sex hormones, as well as IIEF-EF scores before treatment and at 1, 3, and 6 months after treatment. The treatment regimen involves a weekly session for four consecutive weeks, with each session administering 5000 shock wave pulses. Linear regression analysis was utilized to identify factors associated with the efficacy of Li-ESWT treatment. Additionally, the improvement in different severity groups of ED before and after treatment, along with their IIEF-EF scores, was compared.

Outcomes

Li-ESWT was more targeted and effective for young and middle-aged patients with erectile dysfunction who responded to PDE5Is.

Results

The age of enrolled patients ranges from 22 to 53 years old, and the IIEF-EF scores at 1 month, 3 months, and 6 months after treatment were compared to baseline for efficacy assessment, showing significant improvements (P < .0001) in all instances. Linear regression analysis using baseline data revealed predictive factors associated with treatment efficacy: treatment efficacy was negatively correlated with baseline IIEF-EF scores (t = −2.599, P = .013) and positively correlated with baseline LH levels (t = 2.170, P = .036).

Clinical Implications

Given the considerable cost of Li-ESWT treatment and the emphasis on treatment continuity, we hope to identify the most suitable candidates for Li-ESWT therapy, thereby optimizing its application.

Strengths and Limitations

Our findings provide a better solution for nonelderly ED patients who are responsive to PDE5Is. This study was limited by our sample size and follow-up time.

Conclusion

After 3 months of Li-ESWT, the IIEF-EF score gradually stabilizes and short-term maintenance of PDE5Is medication increases the responsiveness to shock wave therapy.
Pay talk in contemporary workplaces
Authors: Denice Patrick , Rosenfeld Jake , Sun Shengwei
Published: September 2024

Drawing on a unique survey of US workers with information about their employers’ policies on pay discussions and whether workers engage in such talk with their coworkers, we provide the most comprehensive investigation into pay talk in workplaces to date. Unlike existing treatments, we focus on core organizational and relational factors that influence whether workers talk about pay. We theorize pay talk as a challenge to managerial discretion, and we hypothesize that organizational attributes related to pay-setting influence workers’ willingness to discuss wages and salaries with colleagues. Managers, in turn, combat such challenges to their discretion by instituting pay secrecy rules. Particular relational factors within organizations are related to workers’ violations of these rules. Findings indicate that the likelihood of pay discussions varies by workplace pay secrecy rules, managerial relations within organizations, and, in certain model specifications, sector and career turning points. Among status characteristics, only age is associated with discussing pay, with younger workers significantly more likely to talk about pay and to violate organizational rules meant to suppress pay discussions.
Incorporating entrepreneurial skills into mathematics teaching in school
Authors: Alimorad Hajar , Daneshfard Farhang
Published: September 2024

Mathematics, as one of the core subjects in education, can be recognized as a tool for strengthening fundamental entrepreneurial skills. In this study, attempt was made to examine how integrating entrepreneurial skills—creativity, responsibility, courage, initiative, tolerance of ambiguity and collaboration ( Palmer  &  Johansson, 2018)—into mathematics teaching compares against mathematical teaching alone in terms of the marks of the students and the learner’s and the teacher’s perceptions about the class. The study was conducted in the summer of 2023 with the participation of 50 students in two classes of 25 students in Iran, who were chosen based on convenience sampling. Given the time available, four chapters of the eighth-grade mathematics textbook were taught. In the experimental group, entrepreneurial skills were integrated into class, and in the control group, no such integration happened. After the end of each chapter in both classes, a test was given to the students. In addition, the views of the experimental group and the instructor about the treatment were sought by survey questions. Comparing the mean scores of the two classes in the tests showed no significant difference. However, the survey questions suggested improvements in the six entrepreneurial skills and a better mathematics learning environment in the experimental group.
I am in Charge, But Not Always in Control
Authors: Crouch Sophie M. , Baranoff John A. , Bunzli Samantha , Mardon Amelia K. , Chalmers K. Jane
Published: September 2024

Objectives:

Beliefs and knowledge about pain can influence how an individual approaches pain management. At present, there have been no investigations into the beliefs and knowledge that females hold about their pelvic pain; therefore, pain intervention approaches may not be targeted at current patient understandings. Exploring beliefs and knowledge may help inform and subsequently improve pain intervention outcomes for pelvic pain by allowing more tailored content to be delivered. This study aimed to identify beliefs and knowledge that females hold about their pelvic pain.

Materials and Methods:

Semistructured interviews (n = 12) were conducted. Based on the common sense model, interview questions investigated participants’ beliefs and knowledge related to the identity (diagnostic labels), cause, consequence, control, and timeline of their pelvic pain. Transcribed interviews were analyzed using an Interpretive Description Framework.

