bluuebunny/crossref_metadata_2025 huggingface dataset:
MEGA-GO: functions prediction of diverse protein sequence length using Multi-scalE Graph Adaptive neural network
Authors: Lee Yujian , Gao Peng , Xu Yongqi , Wang Ziyang , Li Shuaicheng , Chen Jiaxing
Published: January 2025

Motivation

The increasing accessibility of large-scale protein sequences through advanced sequencing technologies has necessitated the development of efficient and accurate methods for predicting protein function. Computational prediction models have emerged as a promising solution to expedite the annotation process. However, despite making significant progress in protein research, graph neural networks face challenges in capturing long-range structural correlations and identifying critical residues in protein graphs. Furthermore, existing models have limitations in effectively predicting the function of newly sequenced proteins that are not included in protein interaction networks. This highlights the need for novel approaches integrating protein structure and sequence data.

Results

We introduce Multi-scalE Graph Adaptive neural network (MEGA-GO), highlighting the capability of capturing diverse protein sequence length features from multiple scales. The unique graph adaptive neural network architecture of MEGA-GO enables a more nuanced extraction of graph structure features, effectively capturing intricate relationships within biological data. Experimental results demonstrate that MEGA-GO outperforms mainstream protein function prediction models in the accuracy of Gene Ontology term classification, yielding 33.4%, 68.9%, and 44.6% of area under the precision-recall curve on biological process, molecular function, and cellular component domains, respectively. The rest of the experimental results reveal that our model consistently surpasses the state-of-the-art methods.

Availability and implementation

The source code and data of MEGA-GO are available at https://github.com/Cheliosoops/MEGA-GO.
Visual social cues and habitat structure influence the behaviour of a nonsocial insect
Authors: Marcantonio Matteo , Le Levier Mathilde , Kourtidis Argiris , Masier Stefano
Published: January 2025

Habitat fragmentation and loss is a known threat to biodiversity. Their combined effect leaves organisms in small isolated habitat patches, contributing to the current biodiversity crisis. The first response of animals to environmental change is typically behavioural. Beyond the physical elements of the environment, the ‘social landscape’ shapes the spatial distribution of the habitats available to organisms. Here, we test the hypothesis that visual social cues and habitat structure alter behaviours in a nonsocial insect, the wood white butterfly (Leptidea sinapis, Linnaeus 1758). We tested 85 wild-caught female individuals from landscapes with various habitat structures in outdoor cages reproducing habitats with or without visual social cues. We demonstrate that the presence of same-sex congeners is a social signal to remain within a suitable patch of habitat. We further show that habitat structure is associated with oviposition success and investment in navigation but not with emigration. Butterflies from smaller, more fragmented habitat patches relied more on routine movement and had lower oviposition success compared with those from larger, less fragmented patches (except at the highest temperatures). Many insect species in Europe, including L. sinapis, are reportedly in decline. Our results indicate the importance of considering both physical and social landscape elements when assessing the impacts of landscape changes on insect behaviour, and consequently in the planning of conservation and habitat restoration efforts. Applying this approach to other nonsocial insects will be critical to fully understand how habitat structure influences their populations and contributes to declines.
BHSo5 A systematic review of randomized trials of weight loss before hernia surgery
Authors: Mclurcan Nadia , Findlay John
Published: January 2025

Introduction

Obesity is one of the main modifiable risk factors of outcome following hernia surgery, and is strongly associated with hernia recurrence and complications. For this reason weight loss is strongly recommended before hernia surgery. However, weight loss can be extremely difficult for patients to achieve. A number of interventions have been described, however, the evidence for this before hernia surgery is unclear. The aim of this study was to systematically review the evidence for randomized controlled trials (RCTs) assessing weight loss interventions before hernia surgery.

Methods

A literature search was performed of the PubMed, EMBASE (https://www.embase.com/) and CENTRAL databases on 30th May 2024 using the following search term: (weight OR obes* OR preoptimization OR prehabilitation OR BMI OR diet OR exercise) and (hernia OR abdominal wall reconstruction) AND randomized. Bibliographies of retrieved articles were searched. Studies were screened and reviewed independently by two authors.

Results

2921 articles were identified. After exclusion of duplicates 1707 studies were screened, 20 articles retrieved, and 4 included. Two described the 30 day and 2 year outcomes of a single RCT of non-pharmacological prehabilitation in ventral hernia surgery. Two described RCTs assessing short periods of very low calorie diet before operations which included hernia surgery. Interventions were associated with greater weight loss, with one RCT showing fewer short term complications.

