bluuebunny/crossref_metadata_2025 huggingface dataset:
P116 A retrospective review of polysomnography results in children referred for suspected obstructive sleep apnoea
Authors: Riach C , Willink R , Teoh L
Published: December 2024

Introduction

Paediatric obstructive sleep apnoea (OSA), if left untreated, can lead to significant morbidity. Adenotonsillar hypertrophy is the most common risk factor, but obese children are also at risk of OSA. Many children undergo adenotonsillectomy without having a prior diagnostic polysomnogram (PSG). We aim to identify risk factors which may predispose to OSA in our referred paediatric cohort.

Methods

This was a retrospective review of children who underwent PSG between Feb 2022-Jan 2024. For categorical variables [sex, ethnicity, co-morbidities (atopy/neuromuscular disease/syndromes)], the primary outcome was OSA (AHI≥1). For continuous variables (age, BMI, OSA-18 score, tonsillar grade), the outcome was Apnoea-Hypopnoea Index (AHI). Five patient groups were considered: full cohort, surgery/no surgery, diagnostic/titration PSG. We obtained p-values for two-sided tests of association between 10 variables and corresponding outcomes, giving 50 tests with critical p-values of 0.05/50=0.0010.

Results

Ninety-six studies were conducted in patients with a median age 7.6 years, range 0.3-16.4. (Diagnostic:Titration, 72:24; Male:Female, 65:31; European:Māori/Pasifika, 55:36). Median BMI was 18.6, range 11.7-57.1. For diagnostic studies (median AHI 2.8/hour, range 0-132.3), a positive association between BMI and AHI is demonstrated (p=0.0001, Kendall τ=0.32, 95% CI 0.16-0.46). The association is stronger when patients with neuromuscular disease/syndromes (28/96) are excluded (p=0.00002, Kendall τ=0.41, 95% CI 0.24-0.56).

Discussion/Conclusion

In children referred for a diagnostic PSG, AHI tends to increase with BMI. Screening for OSA symptoms should be considered in children with a high BMI and a diagnostic PSG performed.
P122 Various factors determine the impact of Caffeine on Athletes’ sleep
Authors: Sajadi Hezaveh Z , Bodur M , Barkell J , Li X
Published: December 2024

Introduction

Athletes are drawn to caffeine due to its perceived performance-enhancing effects. However, it can lead to undesirable effects such as sleeplessness and insomnia. This systematic review aimed to evaluate this potential impact by exploring the literature and existing clinical trials.

Methods

A systematic search was performed across Web of Science, Cinahl, PubMed/MEDLINE, Embase, Cochrane Central Registry of Controlled Trials (CENTRAL), Scopus, and Scienceopen for randomized placebo-controlled clinical trials published from 1980 to December 2023. Full-text screening and quality assessment using RoB-2 tool were performed by two independent researchers. Due to heterogeneity in outcome measures and various reporting strategies, a meta-analysis was not feasible.

Results

Out of 2050 articles, nine studies were deemed eligible for inclusion in this review. Some included studies reported significant reductions or increases in sleep quality following caffeine consumption, while others found no significant changes. Similarly, findings regarding sleep duration, awakenings, sleep efficiency, and sleep onset latency varied across studies. Studies also reported conflicting results regarding insomnia. Studies were categorized as low risk of bias, except for two as unclear, and one as high risk.

Discussion

Overall, caffeine may influence the sleep of athletically trained populations in various ways, dependent on factors such as the timing of caffeine intake relative to exercise and sleep time, and individual characteristics such as habitual caffeine consumption and body weight. This review provides insight into the complex relationship between caffeine supplementation and sleep in athletes, highlighting the need for nuanced understanding and tailored recommendations.
P126 Sleep Regularity and Circadian Alignment Intervention for Improving Mental Health in Athletes (SCIMA): Study Protocol
Authors: Walsh E , Leota J , Drummond S , Liddle S , Facer-Childs E
Published: December 2024

Introduction

Sleep, circadian rhythms, and mental health are reciprocally interlinked. The SCIMA protocol was developed for this study through an iterative co-design process, involving guidance from athletes through qualitative interviews, as well as recommendations from experts. The following protocol aims to a) develop and pilot this intervention in athletes b) determine whether changes in sleep regularity and circadian alignment can lead to improved mental health.

Methods

Approximately 40 athletes will be allocated to the intervention condition. The intervention will be conducted over a period of 4 weeks as well as a prior 2-week baseline assessment. The main guidelines of SCIMA are to establish a regular sleep–wake schedule that has been informed by individual circadian biology. The intervention contains additional components to assist in maintaining this routine, including group psychoeducation, weekly behavioural coaching, light therapy and blue light blocking glasses. Mental health, DLMO, performance and sleep will be assessed pre and post intervention and mood will be tracked through Ecological Momentary Assessment twice daily. Adherence to the intervention will be measured through goal attainment scaling. Wrist worn monitors and daily sleep diaries will be used to track sleep over the baseline/intervention period.