Results:

Participants reported holding biopsychosocial understandings of pain; however, many described their own pain experience in a way that was more aligned with the biomedical model of pain, suggesting incongruence in pain understanding. Participants valued their ability to take charge of their pain management, highlighting bodily autonomy and being proactive in pain management approaches. This approach to management did not provide total control over participants’ pelvic pain. Pelvic pain was perceived as disruptive of life, both at present and into the future, with the predictability of pain varying over time.

Conclusion:

This study provides insight into the perspectives of females with pelvic pain. Recommendations for clinicians are provided with a focus on delivering targeted education and equipping patients with helpful representations of their pain.
You Don’t Always Get What You Want!
Authors: Morgan Philip G. , Sedensky Margaret M.
Published: September 2024

GAS-1: Mitochondrial protein controls sensitivity to volatile anesthetics in the nematode Caenorhabditis elegans. By Kayser EB, Morgan PG, and Sedensky MM. ANESTHESIOLOGY 1999; 90:545–54. Reprinted with permission.

Background

Mutations in several genes of Caenorhabditis elegans confer altered sensitivities to volatile anesthetics. A mutation in one gene, gas-1(fc21), causes animals to be immobilized at lower concentrations of all volatile anesthetics than in the wild type, and it does not depend on mutations in other genes to control anesthetic sensitivity. gas-1 confers different sensitivities to stereoisomers of isoflurane, and thus may be a direct target for volatile anesthetics. The authors have cloned and characterized the gas gene and the mutant allele fc21.

Methods

Genetic techniques for nematodes were as previously described. Polymerase chain reaction, sequencing, and other molecular biology techniques were performed by standard methods. Mutant rescue was done by injecting DNA fragments into the gonad of mutant animals and scoring the offspring for loss of the mutant phenotype.

Results

The gas-1 gene was cloned and identified. The protein GAS-1 is a homologue of the 49-kd (IP) subunit of the mitochondrial NADH-ubiquinone-oxidoreductase (complex I of the respiratory chain). gas-1(fc21) is a missense mutation replacing a strictly conserved arginine with lysine.

Conclusions

The function of the 49-kd (IP) subunit of complex I is unknown. The finding that mutations in complex I increase sensitivity of C. elegans to volatile anesthetics may implicate this physiologic process in the determination of anesthetic sensitivity. The hypersensitivity of animals with a mutation in the gas-1 gene may be caused by a direct anesthetic effect on a mitochondrial protein or secondary effects at other sites caused by mitochondrial dysfunction.
Development of the West China Tinnitus Impact Inventory and Analysis of Its Reliability and Validity
Authors: Wang Qiang , Zhao Yu , Wang Yibo , Wu Yunyu , Meng Zhaoli
Published: September 2024

Objectives:

Owing to differences in cultural background, education level, and lifestyle, certain items of existing tinnitus evaluation scales are difficult for Chinese patients to understand, despite being translated. However, few independently developed scales have been developed specifically for Chinese patients. Therefore, with this study, we aimed to construct a tinnitus scale, the West China Tinnitus Impact Inventory (WCTII), suitable for the accurate reflection of the impact and severity of the disease in this population.

Design:

Basic items were obtained through semistructured interviews with patients with tinnitus. We invited 23 domestic experts on tinnitus to form an expert group. The basic items were modified using the Delphi method. Cronbach’s α values for the scale scores and correlation coefficients between the items and the scale scores were calculated. Items with correlation coefficients <0.5 were deleted. Exploratory factor analysis was conducted to determine the scale structure of the items remaining after item deletion. The intragroup correlation coefficient was used to assess the scale’s test–retest reliability. The Pearson correlation coefficient between the scale scores and the scores for the Chinese-Mandarin version of the Tinnitus Handicap Inventory was used to evaluate concurrent validity.

Results:

After five rounds of expert correspondence and exploratory factor analysis, we determined the content and structure of the scale. The WCTII consists of 19 items in 4 subscales, namely, F1: the impact of tinnitus on emotion (items 1 to 9); F2: the impact of tinnitus on sleep (items 10 to 12); F3: patients’ beliefs about their tinnitus (items 13 to 16, 19); and F4: the impact of tinnitus on auditory processing ability (items 17 to 18). The overall Cronbach’s α was 0.934. The Cronbach’s α values for F1 to F4 were 0.912, 0.843, 0.829, and 0.838, respectively. The intragroup correlation coefficient (95% confidence interval) of the total scale and F1 to F4 were 0.779 (0.549 to 0.886), 0.738 (0.496 to 0.860), 0.826 (0.713 to 0.897), 0.720 (0.536 to 0.836), and 0.715 (0.532 to 0.832), respectively. The correlation between the WCTII and Chinese-Mandarin version of the Tinnitus Handicap Inventory scores was 0.849 (p < 0.001).