Conclusions

Weight loss before hernia surgery is strongly recommended, but the evidence for this is limited to 3 RCTs, with just one finding short-term benefit. This highlights the need for dedicated robust RCTs.
BHSeP36 Laparoscopic mesh repair of sciatic hernia containing ureter and small bowel: a case report
Authors: Robinson Tanya , Nath Jay , Khan Shakeeb
Published: January 2025

Sciatic hernia is one of the rarest forms of pelvic hernia, accounting for around 0.01% of all abdominal wall hernias. They are more common in females, and the presentation can vary depending on the hernia contents. The literature initially suggested repair with open trans-gluteal or trans-abdominal approaches, though in more recent years there has been a shift towards laparoscopic techniques. We report our experience of performing laparoscopic mesh repair of a sciatic hernia in a 79 year old woman. The patient was experiencing abdominal pain and subsequent investigations revealed an off-baseline eGFR and a CT scan showing hydroureteronephrosis secondary to a sciatic hernia containing ureter and non-obstructed small bowel. Laparoscopic repair of the sciatic hernia was performed using placement of a self-expanding polypropylene mesh patch; cyanoacrylate glue was used to fix the mesh in place and to close the peritoneum. The patient made a good post-operative recovery and was discharged home the same day. In conclusion, this rare form of hernia was successfully treated using a laparoscopic approach with placement of a mesh patch and cyanoacrylate glue.
BHSeP43 Is small stitch technique feasible for emergency midline laparotomy closures?
Authors: Momin Erbaz , Bhagtani Priyanka
Published: January 2025

Introduction

European & American Hernia Societies have already updated their guidelines to recommend small stitch technique with wound suture ratio of 1:4 for elective midline laparotomy. However there is insufficient evidence for emergency laparotomy. We have conducted a study to generate more data on the subject.

Materials and methods

Consecutive 112 patients undergoing emergency midline laparotomy were included in the study. All patients underwent laparotomy closure with small stitch technique with 1:4 wound suture ratio. Skin was approximated in clean or clean-contaminated cases whereas it was left open for delayed primary or secondary closure in contaminated or infected cases. Patients had weekly follow up for the first 30 days and then later at one year or if symptomatic or develop a swelling around the laparotomy scar.

During the follow up patients are assessed for hernia by Clinical as well as Ultrasound examination.

The endpoints are development of hernia during the follow up.

Results

The study is in progress, Our patient assessment, data collection and analysis is expected to be over in July.
BHSeP46 Growing from strength to strength—results from a tertiary abdominal wall reconstruction centre
Authors: Kalaiselvan Ramya , Rajaretnam Niro , Fitzgerald-Smith Angela , Benson Alex , Samad Ajai , West Chris , Scott Michael
Published: January 2025

Introduction

Abdominal wall reconstruction (AWR) is now well-established as a sub-speciality in general and plastic surgery. We present the results of our well-established high-volume multi-disciplinary team (MDT) from a tertiary referral centre.

Methods

Retrospective review of cases from weekly abdominal wall reconstruction MDT from 01 June 2016—31 May 2024 was done. Key stakeholders included 3 Consultants in General surgery and 3 in Plastic surgery, 2 Consultant Anaesthetists and dedicated AWR MDT co-ordinator. Results are presented as Average (range).

Results

During the study period, 3078 patients have been discussed. This includes referrals from other hospitals. We have performed 123 (109–145) AWR operations per year. Mean BMI 30.5 (16.9–55.4). More than 95% of the patients received pre-operative Botox injections which were done by a Single Consultant Anaesthetist as a day case procedure. 78% underwent Rives-Stoppa procedure and 22% underwent posterior component separation with <4% patients who underwent bridging. 96% patients underwent concomitant abdominoplasty/panniculectomy (vertical, transverse, fleur-de-lis) with radical skin and sub-cutaneous fat excision weighing average of 1611 (150–18 000) grams. Bio-synthetic absorbable mesh was used in >80% of the patients. Return to theatre was 1.5% with 30-day mortality <0.5%. Incisional hernia recurrence rate was <3% (excluding the patients who underwent bridged repair). 150 patients remain on our waiting list to be operated.

Conclusion

We have demonstrated, again, that working in an MDT for such highly complex group of patients works very well, giving excellent outcomes. Team working with general and plastic surgeons has offered our patients a true multi-disciplinary knowledge and skills.
Incorporation of selenophene into thienoazacoronene-based nonfullerene acceptor: impact on photophysical and photovoltaic properties
Authors: Kubota Motohisa , Umeyama Tomokazu , Suzuki Wataru , Koganezawa Tomoyuki , Akiyama Midori , Imahori Hiroshi
Published: January 2025

The singlet exciton (S1) lifetime of nonfullerene acceptor (NFA) films is a crucial factor influencing their photovoltaic performances, as a longer S1 lifetime increases the exciton diffusion length. We previously reported that a NFA with a two-dimensionally π-extended thienoazacoronene (TAC) central core, S-TACIC, exhibits an exceptionally long S1 lifetime in the film. In this study, we examined the effects of replacing thiophene with selenophene on the photophysical and photovoltaic properties. Fluorescence decay measurements showed that the S1 lifetime of the selenophene-substituted TAC-based NFA (Se-TACIC) is longer in solution (500 ps) but significantly shorter in the film (<200 ps) compared to S-TACIC (220 ps in solution and 1,590 ps in film). When blended with the polymer donor PBDB-T, the Se-TACIC-based organic photovoltaic (OPV) device exhibited a lower power conversion efficiency (5.58%) than the S-TACIC-based one (9.92%), due to inferior photovoltaic parameters of the Se-TACIC-based OPV device.
‘I learnt to hide my smile’: a young man’s perspective of living with erosive oral lichen planus
Authors: Nolan Brian
Published: January 2025