Discussion

There are currently no intervention studies on circadian alignment and sleep regularity for athletes’ mental health. Existing research is mostly cross-sectional and subjective, lacking evidence for causation. Clarifying the relationship between sleep, circadian rhythms, and mental health in professional athletes across different sports and individual characteristics will enhance our understanding of how sleep and circadian health affect their mental well-being.
P130 Predictors of CPAP use in female OSA patients
Authors: Wimms A , Campos-Rodriguez F , Topfer V , Lips A , Fietze I , Willes L , Decker M , Benjafield A , Woehrle H
Published: December 2024

Introduction

It has been shown that quality of life (QoL) can be significantly improved in symptomatic female OSA patients when treated with CPAP. Therefore, we sought to understand the predictors of CPAP compliance in females.

Methods

A post-hoc analysis was conducted on data from a female specific OSA clinical trial. 122 female OSA patients (age 53.7 ± 9.5 years, BMI 32.8 ± 6.2 kg/m2, AHI 39.0 ± 18.2/h) from Germany and Spain had undertaken 3 months of CPAP treatment, with sleep and quality of life metrics collected pre and post CPAP usage. From the 111 patients who completed the study, 75/111 (67.6%) were compliant to CPAP (average usage ≥ 4 h/night). Logistic regression analyses were performed to investigate potential predictors of CPAP compliance, including demographics, comorbidities, sleep parameters, and pre-study quality of life.

Results

Predictors for CPAP compliance in female patients were increased age (p=0.0043), and higher ODI (p=0.0159). There were no relationships (p>0.05) found between CPAP compliance and comorbidities (anxiety, depression, diabetes, heart disease, hypertension, insomnia), or pre-study quality of life metrics (ESS, FOSQ, EQ-5D, PHQ scores). CPAP compliance was a significant factor in improvements in FOSQ and PH-Q scores, but not ESS scores.

Discussion

In this analysis we found that CPAP compliance strongly influenced QoL, measured by the FOSQ and PH-Q. Younger females, and those who have less severe oxygen desaturation indexes, may be more likely to struggle to reach CPAP compliance, and therefore may need additional support when starting CPAP.
P131 The Value of Sleep Psychology
Authors: Winter S , Crocker S , Rolls T , Curtin D , Szollosi I
Published: December 2024

Introduction

Sleep Psychology is a vital but under resourced in the management of sleep disorders. An understanding of the case mix, function and role of sleep psychology within the multidisciplinary team is vital to achieving optimal patient outcomes and service efficiencies.

Methods

Patients referred to sleep psychology in a multidisciplinary sleep service at a major tertiary hospital between 1 June 2023 and 31 May 2024 were included. The primary referral sleep question/s for intervention and number of treatment sessions relative to sleep psychology resource (FTE) was collated.

Results

A total of 184 unique referrals were received for the sleep psychology service over the 12 month period. The most commons sleep complaints for intervention were insomnia (78.8%) and COMISA (47.9%), followed by hypersomnia/excessive daytime sleepiness (19.6%) and CPAP/NIV compliance (17.9%). Other presentations for intervention included trauma (9.8%), irregular sleep-wake cycle (8.7%), central disorders of hypersomnolence (8.2%), as well as less frequent presentations of parasomnias, nightmares, delayed sleep phase disorder and substance misuse. Patients had an average of 1.54 sleep complaints for targeted intervention. On completion of intervention patients were seen for an average of 4.2 appointments representing 593 revenue generating occasions of service from 0.8 FTE of sleep psychology resource. On commencement of a direct to psychology referral pathway for a primary insomnia presentation from July 2023, 14% of referrals to psychology bypassed lengthy physician waitlists to access treatment.

Discussion

Sleep Psychology adds treatment diversity and flexibility to the multidisciplinary management of sleep disorders, improving system efficiencies and patient outcomes.
P132 Feasibility and acceptability of switching from a previous-generation to a new-generation full-face mask for positive airway pressure therapy of sleep apnea using remote care
Authors: Zhu X , Benjafield A , Deas R , Willes L , Girish S , Cheah P , Moodley S , Gray E , Banodkar N , Armitstead J
Published: December 2024

Introduction

Mask selection could affect an individual’s experience with positive airway pressure (PAP) treatment for obstructive sleep apnea, but there is very limited data on the impact of switching to a different mask once established on PAP therapy. This study investigated the patient’s experience when switching from a previous-generation full-face mask (FFM) to a new-generation FFM via remote care.

Methods

A new FFM (AirFit F30i) was successfully fitted to 107 participants during video conferencing sessions. Participants completed online questionnaires on day 1, day 3, day 7, day 30 and day 90 after FFM switch to collect subjective feedback and quality of life data; objective PAP device data were also downloaded.

Results

Residual apnea-hypopnea index did not significantly differ from baseline at day 30 (0.2±1.1/h [p=0.142]) or day 90 (0.2±1.0/h [p=0.061]). Average daily usage was significantly increased from baseline at day 30 (+0.4±1.5 h/day [p=0.033]) but not day 90 (+0.2±1.4 h/day [p=0.216]). Functional Outcomes of Sleep Questionnaire (FOSQ-10) score was similar at baseline and day 90 (change from baseline to day 90: 0.43±2.57 [p=0.174]). Subjective ratings for comfort, seal, and usability of the new-generation FFM were significantly better than the predefined acceptability level. Rates of PAP-related side effects were generally acceptable.