Conclusions:

The WCTII yielded satisfactory reliability and validity, indicating that it can be used to assess the severity of tinnitus in Chinese patients.
Effects of Yoga in the Care of Patients With Heart Failure
Authors: Achury-Saldaña Diana , Andrade-Fonseca David , Gallego-Ardila Andrés Daniel , Angarita Angie , Ayala-Gutiérrez Johan , Sánchez Mayra Alejandra , Thriat-Infante Marian
Published: September 2024

This review delves into the potential benefits of integrating yoga into the care of patients with heart failure. A systematic literature review was undertaken through electronic searches of indexed databases. Quality assessment utilized the Cochrane risk-of-bias tool, and data on population characteristics, interventions, and clinical, biochemical, and functional outcomes were meticulously extracted. Six randomized trials, encompassing 296 individuals with a left ventricular ejection fraction between 30 and 50%, and functionally classified per the New York Heart Association as I, II, or III, were included. Despite limited published experimental research, yoga demonstrates promising effectiveness in enhancing outcomes such as quality of life, functional capacity, and clinical markers. Notably, safety and adherence outcomes remain unexplored. Future studies should prioritize a representative sample size, methodological rigor, and adherence to established yoga intervention guidelines in randomized clinical trials, ensuring comprehensive evaluation across short-, medium-, and long-term perspectives.
Comparison of rotational stability of the implantable collamer lens after using a vertical or horizontal implanting orientation
Authors: Zhao Keming , Wan Linxi , Chen Xi , Ye Yiming , Yang Ying , Zhuang Jing , Yu Keming
Published: September 2024

Purpose:

To compare rotational stability of the implantable collamer lens (ICL) between horizontal and vertical implantation.

Setting:

Zhongshan Ophthalmic Center, Guangzhou, China.

Design:

Prospective 1:1 matched design.

Methods:

94 cases (185 eyes with a vertical elliptical ciliary sulcus) were included with a 1:1 matched design based on ciliary sulcus morphology, preset deviation angle, and vault. Follow-ups at 4 days, 1 month, 3 months, and 6 months postsurgery measured rotational angles using slitlamp photography. Latent class trajectory modeling was used to investigate the postoperative rotational angle trajectories.

Results:

6 months postoperatively, both groups exhibited similar visual acuity and refractive outcomes. The horizontal group had a significantly greater rotation angle than the vertical group (Fgroup = 13.638, P < .001). In addition, a statistically significant difference (P = .004) in the average trajectories of rotational angles was observed. The vertical group displayed a greater presence in the low-stable trajectory subgroup while demonstrating a reduced presence in the moderate-increase and high-fluctuation trajectory subgroups compared with the horizontal group. The horizontal group had a 3.750 times higher risk of rotation angle ≥3 degrees compared with the vertical group, which represented a statistically significant difference (95% CI, 1.346-10.446). In both groups, a positive correlation between the preset deviation angle and the rotation angle was observed, with correlation coefficients of 0.320 (P = .030) and 0.371 (P = .011), respectively.

Conclusions:

Vertical ICL implantation showed better rotational stability than horizontal implantation in eyes with a vertical elliptical ciliary sulcus, offering guidance for ICL surgery.
Acute rheumatic fever and rheumatic heart disease: updates in diagnosis and treatment
Authors: Rwebembera Joselyn , Beaton Andrea
Published: September 2024

Purpose of review

To summarize the latest developments in rheumatic fever and rheumatic heart disease (RHD) prevention, (early) diagnosis, and treatment.

Recent findings

The revised Jones criteria have demonstrated increased sensitivity and specificity for rheumatic fever diagnosis in high-risk populations. The management of rheumatic fever remains symptom-based, with no treatment options proven to alter the disease course or prevent chronic RHD. The revised World Heart Federation (WHF) guidelines for the echocardiographic diagnosis of RHD encourage task-shifting of RHD screening, extending reach in endemic regions. These guidelines also present an A–D classification of RHD and provide recommendations for the management of early disease. Integrated models for RHD screening within existing health structures are emerging and automated intelligence is showing potential to support RHD screening and diagnosis. Innovative strategies to foster adherence and equitable access to secondary prophylaxis, such as re-examination of the efficacy of oral penicillin, trials of longer acting penicillin formulations and implants are underway. There is renewed interest and investment in a well tolerated and effective GAS vaccine.

We are living in a time of possibility with global acceleration to address the prevailing burden of RHD. Together, we can ensure that RHD does not once again fall off the global health agenda, until equitable elimination has been achieved.
Diastolic dysfunction: assessment and implications on the single ventricle circulation
Authors: Hassan Ahmed A. , Van De Bruaene Alexander , Friedberg Mark K.
Published: September 2024

Purpose of review

Patients with a functionally single ventricle (SV) are palliated with a series of procedures leading to a Fontan circulation. Over the life span, a substantial proportion of SV patients develop heart failure that can arise from circulatory or ventricular failure. Diastolic dysfunction (DD) is an important determinant of adverse outcomes in SV patients. However, assessment and categorization of DD in the SV remains elusive. We review recent literature and developments in assessment of DD in the SV and its relation to clinical outcomes.