Psychodermatology is an increasingly recognized entity of clinical dermatology. This patient viewpoint illustrates the case of a patient with oral lichen planus, apparent since his later adolescent years. The patient describes the psychosocial implications of the aesthetic appearance of his gumline. The erosive and ulcerated component of erosive oral lichen planus can have a major impact on patients, particularly during the formative adolescent years of life.
Beyond Balancing: Australia’s Dual-track China Policy
Authors: Chen Lisha , Zhang Baohui
Published: January 2025

This paper disputes the popular view that Australia has embraced a balancing posture against China after ditching its previous hedging policy. This is because a balancing perspective does not reconcile with the fact that Australia still actively cultivates economic ties with China. Instead, this paper proposes a new dual-track approach to explain Australia’s China policy. It posits that states can simultaneously pursue balancing and cooperation toward rising powers even after the establishment of threat certainty. Gains from trade with rising powers enhance their long-term aggregate power, which in turn enables more effective balancing against rising powers. Australia, a typical trading state, is particularly motivated to pursue this dual-track strategy toward China to maximize both its security and power. Although this dual-track approach also exhibits the co-presence of balancing and cooperation, it is very different from the hedging approach. While the hedging approach rests on the uncertainty of threats posed by a rising power, the dual-track approach is defined by such certainty. Whereas the hedging approach pursues limited and restrained balancing to manage the security dilemma with rising powers, the dual-track approach practices hard balancing. While the hedging approach uses economic engagement to shape a rising power’s intentions and behaviors, the dual-track approach only seeks profit from a rising power’s economic ascent. Finally, while the hedging approach allows largely unrestrictive economic cooperation, the dual-track approach incorporates geoeconomics to restrict cooperation in security sensitive domains. This dual-track perspective not only offers a new and novel perspective on how states respond to power shifts but also explains the “fear and greed” motto that underlies Australia’s China policy.
Association between air pollutants and out-of-hospital cardiac arrest: a 5-year time series analysis
Authors: Wang Jingjing , Zhou Qiang , Ni Song , Li Jie , Qin Chongzhen , Deng Wangsheng , Deng Zhe
Published: January 2025

Aims

We aimed to analyse the yet unclear correlation between air pollutant concentrations and out-of-hospital cardiac arrest (OHCA) in Shenzhen, China.

Methods and results

A 5-year time series analysis of all OHCA events reported to the Shenzhen Emergency Center was conducted. Quasi-Poisson regression, controlling for meteorological variables (daily mean relative temperature and humidity) with multivariable fractional polynomial and using Fourier series to adjust for long-term trends and account for periodic patterns, was used to assess the association among particulate matter of 2.5 μm (PM2.5), ozone (O3), particulate matter of ≥10 μm (PM10), carbon monoxide (CO), nitrogen dioxide (NO2), sulfur dioxide (SO2), and OHCA. Data from 16 769 patients who experienced OHCA were analysed. An increase of 10 μg/m3 in PM2.5 was associated with a higher risk of OHCA (relative risk (RR): 1.026 [95% confidence interval [CI]: 1.001–1.053]) on lag Day 1. A similar increase in PM10 was linked to an immediate risk of OHCA on the onset day (RR: 1.02 [95% CI: 1.005–1.036]) and a cumulative risk on lag Day 1 (RR: 1.021 [95% CI: 1.003–1.039]). An increased risk of OHCA was associated with NO2 and O3 exposure, while a reduced risk of OHCA was associated with SO2 and CO exposure in the subsequent 5 days. The relationship between PM2.5 and OHCA varied by gender and arrest rhythm. A reduction in the average daily PM2.5 concentration by 1 µg/m³ could decrease the incidence of OHCA attributable to PM2.5 exposure by 4.60%, while a reduction by 3 µg/m³ could decrease it by 18.41% on lag Day 1. PM2.5 was significantly associated with the occurrence of OHCA on lag Day 1. This association was modulated by gender and arrest rhythm.