Discussion

Remote management of mask change was associated with good outcomes in terms of objective device data and patient acceptability. This approach could be used to improve the overall therapy experience for individuals requiring a PAP therapy mask change for any reason.
Simulated burn pit smoke condensates cause sustained impact on human airway epithelial cells
Authors: Ghosh Arunava , Rogers Jr. Keith L , Gallant Samuel C , Brocke Stephanie A , Speen Adam M , Kim Yong Ho , Gilmour M Ian , Randell Scott H , Jaspers Ilona
Published: December 2024

Inhalation of smoke from burn pits during military deployment is associated with several adverse pulmonary outcomes. We exposed human airway epithelial cells to smoke condensates from burn pit waste materials. Single and repeated exposure to condensates triggered unique and common responses in terms of gene expression that were sustained through the recovery phase. Source material and combustion condition influenced the outcome. Intensified response in female donor cells indicated a determining role of biological sex. The observations indicate a lasting impact of burn pit smoke exposure on epithelial gene expression, potentially contributing to disease pathogenesis.
The thermal optimum of photosynthetic parameters is regulated by leaf nutrients in neotropical savannas
Authors: de Sousa Oliveira Tony César , Veenendaal Elmar , Domingues Tomas Ferreira
Published: December 2024

Global warming significantly threatens species in the Cerrado, the world’s largest savannah. Therefore, understanding how plants respond to temperature change, particularly in relation to leaf-level photosynthetic capacity, is crucial to understanding the future of Cerrado vegetation. Here, we determined the optimum temperature of the maximum rate of RuBP-carboxylation and maximum electron transport rate (TOptV and TOptJ, respectively) of 12 tree species in two opposite borders (northeastern and southeastern) of the Cerrado with distinct temperature regimes. We focused on four widespread species found in both sites, four restricted to the northeast, and four to the southeast. We compared TOptV and TOptJ between regions and between widespread species (co-occurring in both sites) and species restricted to each ecoregion. Additionally, we also explored the relationship between TOptV and TOptJ with leaf nitrogen (N), phosphorus (P) and potassium (K). As a result, we found that TOptV and TOptJ values were similar across species, regardless of the study region or species distribution range. The similarity of TOpt values among species suggests that photosynthetic performance is optimized to current temperatures. Additionally, we also observed that the TOptV and TOptJ were similar to the local maximum ambient temperatures. Therefore, if these species do not have enough plasticity, the increasing temperature predicted for this region may reduce their photosynthetic performance. Finally, the studied species exhibited general relationships between the TOptV and TOptJ and foliar key nutrients, particularly with P, suggesting the nutrient availability has an important role in the thermal acclimation of leaves. These findings offer valuable insights into physiological and ecological mechanisms in photosynthesis performance present in the Cerrado species.
Evaluation of the relationship between day or night birth time and morbidities and mortality in premature infants less than 32 weeks in a Turkish NICU
Authors: Akin Mustafa Senol , Cakir Ufuk
Published: December 2024

Staffing levels, fatigue, and intervention timing may vary based on working hours and potentially influence the clinical outcomes of newborns. It remains unclear how the birth time of premature infants throughout the day affects their clinical outcome. This study aimed to compare the clinical outcomes of premature infants born during and after work hours. In this single-center retrospective cohort study, infants born at <32 weeks of age were categorized into two groups based on birth time. The first group included infants born during daytime working hours on weekdays, whereas the second group included infants born during nighttime working hours on weekdays, weekends, and public holidays. Both groups were compared in terms of clinical outcomes. Data from 572 patients born at <32 weeks of age were analyzed, with 137 (24%) infants in the on-hours group and 435 (76%) in the off-hours group. No significant differences were observed between the groups in terms of gestational age (GA) (27.4 ± 2.8 weeks vs. 27.7 ± 2.7 weeks), birth weight (BW) (1132 ± 459 g vs. 1064 ± 450 g), and gender distribution (53.2% vs. 55.4% male) (P > .05). There were no significant differences in other clinical outcomes, morbidities, or mortality rates between the groups (P > .05). Despite potential fluctuations in neonatal intensive care unit (NICU) staffing levels during on- and off-duty hours, the morbidity and mortality of premature infants aged <32 weeks were not affected in our unit. Each NICU should assess whether delivery time influences clinical outcomes, based on unique care conditions. The change in clinical outcomes depending on the time of birth may be particularly important in low- and middle-income countries (LMIC). Negative results may be an indication that the staff is under excessive workload. In addition, by providing a solution to the cause of the detected problem, both clinical outcomes may be improved and patient care costs due to morbidity may be reduced. Our results may be particularly important for studies to be conducted on this subject in LMIC.
Increase of niche filling with increase of host richness for plant-infecting mastreviruses
Authors: Ben Chéhida Sélim , Devi Bunwaree Heemee , Hoareau Murielle , Moubset Oumaima , Julian Charlotte , Blondin Laurence , Filloux Denis , Lavergne Christophe , Roumagnac Philippe , Varsani Arvind , Martin Darren P , Lett Jean-Michel , Lefeuvre Pierre
Published: December 2024