Recent findings

DD is prevalent in the SV and associated with worse outcomes. Occult DD can be exposed with provocative testing by exercise or preload challenge during catheterization. Likewise, sensitivity to detect DD may be increased via assessment of atrial function and strain imaging. Recent studies revisiting previous concepts such as incoordinate diastolic wall motion show that these are associated with SV end-diastolic pressures and post-Fontan recovery, yielding accessible DD assessment. Emerging technologies such as ultrafast ultrasound (UFUS) can provide noninvasive assessment of myocardial stiffness, inefficient diastolic flow patterns and intraventricular pressure gradients, thereby yielding new tools and insights into diastolic myocardial and hemodynamic properties.

Characterizing DD in the SV continues to have substantial limitations, necessitating synthesis of multiple parameters into an overall assessment, accounting for their change over time, and in the context of the patient's clinical status. New and emerging techniques may help advance DD assessment and the ability to track response to treatment of new targets.
Management of undescended testis
Authors: Saylors Seth , Oyetunji Tolulope A.
Published: September 2024

Purpose of review

Describe why this review is timely and relevant.

Undescended testis, or cryptorchidism, is a common diagnosis encountered by pediatricians that requires timely collaboration with pediatric surgical specialists to optimize outcomes for these patients. As this topic continues to be heavily researched, it is imperative to understand current recommendations and emerging management options including new surgical techniques, as well as common pitfalls in care highlighted in the literature.

Recent findings

Describe the main themes in the literature covered by the article.

This review primarily examines current practice in management including delays in surgical referral, with unnecessary imaging being a key factor that delays time to surgery. This review briefly discusses the diagnosis of undescended testis and the various surgical techniques used including the more recently proposed laparoscopic staged traction orchiopexy (Shehata technique). The ineffectiveness of hormonal therapy is also addressed.

describe the implications of the findings for clinical practice or research.

This review emphasizes prompt evaluation and diagnosis of undescended testis to facilitate appropriately timed surgical intervention, which plays a major role in outcomes for these patients. Identifying patients at risk of delayed referral is an area of focus for improvement, along with better resource utilization with fewer imaging. Familiarization of surgical options can also facilitate better patient education and provider understanding of risks/benefits.
Advances in understanding and managing pediatric heart failure and transplant
Authors: Xu Wenyuan , Richmond Marc
Published: September 2024

Purpose of review

This article highlights the most recent advances in a review of the current literature in the field of pediatric heart failure and transplantation.

Recent findings

Diagnostically, the identification of new genetic factors has contributed to a deeper understanding of cardiomyopathy in children. Novel medications like sacubitril/valsartan and Sodium-Glucose cotransporter-2 (SGLT2) inhibitors, which are now standard in the adult population are being studied in pediatric population and offer new promise of pediatric heart failure treatment. Ventricular assist devices are more commonly used in cardiomyopathy patients and single ventricle patients as a bridge to transplant. Recent pediatric heart transplant society (PHTS) data demonstrated that waitlist survival improved significantly over the past decades (i) and new treatments such as daratumumab and eculizumab have been used in high-risk populations and demonstrate promising results. TEAMMATE trial is the first multicenter randomized clinical trial (RCT) in pediatric heart transplant (HT) to evaluate the safety and efficacy of everolimus (EVL) and low-dose tacrolimus (TAC) compared to standard-dose TAC and mycophenolate mofetil (MMF). It will provide valuable information about the safety and efficacy of EVL, TAC, and MMF (ii).

Donor cell-free DNA has been used more in pediatric transplant recipients and has significantly decreased invasive EMB (iii).

This past 5 years have witness dramatic progress in the field of pediatric heart failure and transplantation including more use of mechanical support in heart failure patients with various underlying etiology, especially use of mechanical support in single ventricle patients and the use of sacubitril/valsartan and SGLT2 inhibitors in the pediatric population. The problem of the highly sensitized transplant recipient remains, although novel therapeutics have been added to our toolbox of options to maintain healthy allograft function. Ongoing research aims to further enhance our understanding and management of pediatric heart failure, emphasizing the need for continued innovation in this complex field.
Association of internship with performance on American Board of Physical Medicine and Rehabilitation certification examinations
Authors: Driscoll Sherilyn W. , Pruitt David W. , Sabharwal Sunil , Raddatz Mikaela M. , Kinney Carolyn L.
Published: September 2024