Conclusion

Improving the levels of PM2.5, NO2, and O3 could decrease the risk of OHCA and the demand for emergency medical service related to PM2.5 exposure.
Millennial axially symmetric Magneto-Coriolis modes in Earth’s fluid core
Authors: Dumberry Mathieu , Gerick Felix , Gillet Nicolas
Published: January 2025

Magneto-Coriolis (MC) modes in Earth’s fluid core involve oscillations sustained by the combined effect of the Lorentz and Coriolis forces. Here, we investigate the properties of MC modes that involve purely axisymmetric flow, which we term axiMC modes. We provide a basic description of the wave dynamics of these modes, and simple predictions for the expected scalings of their frequency $\omega$, decay rate $\lambda$ and quality factor Q based on a uniform ambient magnetic field. In particular, Q scales with the Elsasser number $\Lambda$, which depends on the square of the r.m.s. strength of the azimuthally averaged meridional field. When $\Lambda \gt 1$, $Q\gt 1$ and axiMC modes may be excited; when $\Lambda \ll 1$, $Q\ll 1$ and axiMC modes revert to quasi-free magnetic decay modes. We present computations of axiMC modes in an inviscid, electrically conducting sphere for two idealized ambient magnetic field configurations, a uniform axial field and an axial poloidal field. We show that a flow gradient in the axial direction is a key property of axiMC modes. For the uniform axial field, $\omega$, $\lambda$ and Q follow the scalings expected for a uniform field. For the axial poloidal field, the structure of the modes changes substantially when $\Lambda \gtrsim 1$, becoming more concentrated in regions of lower field strength. The combination of this structural change and advection of field lines by flow significantly increases $\lambda$, resulting in a Q that remains close to 1 even at high $\Lambda$. For a magnetic field strength inside the Earth’s core of a few mT, the gravest axiMC modes are expected to have periods in the range of one thousand to a few thousand years and a Q not substantially above 1. AxiMC modes may be connected to a part of the observed millennial changes in Earth’s magnetic field, may exchange axial angular momentum with the mantle, and hence may also explain a part of the observed millennial changes in length of day.
Implantation of a temporary microaxial left ventricular assist device via the right axillary artery in a patient with aberrant right subclavian artery
Authors: Amar Gabrielle , Elgar Guy , Shimamura Junichi , Ohira Suguru
Published: January 2025

A temporary microaxial left ventricular assist device is commonly implanted via the right axillary artery to treat decompensated heart failure or cardiogenic shock. However, limited literature describes implantation in a variant aortic arch anatomy setting. We present a case of implantation via the right axillary artery in a patient with an aberrant right subclavian artery (Arteria Lusoria) as a bridge to heart transplantation.
Improving retrospective data on recent household deaths: a multi-arm randomized trial in Guinea-Bissau
Authors: Torrisi Orsola , Fisker Ane B , Fernandes Didier A A , Helleringer Stéphane
Published: January 2025

Background

In countries with limited civil registration and vital statistics systems, assessing the impact of health crises requires precise retrospective mortality data. We tested whether calendar methods improve survey or census data on dates of recent household deaths registered in a Health and Demographic Surveillance System (HDSS).

Methods

Between April and June 2023, we randomized 578 households with HDSS-registered deaths in Guinea-Bissau to interviews by using (i) a standard questionnaire with close-ended questions about dates of deaths, or similar questionnaires supplemented with (ii) a physical calendar of local events printed on paper or (iii) a digital calendar implemented on tablets. We evaluated the accuracy of reported dates through record linkages to HDSS data.

Results

No deaths were reported in 11.8% of the 508 participating households. In other households (n = 448), informants reported 574 deaths since January 2020. Relative to the standard questionnaire, neither the physical calendar nor the digital calendar improved the proportion of deaths reported in the same month and year as recorded by using surveillance data. The physical and digital calendars reduced the share of missing data on dates of deaths (6.1% and 3.2%, respectively, versus 13.1% with the standard questionnaire). Reported dates of deaths obtained by using the digital calendar were more weakly correlated with surveillance data than those collected in other arms. Using the digital calendar also added 1.15 minutes to the data collection.

Conclusion

Digital calendars do not improve the reporting of dates of deaths in surveys or censuses. Further trials of the use of a physical calendar in retrospective interviews about recent household deaths are warranted.
Gauss quadrature rules for integrals involving weight functions with variable exponents and an application to weakly singular Volterra integral equations
Authors: Allouch Chafik , Milovanović Gradimir V
Published: January 2025

This paper presents a numerical integration approach that can be used to approximate on a finite interval, the integrals of functions that contain Jacobi weights with variable exponents. A modification of the integrand close to the singularities is needed, and a new modification is proposed. An application of such a rule to the numerical solution of variable-exponent weakly singular Volterra integral equations of the second kind is also explored. In the space of continuous functions, the stability and the error estimates are demonstrated, and numerical tests that validate these estimates are conducted.
Compound Poisson particle approximation for McKean–Vlasov SDEs
Authors: Zhang Xicheng
Published: January 2025