Now that it has been realized that viruses are ubiquitous, questions have been raised on factors influencing their diversity and distribution. For phytoviruses, understanding the interplay between plant diversity and virus species richness and prevalence remains cardinal. As both the amplification and the dilution of viral species richness due to increasing host diversity have been theorized and observed, a deeper understanding of how plants and viruses interact in natural environments is needed to explore how host availability conditions viral diversity and distributions. From a unique dataset, this study explores interactions of Mastrevirus species (family Geminiviridae) with Poales order hosts across 10 sites from three contrasting ecosystems on La Réunion. Among 273 plant pools, representing 61 Poales species, 15 Mastrevirus species were characterized from 22 hosts. The analysis revealed a strong association of mastreviruses with hosts from agroecosystems, the rare presence of viruses in coastal grasslands, and the absence of mastreviruses in subalpine areas, areas dominated by native plants. This suggests that detected mastreviruses were introduced through anthropogenic activities, emphasizing the role of humans in shaping the global pathobiome. By reconstructing the realized host–virus infection network, besides revealing a pattern of increasing viral richness with increasing host richness, we observed increasing viral niche occupancies with increasing host species richness, implying that virus realized richness at any given site is conditioned on the global capacity of the plant populations to host diverse mastreviruses. Whether this tendency is driven by synergy between viruses or by an interplay between vector population and plant richness remains to be established.
Minimum inhibitory concentrations of extended spectrum cephalosporins: A systematic review and meta-analysis of Neisseria gonorrhoeae treatment failures
Authors: Miari Victoria Fotini , Mosoff Jonna Messina , Chico R Matthew
Published: December 2024

Background

Neisseria gonorrhoeae is one of the recognised global antimicrobial resistance priorities. Extended spectrum cephalosporins, the last remaining reliable antimicrobial, increasingly fail to clear N. gonorrhoeae infections, especially pharyngeal gonorrhoea, leading to limited future treatment options.

Methods

We conducted a systematic review and meta-analysis of gonococcal treatment failures and compared the minimum inhibitory concentrations (MIC) of isolates from pharyngeal and extra-pharyngeal anatomical sites (PROSPERO registration: CRD42020189101).

Results

The overall pooled mean MIC for cefixime was 0.17 mg/L (95% [CI]: 0.07, 0.41) and ceftriaxone was 0.10 mg/L (95% [CI]: 0.05, 0.22). For cefixime, the mean MIC estimates for pharyngeal and extra-pharyngeal treatment failures were 0.05 mg/L (95% [CI]: 0.02, 0.14) and 0.29 mg/L (95% [CI]: 0.11, 0.81), and for ceftriaxone 0.09 mg/L (95% [CI]: 0.03, 0.22) and 0.14 mg/L (95% [CI]: 0.03, 0.73), respectively. The pooled mean MICs for pharyngeal isolates are below the phenotypic European Committee on Antimicrobial Susceptibility Testing (EUCAST) resistance breakpoint for both antimicrobials (>0.125 mg/L).

Conclusions

Our findings underscore the need to review the current resistance breakpoints used for pharyngeal infection and the urgency to establish international standards for MIC testing, and advance efforts of the World Health Organization’s global action plan to control the spread and impact of antimicrobial resistance in N. gonorrhoeae. Ongoing susceptibility testing of gonococcal isolates and surveillance of treatment failures are central to informing appropriate public health responses.
The Effect of Using a Standardized Questionnaire on Sexual History Documentation and Testing to Diagnose Gonorrhea and Chlamydia Among Men Who have Sex with Men with HIV
Authors: deMontigny Avila Danielle , Rabe Brooke , Aravagiri Arunmozhi , Joseph Martin , Lim James Ray M. , Naveed Maryam , Rappel Raina , Villanueva Berna , Khandekar Maithili , Zinkeng Atehkeng , Yates Sarah , Fantry Lori E.
Published: December 2024

Background: Most Neisseria gonorrhoea (GC) and Chlamydia trachomatis (CT) infections in men who have sex with men (MSM) are diagnosed at extragenital sites. However, testing at these sites is often lacking. The purpose of this study was to determine if a standardized questionnaire administered by physicians and clinical assistants improves documentation of sex activity and increases extragenital testing and diagnoses of GC and CT among MSM.

Methods: A standardized sexual history questionnaire was implemented on 11/1/2022. Electronic medical records of 664 MSM with HIV, including 1064 encounters, were reviewed to compare pre- and post- implementation sexual history documentation, adequacy of documentation, extragenital GC and CT testing, and GC and CT diagnoses. Analysis included Chi-square and exact tests and logistic regression adjusting for physician cluster effects.

Results: The standardized questionnaire was used by 53.7% of physicians and 85.9% of coordinators. Documentation of whether sexual activity occurred increased from 79.3% [95%confidence interval (CI) 0.758- 0.828] in the pre-intervention pre-COVID-19 period to 95.2% (95% CI 0.925-0.970) in the post-intervention period with an adjusted odds ratio of 4.7 (95% CI 2.7-8.8). Specific questions about anal and oral sex increased from 42.0% to 88.1% (p < 0.001) and 23.7% to 88.7% (p < 0.001), respectively. Anal and pharyngeal testing increased from 14.4% to 20.2% (p = 0.040) and 17.2% to 23.3% (p = 0.045), respectively.