Physical Medicine and Rehabilitation (PM&R) residents must complete twelve months of fundamental skills training prior to beginning PM&R residency. The objective of this study is to determine if characteristics of the first post-graduate year (PGY-1) impact performance on American Board of PM&R (ABPMR) initial certification examinations. A retrospective review was conducted on a deidentified ABPMR database of physicians who completed PM&R residency and took the Part I Examination between 2008 and 2022. Physicians who completed categorical residency programs in PM&R had higher pass rates on Part I than physicians who completed advanced programs. Physicians who completed a categorical program had higher scaled scores on the Part II Examination than physicians who completed either a transitional or non-transitional advanced program but pass rates did not differ. Completing less than 3 months of training in internal medicine prior to starting PM&R was associated with lower Part I and Part II Examination scaled scores than completing 3 or more months. Physicians who completed six or more months of internal medicine had higher Part I and Part II Examination pass rates and scaled scores than physicians who completed six or more months in surgery.
“Mastectomy for individuals with gender dysphoria below 26 years of age: A systematic review and meta-analysis”
Authors: Miroshnychenko Anna , Roldan Yetiani M , Ibrahim Sara , Kulatunga-Moruzi Chan , Dahlin Kristen , Montante Steven , Couban Rachel , Guyatt Gordon , Brignardello-Petersen Romina
Published: September 2024

Background:

Gender dysphoria (GD) refers to psychological distress associated with the incongruence between one’s sex and one’s gender. In response to GD, birth-registered females may choose to undergo mastectomy. In this systematic review, we summarize and assess the certainty of the evidence on the effects of mastectomy.

Methods:

We searched MEDLINE, Embase, PsycINFO, Social Sciences Abstracts, LGBTQ+ Source, and Sociological Abstracts through June 20, 2023. We included studies comparing mastectomy to no mastectomy in birth-registered females under 26 years of age with GD. Outcomes of interest included psychological and psychiatric outcomes, and physical complications. Pairs of reviewers independently screened articles, abstracted data, and assessed risk of bias of the included studies. We performed meta-analysis and assessed the certainty of the evidence using the GRADE approach.

Results:

We included 39 studies. Observational studies (n=2) comparing mastectomy to chest binding provided very low certainty evidence for the outcome of GD. One observational study comparing mastectomy to no mastectomy provided very low certainty evidence for the outcomes global functioning and suicide attempts, and low certainty evidence for the outcome non-suicidal self-injury (aOR 0.47 [95% CI 0.22 to 0.97]). Before-after (n=2) studies provided very low certainty evidence for all outcomes. Evidence from case series (n=34) studies ranged from high to very low certainty.

Conclusion:

Case series studies demonstrated high certainty evidence for the outcomes of death, necrosis, and excessive scarring; however, these are limited in methodological quality. In comparative and before-after studies the evidence ranged from low to very low certainty.
Advances in the treatment of IDH-mutant gliomas
Authors: Baek Chooyoung , Laurenge Alice , Touat Mehdi
Published: September 2024

Purpose of review

Isocitrate dehydrogenase (IDH) mutation is a defining molecular driver of WHO grade 2–4 astrocytomas and oligodendrogliomas. In this article, we review the recent therapeutic approaches specifically targeting IDH-mutant gliomas and summarize ongoing clinical trials in this population.

Recent findings

The IDH inhibitor vorasidenib recently demonstrated its efficacy after surgical resection in grade 2 IDH-mutated gliomas. Several studies in patients with IDH-mutant gliomas are currently exploring various strategies to target IDH mutations, including the use of small-molecule inhibitors, immunotherapies, peptide vaccines and agents targeting metabolic and epigenomic vulnerabilities.

Mutant-IDH targeting holds significant promise in treating progressive or recurrent IDH-mutant gliomas. Recent results with IDH inhibitors will change practice and influence the existing guidelines in a near future.
Patterns of sexual dimorphism in the armoured tardigrades
Authors: Vecchi Matteo , Calhim Sara
Published: September 2024

Sexual dimorphism is widespread among animals, with diverse patterns and proposed explanations observed across the Tree of Life. Here we present the first formal analysis of the patterns of sexual dimorphism in body size and cephalic sensory appendages across 40 species (from 10 genera) of armoured tardigrades (Echiniscidae). Phylogenetic signal was found for body size traits and the cephalic papilla relative size, indicating that the association between these traits between the sexes has high evolutionary persistence. The Echiniscidae body size dimorphism is generally female-biased, which would be in accordance with the fecundity hypothesis. No strong evidence of allometric patterns of body size sexual dimorphism was found. In contrast, some of the cephalic appendages show male-biased sexual dimorphism, particularly those that, by being more innervated, are thought to function as chemodetection organs used by males during mate search. The latter is consistent with the sexual selection hypothesis. As the first systematic quantification and analysis of the patterns of sexual dimorphism in the phylum Tardigrada, this study provides important insights into their ecology and evolution, such as corroborating the suggestion that cephalic appendages evolved for mate searching.
Genome sequence data for 61 isolates of Xanthomonas campestris pv. campestris from brassica crops in Serbia
Authors: Popović Milovanović Tatjana , Greer Shannon , Iličić Renata , Jelušić Aleksandra , Brown Daisy , Hussain Mikaeel , Harrison Jamie , Grant Murray , Vicente Joana , Studholme David John
Published: September 2024