We present a comprehensive discretization scheme for linear and nonlinear stochastic differential equations (SDEs) driven by either Brownian motions or $\alpha $-stable processes. Our approach utilizes compound Poisson particle approximations, allowing for simultaneous discretization of both the time and space variables in McKean–Vlasov SDEs. Notably, the approximation processes can be represented as a Markov chain with values on a lattice. Importantly, we demonstrate the propagation of chaos under relatively mild assumptions on the coefficients, including those with polynomial growth. This result establishes the convergence of the particle approximations towards the true solutions of the McKean–Vlasov SDEs. By only imposing moment conditions on the intensity measure of compound Poisson processes our approximation exhibits universality. In the case of ordinary differential equations (ODEs) we investigate scenarios where the drift term satisfies the one-sided Lipschitz assumption. We prove the optimal convergence rate for Filippov solutions in this setting. Additionally, we establish a functional central limit theorem for the approximation of ODEs and show the convergence of invariant measures for linear SDEs. As a practical application we construct a compound Poisson approximation for two-dimensional Navier–Stokes equations on the torus and demonstrate the optimal convergence rate.
A water footprint inventory for a textile organization: a case study in the denim washing industry based on the integrated reverse osmosis system
Authors: Aykaç Özen Hülya , Temiz Ekin , Çoruh Semra
Published: January 2025

The consideration of scarcity and overexploitation of freshwater at the organizational level has increased interest in the water footprint (WF). The water footprint measures freshwater use for activities, taking into account water consumption and pollution contamination by classifying consumed water into groundwater and surface water (blue water), rainwater (green water), and polluted water (grey water). This study aims to identify a comprehensive WF inventory analysis for a denim washing company and assess the grey WF based on the effluent concentration of pollution indicators (chemical oxygen demand [COD], suspended solids [SS], ammonium nitrogen [NH4-N], and phenol) measured monthly in 2021. The company used well water for its operations, which constituted 61.79% of the total water use of the facility; water used by the company by reverse osmosis (RO) accounted for 37.60% of total water consumption, and rainwater made up 0.61% of the volume of water used overall. The grey water footprints of COD, SS, NH4-N, and phenol were calculated as 59,981.53 m3, 31,747.21 m3, 10,514 m3, and 48,190 m3, respectively. The results illustrate that the COD, which accounted for 40% of the pollutants, had the highest grey WF in the company, corresponding to the amount of freshwater required to assimilate pollutants to meet water quality standards. In addition, the effect of the RO system on the blue WF of this company was analyzed by considering two different scenarios. Reverse osmosis considerably affected the blue WF, accounting for over 37% of this company’s water use. It suggests that a wastewater treatment plant using RO is an ideal option for recovering water. The main contributions of this study are comprehensively assessing the water footprint components of the denim washing company and understanding sector-specific water footprint at the organization level.
P09 Exploring prescribers’ reasons for prescribing piperacillin/tazobactam in Cwm Taf Morgannwg University Health Board
Authors: Price Sian
Published: January 2025

Background

Using broad-spectrum antibiotics such as piperacillin/tazobactam (TZP) increases the risk of antibiotic-resistant infections and Clostridioides difficile infection.1 Appropriate antibiotic prescribing in Cwm Taf Morgannwg University Health Board (CTMUHB) is regarded as being in line with one or more of the following recommended prescribing principles (RPP):2 in accordance with CTMUHB antimicrobial guidelines;3 in accordance with culture and sensitivity results; or on the advice of a microbiologist. A snapshot audit in Princess of Wales Hospital in 2022 classed 9 out of 16 (56%) of TZP prescriptions as inappropriate.4

Objectives

To explore and describe prescribers’ reasons behind prescribing TZP outside of the RPP in CTMUHB.

Methods

A quantitative, cross-sectional study was conducted across the three acute sites in the Health Board, surveying all medical and non-medical prescribers (NMPs). An electronic (Microsoft Forms) self-completed, anonymous questionnaire with quantitative and qualitative questions was used to collect responses. Nominal (categorical) and ordinal (Likert scale) data were analysed and reported in terms of frequencies and percentages. Thematic analysis was used to examine the qualitative data.

Results

A total of 92 prescribers (66 medical, 26 non-medical) were included in the data analysis. Of these, 96% (n=88) stated that they were aware of the CTMUHB antimicrobial guidelines and knew how to access them. Fifty-five percent of respondents (n=51) had prescribed TZP outside of the RPP (71% of medical prescribers and 15% of NMPs). The most common reason for this was ‘consultant/senior preference’ (59% of respondents). This reason was given by 25% of NMPs (1/4) compared with 62% (29/47) of medical prescribers.

Conclusions

‘Prescribing etiquette’ and medical hierarchy in secondary care appears to be the biggest influence on prescribing5 with ‘consultant/senior preference’ being the most common reason given for prescribing outside of the RPP. This practice seems to impact medical prescribers more than NMPs. Further research in the form of focus groups or interviews with senior doctors is required to explore in more depth the reasons why they use TZP outside of the RPP.
Early and multiple doses of zoledronate mitigates rebound bone loss following withdrawal of receptor activator of nuclear factor kappa-B ligand inhibition
Authors: Kim Albert S , Taylor Victoria E , Castro-Martinez Ariel , Dhakal Suraj , Zamerli Amjad , Mohanty Sindhu T , Xiao Ya , Simic Marija K , Pantalone Alyssa , Chu Julian , Cheng Tegan L , Croucher Peter I , Center Jacqueline R , Girgis Christian M , McDonald Michelle M
Published: January 2025