Conclusions: This study demonstrates that using a standardized questionnaire during clinical encounters can improve documentation of sexual activity and testing for GC and CT at extragenital sites.
Protective Behaviors Following Digital COVID-19 Exposure Notifications, Washington State, September 1, 2021, to March 1, 2022
Authors: Briggs Nicole L. , Guthrie Brandon L. , Elder Adam S. , Revere Debra , Molino Andrea R. , West Laura M. , Higgins Amanda , Karras Bryant T. , Baseman Janet G.
Published: December 2024

Context:

Digital exposure notification (EN) systems were widely used to supplement public health case investigations and contact tracing during the 2019 coronavirus disease (COVID-19) pandemic. In Washington State, the state Department of Health (DOH) implemented one such system, WA Notify, which generated ENs based on smartphone Bluetooth proximity detection. However, the privacy preserving measures of this technology prevented collection of information on how users responded after seeing an EN on their device.

Objective:

To understand the influence of ENs on intended and implemented protective behaviors among WA Notify users.

Design:

Two self-report surveys were administered by the WA DOH: a baseline survey regarding planned protective behaviors, available immediately after seeing an EN, and a follow-up survey distributed 2 weeks later regarding actual protective behaviors implemented. Self-reported planned and implemented protective behaviors were compared across 3 time periods relevant to the COVID-19 pandemic. Poisson regression was used to compare the probability of engaging in various protective behaviors across demographic characteristics and other contextual factors.

Setting:

Washington State.

Participants:

A total of 4280 individuals who chose to respond to both surveys and who completed the initial survey between September 1, 2021, and March 1, 2022.

Main Outcome Measure(s):

Self-reported plans for and engagement in protective behaviors (quarantining, testing, and symptom watching).

Results:

The proportion of individuals who reported implementing quarantining and symptom watching after seeing an EN was higher than the proportion that reported planning to engage in each respective behavior. Respondents who reported experiencing symptoms when seeing an EN were more likely to quarantine and test for COVID-19 compared to those with no symptoms.

Conclusion:

Plans to engage in protective behaviors after initially seeing an EN can change and may be influenced by evolving personal and contextual factors. Future digital EN systems can be improved through messaging tailored to encourage protective behaviors relevant to disease prevention.
M102, a combined NRF2 and HSF-1 activator for neuroprotection in amyotrophic lateral sclerosis
Authors: Keerie Amy F. , Martins Raquel Rua , Allen Chloe F. , Bowden Katie , Al Mashhadi Sufana , Marlow Thomas , Myszczynska Monika , Thakur Nikitha , Beal Selina N. , Shaw Allan , Suresh Shivani , McKinnon Scott N. , Daniel Alex , Wells Tyler , Kalfus Ira N. , Shan Ning , Shaw Pamela J. , Ferraiuolo Laura , Mead Richard J.
Published: December 2024

M102 is a central nervous system (CNS) penetrant small molecule electrophile which activatesin vivothe NFE2-related factor 2 antioxidant response element (NRF2-ARE) pathway, as well as transcription of heat-shock element (HSE) associated genes. In the TDP-43Q331Ktransgenic mouse model of ALS dosed subcutaneously at 5mg/kg OD or 2.5mg/kg BD with M102, significant improvements in compound muscle action potential (CMAP) amplitude of hind limb muscles and gait parameters were observed at 6 months of age, with associated target engagement.

An oral dose response study of M102 in SOD1G93Atransgenic mice showed a dose-dependent improvement in the CMAP of hindlimb muscles which correlated with preservation of lumbar spinal motor neurons at the same time point. These data enabled prediction of human efficacious exposures and doses, which were well within the safety margin predicted from Good Laboratory Practice (GLP) toxicology studies.

A parallel program of workin vitroshowed that M102 rescued motor neuron survival in co-culture with patient-derived astrocytes from sporadic,C9orf72andSOD1cases. Markers of oxidative stress, as well as indices of TDP-43 proteinopathy were also reduced by exposure to M102 in thesein vitromodels.

This comprehensive package of preclinical efficacy data across two mouse models as well as patient-derived astrocyte toxicity assays, provides a strong rationale for clinical evaluation of M102 in ALS patients. Combined with the development of target engagement biomarkers and the completed preclinical toxicology package, a clear translational pathway to testing in ALS patients has been developed.

One Sentence Summary

M102, a dual NRF2/HSF1 activator, slows disease progression in 2 mouse models and exerts neuroprotection in human cellular models of ALS.
The strength of selection for costly toxin production increases with growth rate
Authors: Bisesi Ave T. , Chacón Jeremy M. , Smanski Michael J. , Harcombe William R.
Published: December 2024

Microbes adopt a diversity of strategies to successfully compete with coexisting strains for space and resources. One common strategy is the production of toxic compounds to inhibit competitors, but the strength and direction of selection for this strategy varies depending on the environment. In particular, existing theoretical and experimental evidence suggests growth in spatially-structured environments makes toxin production more beneficial because competitive interactions are localized. Because higher growth rates increase the localization of resource competition in a structured environment, theory predicts that toxin production should be especially beneficial under these conditions. We tested this hypothesis by developing a genome-scale metabolic modeling approach and complementing it with comparative genomics to investigate the impact of growth rate on selection for costly toxin production. Our modeling approach expands the current abilities of the dynamic flux balance analysis platform COMETS to incorporate signaling and toxin production. Using this capability, we find that our modeling framework predicts that the strength of selection for toxin production increases as growth rate increases. This finding is supported by comparative genomics analyses that include diverse microbial species. Our work emphasizes that toxin production is more likely to be maintained in rapidly-growing, spatially-structured communities, thus improving our ability to manage critical microbial communities and informing natural product discovery.
Visible neural networks for multi-omics integration: a critical review
Authors: Selby David Antony , Jakhmola Rashika , Sprang Maximilian , Grossmann Gerrit , Raki Hind , Maani Niloofar , Pavliuk Daria , Ewald Jan , Vollmer Sebastian J
Published: December 2024