This Data Note describes genome sequencing data for 61 isolates of the bacterial pathogen Xanthomonas campestris pv. campestris collected from Brassica and Raphanus crops between 2010 and 2021 in Serbia. We present the raw sequencing reads and annotated contig-level genome assemblies and we determined the races of ten isolates. The data can be used to test hypotheses, phylogeographic analyses and inform design of informative molecular markers for population genetics studies. When combined with phenotypic data, they could be used to dissect relationships between genotype and phenotypes such as host range and virulence. Finally, these genome sequences expand our inventory of plasmids known to reside in this pathogen.
Genetic heterogeneity in the Salmonella Typhi Vi capsule locus: a population genomic study from Fiji
Authors: Getahun Strobel Aneley , Hayes Andrew J. , Wirth Wytamma , Mua Mikaele , Saumalua Tiko , Cabenatabua Orisi , Soqo Vika , Rosa Varanisese , Wang Nancy , Lacey Jake A. , Hocking Dianna , Valcanis Mary , Jenney Adam , Howden Benjamin P. , Duchene Sebastian , Mulholland Kim , Strugnell Richard A. , Davies Mark R.
Published: September 2024

A corrigendum of this article has been published full details can be found at 10.1099/mgen.0.001310.

Typhoid fever is endemic in many parts of the world and remains a major public health concern in tropical and sub-tropical developing nations, including Fiji. To address high rates of typhoid fever, the Northern Division of Fiji implemented a mass vaccination with typhoid conjugate vaccine (Vi-polysaccharide conjugated to tetanus toxoid) as a public health control measure in 2023. In this study we define the genomic epidemiology of Salmonella Typhi in the Northern Division prior to island-wide vaccination, sequencing 85% (n=419) of the total cases from the Northern and Central Divisions of Fiji that occurred in the period 2017–2019. We found elevated rates of nucleotide polymorphisms in the tviD and tviE genes (responsible for Vi-polysaccharide synthesis) relative to core genome levels within the Fiji endemic S. Typhi genotype 4.2. Expansion of these findings within a globally representative database of 12 382 S. Typhi (86 genotyphi clusters) showed evidence of convergent evolution of the same tviE mutations across the S. Typhi population, indicating that tvi selection has occurred both independently and globally. The functional impact of tvi mutations on the Vi-capsular structure and other phenotypic characteristics are not fully elucidated, yet commonly occurring tviE polymorphisms localize adjacent to predicted active site residues when overlayed against the predicted TviE protein structure. Given the central role of the Vi-polysaccharide in S. Typhi biology and vaccination, further integrated epidemiological, genomic and phenotypic surveillance is required to determine the spread and functional implications of these mutations.
Comparing continuum and direct fiber models of soft tissues. An ocular biomechanics example reveals that continuum models may artificially disrupt the strains at both the tissue and fiber levels
Authors: He Xuehuan , Islam Mohammad R. , Ji Fengting , Wang Bingrui , Sigal Ian A
Published: September 2024

Collagen fibers are the main load-bearing component of soft tissues but difficult to incorporate into models. Whilst simplified homogenization models suffice for some applications, a thorough mechanistic understanding requires accurate prediction of fiber behavior, including both detailed fiber-level strains and long-distance transmission. Our goal was to compare the performance of a continuum model of the optic nerve head (ONH) built using conventional techniques with a fiber model we recently introduced which explicitly incorporates the complex 3D organization and interaction of collagen fiber bundles [1]. To ensure a fair comparison, we constructed the continuum model with identical geometrical, structural, and boundary specifications as for the fiber model. We found that: 1) although both models accurately matched the intraocular pressure (IOP)-induced globally averaged displacement responses observed in experiments, they diverged significantly in their ability to replicate specific 3D tissue-level strain patterns. Notably, the fiber model faithfully replicated the experimentally observed depth-dependent variability of radial strain, the ring-like pattern of meridional strain, and the radial pattern of circumferential strain, whereas the continuum model failed to do so; 2) the continuum model disrupted the strain transmission along each fiber, a feature captured well by the fiber model. These results demonstrate limitations of the conventional continuum models that rely on homogenization and affine deformation assumptions, which render them incapable of capturing some complex tissue-level and fiber-level deformations. Our results show that the strengths of explicit fiber modeling help capture intricate ONH biomechanics. They potentially also help modeling other fibrous tissues.
Hyperglycemia selectively increases cerebral non-oxidative glucose consumption without affecting blood flow
Authors: Blazey Tyler , Lee John J. , Snyder Abraham Z. , Goyal Manu S. , Hershey Tamara , Arbeláez Ana Maria , Raichle Marcus E.
Published: September 2024