Rebound bone loss following denosumab discontinuation is an important barrier in the effective long-term treatment of skeletal disorders. This is driven by increased osteoclastic bone resorption following the offset of RANKL inhibition, and sequential osteoclast-directed therapy has been utilized to mitigate this. However, current sequential treatment strategies intervene following the offset of RANKL inhibition and this approach fails to consistently prevent bone loss. Our previous work, using a mouse model of denosumab discontinuation, has shown that the processes that drive the rebound phenomenon occur earlier than when bone loss is detected, namely a rise and overshoot in serum tartrate-resistant acid phosphatase (TRAP). We identified that these changes in serum TRAP may provide an earlier window of opportunity to intervene with sequential therapy following RANKL inhibition withdrawal. Here, we show that early treatment with zoledronate (10 mg/kg, 3 wk following the last dose of OPG:Fc), preceding the rise and overshoot in serum TRAP, effectively mitigates rebound bone density loss through preventing the overshoot in serum TRAP. Further, we show that multiple doses of zoledronate (early treatment and during anticipated BMD loss) is superior in consolidating bone density gains made with RANKL inhibition and preventing rebound BMD loss as measured by DXA. Importantly, we demonstrate the efficacy of early and multi-dose zoledronate strategy in preventing bone loss in both growing and skeletally mature mice. MicroCT analysis showed improved trabecular bone structure in both the femur and lumbar vertebrae with zoledronate treatment compared with control. These increases in bone mass translated to increased fracture resistance in skeletally mature mice. This work provides a novel approach of early and multi-dose sequential treatment strategy following withdrawal of RANKL inhibition, contributing valuable insight into the clinical management of patients who discontinue denosumab therapy.
Preterm birth and risk of bone fractures during childhood and early adulthood
Authors: Alenius Suvi , Miettinen Maija E , Nurhonen Markku , Salmi Samuli , Näsänen-Gilmore Pieta , Haaramo Peija , Tikanmäki Marjaana , Vääräsmäki Marja , Gissler Mika , Mäkitie Outi , Hovi Petteri , Kajantie Eero
Published: January 2025

People born preterm have reduced BMD, subnormal peak bone mass, and an increased risk of osteoporosis. Whether this translates to increased risk of bone fractures is uncertain. We assessed fracture risk from childhood to early adulthood in relation to gestational age and sex by conducting a nationwide register-linkage cohort study comprising all 223 615 liveborn (January 1987–September 1990) singletons (9161, 4.1%; preterm) in Finland. Cox regression models provided hazard ratios (HRs) for fracture diagnosis in public specialty health care in both first and recurrent event settings during the whole follow-up (0–29 years) and during different age periods (0–4, 5–9, 10–29 years). Gestational age was considered categorical (full-term, 39–41 weeks; reference). A total of 39 223 (17.5%) children or young adults had at least 1 fracture. In analyses not stratified by sex, only extremely preterm birth (<28 completed weeks’ gestation) was associated with risk of bone fracture at 0–29 years (adjusted HR [aHR]: 0.46; 95% CI: 0.28–0.74) compared with those born full-term. Among females, gestational age was unrelated to fracture risk at 0–29 years. Among males, extremely and very preterm (28–31 weeks) birth was associated with lower risk of fracture at 0–29 years compared with those born full-term (aHR: 0.38 [95% CI: 0.21–0.71] and 0.75 [95% CI: 0.59–0.95], respectively). Restricting the analyses to the individuals without severe medical condition(s) attenuated the associations. However, the fracture risk varied according age and sex: at 10–29 years, moderately preterm (32–33 weeks) females and extremely and very preterm males had a lower risk (aHR: 0.63 [0.43–0.94], 0.35 [0.17–0.69], and 0.74 [0.57–0.95], respectively), while late-preterm birth (34–36 weeks) was associated with a 1.6-fold higher risk among females at 0–5 years, and a 1.4-fold risk among males at 5–10 years. Analyses on recurrent fractures showed a similar pattern. Children and young adults, in particular males, born extremely or very preterm may have fewer bone fractures; this is partly explained by severe medical conditions in this group.
APOE aggregation in microglia, seeds b-amyloidosis in Alzheimer's disease
Authors: Jiménez-Acosta Miguel A , Luckie-Duque Cristina A , Meraz-Ríos Marco A
Published: January 2025

APOE Aggregation in Microglia.
Tissue-specific modulation of CRISPR activity by miRNA-sensing guide RNAs
Authors: Garcia-Guerra Antonio , Sathyaprakash Chaitra , de Jong Olivier G , Lim Wooi F , Vader Pieter , El Andaloussi Samir , Bath Jonathan , Reine Jesus , Aoki Yoshitsugu , Turberfield Andrew J , Wood Matthew J A , Rinaldi Carlo
Published: January 2025