Biomarker discovery and drug response prediction is central to personalized medicine, driving demand for predictive models that also offer biological insights. Biologically informed neural networks (BINNs), also known as visible neural networks (VNNs), have recently emerged as a solution to this goal. BINNs or VNNs are neural networks whose inter-layer connections are constrained based on prior knowledge from gene ontologies pathway databases. These sparse models enhance interpretability by embedding prior knowledge into their architecture, ideally reducing the space of learnable functions to those that are biologically meaningful. In this systematic review-the first of its kind-we identify 86 recent papers implementing such models and highlight key trends in architectural design decisions, data sources and methods for evaluation. Growth in popularity of the approach is apparently mitigated by a lack of standardized terminology, tools and benchmarks.
Motor imagery and execution activate similar finger representations that are spatially consistent over time
Authors: Odermatt Ingrid Angela , Schönberg Laura , Heimhofer Caroline , Freund Patrick , Wenderoth Nicole , Kikkert Sanne
Published: December 2024

Finger representations in the sensorimotor cortex can be activated even in the absence of somatosensory input or motor output through mere top-down processes, such as motor imagery. While executed finger movements activate finger representations in the primary sensorimotor cortex that are spatially consistent over time within participants, the stability of top-down activated finger representations remains largely unexplored. Given the increasing use of top-down activated sensorimotor representations to both plan implantation of and control brain-computer interfaces, it is crucial to understand the stability of these representations. Here, we investigated the spatial consistency, and thereby reliability, of finger representations activated through motor imagery in the primary somatosensory and primary motor cortex over time. To assess this, participants performed imagined and executed individual finger movements in two 3T fMRI sessions that were ∼2 weeks apart. We observed highly consistent univariate finger-selective activity clusters and multivariate vertex-wise activity patterns within participants over time in both the motor imagery and motor execution task. Using a multivariate across-task decoding approach, we further found that motor execution and motor imagery activate similar finger representations in both the primary somatosensory and primary motor cortex. This demonstrates that motor imagery can be used to identify finger representations related to movement execution. Our findings not only validate the use of top-down processes for brain-computer interface planning and control, but also open up new opportunities for the development of sensorimotor training interventions that do not rely on overt movements.
Biomechanical resilience of the femoral neck post-remission of Cushing’s Syndrome: a comparative analysis using QCT-based Finite Element models
Authors: Soudah Eduardo , Giuliodori Agustina , Hernández Joaquín A.
Published: December 2024

This study aims at evaluating femoral bone-related mechanical properties in female patients with long-term remission of Cushing’s Syndrome (CS). Sixty-four female subjects were included in this study and stratified in two groups: (a) 32 long-term remission of CS patients, and (b) 32 healthy (paired) control subjects. Quantitative Computed Tomography (QCT) was used to derive patient-specific Finite Element (FE) models. A sideways-fall impact was simulated for each subject and the resulting stress and strain values were compare among the two different groups. Our findings indicate that women with CS in remission exhibit impaired biomechanical properties in the femoral neck compared to controls, suggesting compromised bone properties in this population.
Femoral bone growth predictions based on personalized multi-scale simulations: Validation and sensitivity analysis of a mechanobiological model
Authors: Koller Willi , Svehlik Martin , Wallnöfer Elias , Kranzl Andreas , Mindler Gabriel , Baca Arnold , Kainz Hans
Published: December 2024

Musculoskeletal function is pivotal to long-term health. However, various patient groups develop torsional deformities, leading to clinical, functional problems. Understanding the interplay between movement pattern, bone loading and growth is crucial for improving the functional mobility of these patients and preserving long-term health.

Multi-scale simulations in combination with a mechanobiological bone growth model have been used to estimate bone loads and predict femoral growth trends based on cross-sectional data. The lack of longitudinal data in previous studies hindered refinements of the mechanobiological model and validation of subject-specific growth predictions, thereby limiting clinical applications.

This study aimed to validate the growth predictions using magnetic resonance images and motion capture data - collected longitudinally - from ten growing children. Additionally, a sensitivity analysis was conducted to refine model parameters.

A linear regression model based on physical activity information, anthropometric data, and predictions from the refined mechanobiological model explained 70% of femoral anteversion development. Notably, the direction of femoral development was accurately predicted in 18 out of 20 femurs, suggesting that growth predictions could help to revolutionize treatment strategies for torsional deformities.