Multiple studies have shown that hyperglycemia increases the cerebral metabolic rate of glucose (CMRglc) in subcortical white matter. This observation remains unexplained. Using positron emission tomography (PET) and euinsulinaemic glucose clamps, we found, for the first time, that acute hyperglycemia increases non-oxidative CMRglc (i.e., aerobic glycolysis (AG)) in subcortical white mater as well as in medial temporal lobe structures, cerebellum and brainstem, all areas with low euglycemic CMRglc. Surprisingly, hyperglycemia did not change regional cerebral blood flow (CBF), the cerebral metabolic rate of oxygen (CMRO2), or the blood-oxygen-level-dependent (BOLD) response. Regional gene expression data reveal that brain regions where CMRglc increased have greater expression of hexokinase 2 (HK2). Simulations of glucose transport revealed that, unlike hexokinase 1,HK2is not saturated at euglycemia, thus accommodating increased AG during hyperglycemia.
Age-associated transcriptomic and epigenetic alterations in mouse hippocampus
Authors: Bilgic Merve , Gotoh Yukiko , Kishi Yusuke
Published: September 2024

Aging represents a major risk for human neurodegenerative disorders, such as dementia and Alzheimer’s disease, and is associated with a functional decline in neurons and impaired synaptic plasticity, leading to a gradual decline in memory. Previous research has identified molecular and functional changes associated with aging through transcriptomic studies and neuronal excitability measurements, while the role of chromatin-level regulation in vulnerability to aging-related diseases is not well understood. Moreover, the causal relationship between molecular alterations and aging-associated decline in functions of different cell types remains poorly understood. Here, we systematically characterized gene regulatory networks in a cell type–specific manner in the aging mouse hippocampus, a central brain region involved in learning and memory formation, by simultaneously profiling gene expression and chromatin accessibility at a single nuclei level. The analysis of multiome (RNA and ATAC) sequencing recapitulated the diversity of glial and neuronal cell types in the hippocampus, and allowed revealing transcriptomic and chromatin accessibility level changes in different cell types, among which oligodendrocytes and dentate gyrus (DG) neurons exhibited the most drastic changes. We found that aging-dependent chromatin-level changes were more pronounced than transcriptomic changes for genes related to synaptic plasticity among neurons. Our data suggest that BACH2, a candidate transcription factor in the aging- mediated functional decline of DG neurons, potentially regulates genes associated with synaptic plasticity, cell death, and inflammation during aging.
Three-step scalable production of extracellular vesicles from pancreatic beta cells in stirred tank bioreactors promotes cell maturation and release of ectosomes with preserved immunomodulatory properties
Authors: De Beaurepaire Laurence , Dauphin Thibaud , Pruvost Quentin , Salama Apolline , Dupont Aurelien , Dubreil Laurence , Jegou Dominique , Mignot Gregoire , Mahieu Benjamin , Herve Julie , Lieubeau Blandine , Bach Jean-Marie , Bosch Steffi , Mosser Mathilde
Published: September 2024

Small extracellular vesicles (sEV) released by healthy beta cells are promising candidates for diabetes therapy thanks to their aptitude to modulate inflammation, to induce or maintain pancreatic function and to prevent pathogenic mechanisms. To advance the clinical development of therapeutics, there is a crucial need for scalable production methods. Stirred tank bioreactors (STR) are widely used in the industry due to their ability to provide homogeneous gas and nutrient supply, online monitoring, and efficient scale up. Anchorage-dependent cells can be cultured in STR on microcarriers or as spheroids, but may experience shear stress, which can affect sEV phenotype and function. Using pancreatic beta cells, this study identifies critical cell culturing parameters, including culture mode (monolayer vs. spheroids), medium formulation (with or without serum, glucose control), and process parameters (stirring, duration, cell density). The findings show that small spheroid culture promotes beta cell maturation without decreasing the yield of sEV per cell, despite a reduced cell surface exchange area. However, stirring increased expression of cellular stress markers and decreased cell viability. Set up of a three-step bioprocess allowed to maximize cell viability and sEV yields at high cell density over short production duration. sEV produced under these conditions maintained high purity, membrane integrity, and the aptitude to reduce T-lymphocyte proliferation and IFN-γ cytokine secretion in a mixed lymphocyte reaction. Flow cytometry analysis revealed lower CD63/CD81 ratios in STR, indicating enhanced ectosome production. Switch from high glucose expansion to low glucose production medium further allowed to direct sorting of the antigen insulin into beta-sEV. This study demonstrates the feasibility of producing functional sEV from mature beta cells cultured as small spheroids, suitable for upscale. Production of sEV in STR may be particularly beneficial for ectosome-enriched compound loading for therapeutic applications.
Left Atrial Strain as a Predictor of Cardiac Dysfunction in a Murine Model of Pressure Overload
Authors: Salvas John P. , Moore-Morris Thomas , Goergen Craig J. , Sicard Pierre
Published: September 2024

Aim

Left atrial (LA) strain is emerging as a valuable metric for evaluating cardiac function, particularly under pathological conditions such as pressure overload. This preclinical study investigates the predictive utility of LA strain on cardiac function in a murine model subjected to pressure overload, mimicking pathologies such as hypertension and aortic stenosis.