Nucleic acid nanostructures offer unique opportunities for biomedical applications due to their sequence-programmable structures and functions, which enable the design of complex responses to molecular cues. Control of the biological activity of therapeutic cargoes based on endogenous molecular signatures holds the potential to overcome major hurdles in translational research: cell specificity and off-target effects. Endogenous microRNAs (miRNAs) can be used to profile cell type and cell state, and are ideal inputs for RNA nanodevices. Here, we present CRISPR MiRAGE (miRNA-activated genome editing), a tool comprising a dynamic single-guide RNA that senses miRNA complexed with Argonaute proteins and controls downstream CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) activity based on the detected miRNA signature. We study the operation of the miRNA-sensing single-guide RNA and attain muscle-specific activation of gene editing through CRISPR MiRAGE in models of Duchenne muscular dystrophy. By enabling RNA-controlled gene editing activity, this technology creates opportunities to advance tissue-specific CRISPR treatments for human diseases.
Fractionated reirradiation of recurrent high-grade gliomas: Safety with higher reirradiation dose and larger targets
Authors: LeCompte Michael C , Vuppala Neil , Reyes Juan M , Page Brandi , Croog Victoria , Huang Ellen , Redmond Kristin J , Kleinberg Lawrence R
Published: January 2025

Background

The optimal regimen, normal tissue tolerances, and appropriate indications for reirradiation for recurrent high-grade glioma (HGG) are uncertain. The aim of this study was to determine whether higher reirradiation dose was associated with toxicity or survival.

Methods

Patients with HGG treated with fractionated reirradiation at a single institution from 2007 to 2022 were retrospectively reviewed. Metrics evaluated included overall survival (OS), prognostic factors for survival, and treatment-related toxicity.

Results

Two hundred and thirty patients with recurrent HGG were reviewed. Median follow-up was 8.8 months. Median reirradiation dose was 41.4 Gy with 80.4% receiving concurrent systemic therapy. Median cumulative maximum doses to brainstem and optic structures were 77.9 Gy (range: 4.6–146.0 Gy) and 55.1 Gy (3.3–106.3 Gy), respectively. No injuries to these structures were identified. Radiation necrosis (RN) was identified in 9.4%. There were no significant associations between RN and target size, systemic therapy use, or reirradiation dose. Median OS was 10.2 months from reirradiation start. On multivariate analysis, improved OS was associated with better KPS, longer interval between radiotherapy sessions, reirradiation at first recurrence, and reirradiation dose ≥ 41.4 Gy. Median OS for those with IDH wildtype glioblastoma was 8.7 months. On multivariate analysis of an IDH wildtype disease subanalysis, improved OS was associated with longer interval between radiotherapy sessions and higher reirradiation dose.

Conclusions

These data support the safety and efficacy of fractionated reirradiation for recurrent HGG. They suggest higher reirradiation dose may be feasible, including for large treatment volumes and for tumors near the brainstem or optic structures.
Emergence of infective endocarditis due to Serratia spp.: Results of a multicenter cohort
Authors: McCrary L Madeline , Slain Douglas , Shah Sunish , Stoner Bobbi Jo , Marx Ashley H , Schranz Asher J
Published: January 2025

Background

Infective endocarditis due to Serratia spp. (S-IE) has historically been considered a rare entity. Typically linked to injection drug use (IDU), S-IE appears to be a growing problem as the harms of unsafe drug use proliferate. However, guidance on therapy for gram-negative IE remains limited.

Methods

This was a retrospective analysis of adults treated for S-IE at 4 academic health systems in different US states from 2015-2021. Multivariable logistic regression analyzed the association of inpatient mortality with procedural management and combination antibiotic treatment.

Results

159 cases of S-IE were identified with a qualitative overall increase across the period, and a peak in 2019, although trends varied by site. 75% were due to IDU, 57% involved a single left-sided valve and inpatient mortality was 21%. In adjusted analyses, including 117 cases from 3 sites, lower inpatient mortality was associated with procedural intervention (OR 0.14, 95% CI 0.03-0.64) and combination antibiotic therapy (OR 0.15, 95% CI 0.03-0.74).

Discussion

In this multicenter study, we found that S-IE may be increasing, commonly associated with IDU, is treated with varying strategies and carries high inpatient mortality. Procedural intervention and combination antibiotics were associated with lower mortality. Our study is limited by varying methods of case identification and a lack of data on clinical severity and surgical indications. Further study is urgently needed to define best management practices.
Jacob Brucker, Critical History of Philosophy: 'Preliminary Discourse' and 'On The Socratic School'
Authors: 9780192662804  , Catana Leo
Published: January 2025