Statements and Declarations

The authors have no relevant financial or non-financial interests to disclose.
Anti-fibrotic Effects of Atorvastatin Delivered via Keratin-based Hydrogels
Authors: Carroll Evan , Tarabokija Andrew , Chaudhry Henna , Meer Allison , de Guzman Roche C.
Published: December 2024

Implantations of degradable biomaterials for drug delivery or restoration and regenerative medicine cause fibrosis and acute inflammation which may lead to chronic side effects. Additionally, the fibrous encapsulation can itself inhibit the local cells from proliferating and forming new healthy tissue. Current drug delivery models require a new method to decrease the adverse effects following implantation of biomaterials in patients and inhibit the activation signaling sent to quiescent fibroblasts. This research details the novel chemical and physical properties of reduced keratin (KTN) hydrogels extracted from residual human hair with sheared cuticle layers, obtained from barbershops and beauty salons. KTN hydrogels with and without calcium ions conjugated with atorvastatin (Ator), which is thought to affect TGF-ß signaling pathways directly by competitively inhibiting key signal transmitters and cellular responses, were investigated via electron microscopy, absorbance spectroscopy, and computational modeling and simulation to observe the proliferative inhibition of fibroblastic cells in comparison to the alginate hydrogel controls. Hydrogel extracts were tested for non-cytotoxic effects via L929 adipose fibroblast cell culture following ISO 10993-5 standard for safety of medical device biomaterials. Two cell models were exposed to increasing serial concentrations of Ator to evaluate the half maximal effective concentration (EC50). For quiescent fibroblasts, Ator’s EC50was observed at 368 μM in PBS. For mesenchymal stem cells (MSCs), Ator’s EC50was observed at 209 μM in PBS. The mass of drug was normalized in all groups after calculating their timed absorption and release, and KTN hydrogels conjugated with calcium ions and Ator (ATCK) completely absorbed the drug < 0.5 h while KTN hydrogels with Ator alone (ATKR) completely absorbed the drug at 1h. After 7d in PBS, ATCK released Ator at 2.2 ± 0.7% while Ator in calcium alginate spheres (ATLG) was released at 7.8 ± 1.1% and ATKR released 11.2 ± 4.3% of drug. On-going research focuses on other active fibroblastic cell types andin vivoexperimentation to observe foreign body response in subcutaneous mouse tissue.
Extracellular adenosine deamination primes tip organizer development inDictyostelium
Authors: Hathi Pavani , Baskar Ramamurthy
Published: December 2024

Ammonia is a morphogen inDictyosteliumand is known to arise from the catabolism of proteins and RNA. However, we show that extracellular adenosine deamination catalyzed by adenosine deaminase related growth factor (ADGF), is a major source of ammonia and demonstrate a direct role of ammonia in tip organizer development. The tip formed during early development inDictyosteliumis functionally similar to the embryonic organizer of higher vertebrates.adgfmutants fail to establish an organizer and this could be reversed by exposing the mutants to volatile ammonia. Interestingly, bacteria physically separated from theadgf−mounds in a partitioned dish also rescues the mound arrest phenotype suggesting a cross kingdom interaction driving development. Both the substrate, adenosine and the product, ammonia regulateadgfexpression, andadgfacts downstream of the histidine kinasedhkDin regulating tip formation. Thus, the consecutive transformation of extracellular cAMP to adenosine, and adenosine to ammonia are integral steps duringDictyosteliumdevelopment. Remarkably, in higher vertebrates,adgfexpression is elevated during gastrulation and thus adenosine deamination may be an evolutionarily conserved process driving organizer development.
A Mathematical Framework for the Quantitative Analysis of Genetic Buffering
Authors: Karagiannis Jim
Published: December 2024

Genetic buffering plays a pivotal role in orchestrating the relationship between genotype and phenotype in outbred populations. While high-throughput screens have identified many instances of genetic buffering – through the detection of “synthetic lethality” or “synthetic sickness” – a formal and general method for its quantitative analysis across systems is lacking. In this report, an axiomatic mathematical framework that can be used to classify, quantify, and compare buffering relationships between genes is described. Importantly, this methodology employs a ratio scale as its basis, thereby permitting the definition of a novel neutrality model for gene interaction that is referred to as the “parallel” model. This model does not contradict, and instead complements, the commonly used “product” model (more aptly referred to herein as the “serial” neutrality model). Moreover, simple extensions of this newly developed framework permit the unambiguous definition and classification of gene interactions in a formal, general, and mathematical way. Consequently, the concept of genetic buffering as first conceived by Leland Hartwell becomes a specific case within a comprehensive model of gene interaction.
Identification and Pharmacological Characterization of Multiple Allosteric Binding Sites on the Free Fatty Acid 1 Receptor
Authors: Chaturvedi Siddhant , Venka Krishna , Singh Rahul , Kumar Mohandas
Published: December 2024

Free fatty acid receptor 1 (FFA1 or GPR40), activated by medium- and long-chain fatty acids, amplifies glucose-stimulated insulin secretion, making it a promising target for type 2 diabetes. Radioligand studies revealed distinct binding sites for partial and full agonists, with full agonists showing positive cooperativity. Functional assays demonstrated positive cooperativity between agonists and varying interactions with the endogenous fatty acid DHA. These findings suggest three allosterically linked binding sites on FFA1, with activation influenced by key arginine residues. Potent ligands with strong cooperativity hold significant therapeutic potential.
Peptide Information Compression Technology (PICT): A New Frontier in Therapeutic Peptide Discovery
Authors: Wang Hong , Wang Zhu-Yin , Jiang Wei-Ming , Wang Qin-Qin , Miao Lin , Wang Deng , Wang Hai-Tao , Tung Shiu-Feng , Yang Jin-Rui , Yang Bin , Liang Xu-Bo , Li Zhen-Wan , Wang Xue-Ping , Zou Sheng , He Feng , Guo Xiao-Tao , Yan Yuan , Xu Kai-Min , Wang Xiao-Qi , Wang Xin-Bo , Liu Hui-Qing , Li Xiang-Qun
Published: December 2024