Methods

High resolution ultrasound was performed in a cohort of mice (n=16) to evaluate left atrial and left ventricular function at baseline and 2- and 4-weeks after transverse aortic constriction (TAC). Acute adaptations in cardiac function were assessed in a subgroup of mice (n=10) with 3-days post TAC imaging.

Results

We report an increase in LA max volume from 11.0 ± 4.3µL at baseline to 26.7 ± 16.7µL at 4 weeks (p=0.002) and a decrease in LA strain from 19.6 ± 4.8% at baseline to 10.1 ± 6.3% at 4 weeks (p=0.006). In the acute phase, LA strain dysfunction was present at 3-days (p<0.001) prior to alterations in LA volume (p=0.856) or left ventricular (LV) ejection fraction (p=0.120). LA strain correlated with key indicators of cardiac performance including left ventricular (LV) ejection fraction (r=0.563,p<0.001), longitudinal strain (r=-0.643,p<0.001) and strain rate (r=0.387,p=0.007). Furthermore, markers of atrial structure and function including LA max volume (AUC=0.858,p<0.001), ejection fraction (AUC=0.901p<0.001), and strain (AUC=0.878,p<0.001) all predicted LV dysfunction.

Conclusion

LA strain and function assessments provide a reliable, non-invasive method for early detection and prediction of cardiac dysfunction in a model of pressure overload.
Introduced trout hinder the recovery of native fish following an extreme flood disturbance
Authors: Lennox Rory S , McIntosh Angus R , Lai Hao Ran , Stouffer Daniel B , Boddy Nixie C , Zammit Christian , Tonkin Jonathan D
Published: September 2024

In rivers, we are seeing a shift away from natural flow regimes towards larger and more frequent extreme drought and flood events. However, it is unclear how increasing intensity and frequency of extreme flow disturbances will play out alongside existing biotic pressures, such as biological invasions, to impact aquatic biodiversity. In New Zealand, vulnerable native non-diadromous galaxiid fishes face pressure from introduced trout through interspecific competition and predation, which may influence the recovery of native galaxiids after flood disturbances. Here, we employed a capture-mark-recapture study across 12 sites, along a gradient of disturbance following a major flood event, to examine the impact of extreme flooding on the population structure of non-diadromous galaxiids (Galaxias vulgaris and G. paucispondylus), and the effect of trout presence on individual galaxiid growth rates recovering from this event. We found a lower abundance of all non-diadromous galaxiid size classes under higher flood magnitudes, but smaller size classes (i.e., young-of-year and 1-2 year cohorts) were more impacted. Furthermore, the presence of trout, whether at low or high abundances, reduced the individual growth of native non-diadromous galaxiids, despite interspecific effects being a weaker regulator of individual growth compared to conspecific effects. Moreover, trout effects on galaxiids varied by both galaxiid size and density, such that growth of smaller individual galaxiids in low densities were most affected by the presence of trout regardless of trout density. In summary, our results demonstrate that non-diadromous galaxiid population dynamics in future are likely to be affected by flood disturbance regimes and introduced trout presence, the outcome of which involves a complex balance between reduced population persistence and increased individual resistance of larger individuals. Conservation efforts that focus on maintaining strategically placed trout-free source populations of adult galaxiids could therefore be an important tool to enable native dispersal into trout-affected habitat and maintain population resilience in the face of increasingly larger and more frequent extreme events, given that recruitment of non-diadromous galaxiids is higher in the absence of trout.
A non-catalytic function for Rad18 in sustaining glioblastoma proliferation
Authors: Kermi Chames , Benbahouche Nour , Stefancikova Lenka , Siegfried Aurore , Pascussi Jean-Marc , Pannequin Julie , Moreaux Jérôme , Egger Tom , Hugnot Jean-Philippe , Delisle Marie-Bernadette , Moyal Elizabeth , Uro-Coste Emmanuelle , Maiorano Domenico
Published: September 2024

The Rad18 E3 ubiquitin ligase, a non-essential gene, is a key regulator of DNA damage tolerance that also functions in repair of DNA double strand breaks. Rad18 is overexpressed in the aggressive brain cancer glioblastoma (GBM) and its downregulation sensitizes glioblastoma cells to DNA damaging agents. Here we show that Rad18 has an essential role in GBM cells proliferation in the absence of external damage, surprisingly independent of its catalytic activity. Rad18 downregulation leads to cell cycle arrest in the G1 phase in the absence of apparent DNA damage. We also show that Rad18 sustains GBM stem cells self-renewal and survival, as well as the growth of tumor orthotropic xenografts in mice. We also show that increased Rad18 expression enhances the growth of non-transformed cells and induces features of oncogenic transformation. Mechanistically, we show that Rad18 downregulation negatively regulates the Hippo pathway by interfering with the nuclear retention of the YAP1 transcription factor. Altogether, these data show that Rad18 has an essential, non-catalytic function, in GBM proliferation, and propose Rad18 as a key target to sensitize GBM to therapy.