Therapeutic peptides hold tremendous market potential, yet the discovery methods for active peptides lag considerably behind those for small molecules and biological macromolecule drugs. Due to their respective limitations, traditional peptide compound synthesis and display libraries fail to meet the growing demands of the peptide drug market. Here, we introduce a novel Peptide Information Compression Technology (PICT) and, based on this technology, a large-scale physical peptide library and its accompanying high-throughput screening (HTS) platform. By screening for inhibitors of TSLP/TSLPR/IL7Rα and antagonists of MC3R at both the molecular and cellular levels, we have identified active molecules in the single-digital micromolar and nanomolar ranges, respectively. This demonstrates the immense application value of Peptide Information Compression Technology in the efficient discovery of peptide drugs.
Deconvoluting TCR-dependent & -independent activation is vital for reliable Ag-specific CD4+T cell characterization by AIM assay
Authors: Zheng Ming Z. M. , Burmas Lauren , Tan Hyon-Xhi , Trieu Mai-Chi , Lee Hyun Jae , Rawlinson Daniel , Haque Ashraful , Kent Stephen J. , Wheatley Adam K. , Juno Jennifer A.
Published: December 2024

AIM assays are thought to detect antigen (Ag)-specific T cell responses in an HLA- and cytokine-independent manner. Recent studies using AIM assays identified prominent Th17-like (CCR6+) CD4+T cells and circulating follicular T helper cells (cTfh) in anti-viral contexts, but were not observed with peptide/HLA tetramer staining. We demonstrate that CD39+Treg-like and CD26hiTh22-like cells can be activated by cytokines in a TCR-independent manner duringin vitroAg stimulation, leading to non-specific upregulation of prototypical AIM readouts. Transcriptional analysis of memory CD4+T cells that underwent TCR-dependent or -independent activation enabled discrimination ofbona fideAg-specific T cells from cytokine-activated Treg and Th22 cells. CXCR4 downregulation emerged as a hallmark of clonotypic expansion and TCR-dependent activation in memory CD4+T cells and cTfh. Tracking tetramer-binding cells during re-stimulation showed that CXCR4-CD137+cells provide a more accurate measure of the Ag-specific population than standard AIM readouts. This modified assay excludes the predominately CCR6+cytokine-activated T cells that contribute to an average 12-fold overestimation of the Ag-specific population. As AIM assays enable the rapid study of T cell responses against emerging pathogens, our findings provide a highly accurate approach to characterize genuine Ag-specific T cell responses that contribute to protective immunity.
Epigenetic reprogramming induced by Acetyl-CoA and SAM depletion is an evolutionarily-ancient path to malignant growth
Authors: Chen Zhe , Zhang Xiaomeng , Deng Mingxi , Li Chongyang , Nguyen Thi Thuy , Liu Min , Dou Kun , Ishibashi Toyotaka , Wang Jiguang , Yan Yan
Published: December 2024

Despite the vast diversity of life forms and living histories, it appears that all branches of Metazoa face the challenge of tumor growth. Contrary to human tumors, which take years to form, tumors in short-living species can arise within days without accumulating multiple mutations, raising the question whether the paths to tumorigenesis in diverse species have any commonalities.

In a fly tumor model caused by loss of cell polarity genes, we first identified the rise of a glycolytic cell population over time, resembling the Wartburg effect observed in human tumors. We further identified two key metabolic changes in these fly tumors. First, a systemic depletion of acetyl-CoA leads to a reduction in histone acetylation levels and stochastic silencing of actively-transcribed genes. Second, defects in the methionine cycle cause a systemic depletion of S-Adenosyl methionine, which further reduces histone methylation levels and causes stochastic activation of transposons. Perturbation of the methionine metabolic process strongly inhibits tumor growth. Finally, to understand the evolutionary origin of tumorigenesis, we performed comparative studies of fly and human tumors, and identified human tumors that exhibit metabolic signatures similar to those of fly tumors. We found that human tumors with high metabolic similarity to fly tumors have a lower mutational load, younger patient age, and lower DNA methylation levels. This study suggests that tumorigenesis processes have a deep evolutionary origin and highlights that depletion of key metabolites is an evolutionarily-ancient driving force for tumorigenesis.
Mitochondrial adenine base editing of mouse somatic tissues via adeno-associated viral delivery
Authors: Mutti Christian D. , Van Haute Lindsey , Luengo-Gutierrez Lucia , Turner Keira , Silva-Pinheiro Pedro , Minczuk Michal
Published: December 2024

The development of adenine base editing in mitochondria, alongside cytidine base editing, has significantly expanded the genome engineering capabilities of the mitochondrial DNA. We tested the recent advancements in adenine base editing technology using optimised TALEs targeting genesMt-Cytb, Mt-CoIIandMt-Atp6in mouse cells, and observed successful A:T to G:C conversions within the target windows of each gene. Then, we used the best performing pairs targeting theMt-Atp6gene to inject mice using adeno-associated viral delivery to post-mitotic tissue. We observed limited efficiency of adenine edits in mouse somatic tissue after 4 weeks, suggesting the necessity of further optimisation of this technology.