The German historian and minister Johann Jacob Brucker (1696–1770) is widely recognized as the father of modern historiography of philosophy. In 1742–1744, he published his Historia critica philosophiae in Leipzig. The second edition was published in 1766–1767. The Historia was the most comprehensive history of philosophy produced in the eighteenth-century, influencing general histories of philosophy and many encyclopedia over the following two hundred years. It is important for both contemporary philosophers and historians of philosophy to be aware of Brucker’s work, given that many of our modern assumptions pertaining to the discipline of the history of philosophy ultimately derive from his work: methodological concepts (e.g. ‘system of philosophy’); mechanisms of admittance and non-admittance to the canon (e.g. criteria concerning the philosopher’s style of philosophizing, gender, nationality, geographical origin, religion); and broad characterizations of periods in the history of philosophy (e.g. ‘Neoplatonism’) in many cases relate back to Brucker’s Historia. If we want to achieve an unbiased and rational discussion of philosophy’s past, it is important to have access to the sources which have informed our understanding and evaluation of the history of philosophy. Unfortunately, Brucker’s Latin text is inaccessible to most contemporary readers, and there is currently no English translation available. The present book provides a partial translation of his work, namely the Preliminary Discourse, outlining the methodological precepts, and On the Socratic School, illustrating how these precepts were put into practice and providing a unique insight into the eighteenth-century debate about Socrates and his school.
Introduction
Authors: Robertson Katie , Wilson Alastair
Published: January 2025

This chapter introduces the overall aims and themes of this volume and relates them to the individual chapters. It first presents and compares different conceptions of levels of explanation which have figured in philosophy of science and in philosophy more broadly, distinguishing explanatory levels from related accounts of levels including compositional levels and levels of organization. It then identifies some themes which unite the chapters of the volume: the function of explanatory levels in scientific and philosophical reasoning, the implications of using models which span different explanatory levels, and the prospects for different levels of explanation of the phenomenon of levels of explanation itself. It concludes with summaries of the individual chapters, highlighting their connections to the broader themes of the volume.
How the Reductionist Should Respond to the Multiscale Argument, and What This Tells Us About Levels
Authors: Franklin Alexander
Published: January 2025

Recent literature has raised the multiscale argument against reduction (see, e.g., Batterman (2013), Bursten (2018), Wilson (2017)). These authors observe that numerous successful scientific models appeal to features and properties from a wide range of spatial/temporal scales. This is taken to undermine views that the world is sharply divided into distinct levels, roughly corresponding to different scales, and that each higher level is reducible to the next lowest level. In this chapter I show that this does not undermine a version of reduction that accepts methodological pluralism in science, yet maintains that the adequacy of any model can be explained by appeal to details at smaller scales. I go on to discuss a case study—dislocations in steel—used by Batterman and Wilson in defence of the multiscale argument. I conclude by arguing that, in light of the multiscale argument, an attenuated conception of levels is required.
Exclusion Excluded
Authors: Weslake Brad
Published: January 2025

The non-reductive physicalist would like to believe that mental properties are not identical to physical properties; that there are complete causal explanations of all events in terms of physical properties; and that there are sometimes explanations of events in terms of mental properties. However, some have argued that these claims cannot all be true, since they are collectively inconsistent with a principle of causal exclusion. This chapter argues that the best formulation of the interventionist theory of causation entails the falsity of the exclusion principle. However, it does so at the cost of revealing a weakness in the interventionist theory itself.
Levels of Fundamentality in the Metaphysics of Physics
Authors: Crowther Karen
Published: January 2025

Within physics there are two ways of establishing the relative fundamentality of one theory compared to another, via two senses of reduction: ‘inter-level’ and ‘intra-level’. The former is standardly recognised as roughly correlating with the chain of ontological dependence (i.e., the phenomena described by theories of macro-physics are typically supposed to be ontologically dependent on the entities/behaviour described by theories of micro-physics), and thus has been of interest to naturalised metaphysics. The latter, though, has not been considered interesting for metaphysics, because it is not thought to correlate either with ontological dependence nor causal or dynamical dependence. I argue, however, that this is a mistake, and that actually the intra-level relation does reflect ontological dependence (in the same sense as the inter-level relation) and thus should not be neglected by metaphysics of physics. This argument further supports the assertion that the same notion of fundamentality underlies both the inter- and intra-level claims of fundamentality in physics, and that this notion of relative fundamentality in physics correlates with that of metaphysics.
A Dormitive Virtue Puzzle
Authors: Taylor Elanor
Published: January 2025

In Molière’s comedy The Imaginary Invalid, a doctor “explains” that opium reliably induces sleep because it has a “dormitive virtue.” Molière intended this to be a satirical play on the use of opaque scholastic concepts in medicine, and since then the phrase “dormitive virtue” has become a byword for explanatory failure. However, contemporary work on the metaphysics of grounding and dispositions appears to permit explanations with a strikingly similar structure. This chapter explores competing verdicts on dormitive virtue explanation, using a model of explanation called “Contextualist Pluralist Non-Realist Backing,” or CPN Backing. The chapter shows that CPN Backing illuminates the puzzle about dormitive virtue explanation, shows what is required for a resolution, and makes sense of conflicting responses to this case.
Why Are There High-Level Regularities?
Authors: Bhogal Harjit
Published: January 2025

Fodor famously asked the question of why there is anything except physics. Assuming physicalism, there is a sense in which physics is all there is. However, there are lots of non-physical regularities in the world—regularities of economics and biology and history and so on. Isn’t it surprising that such regularities arise from the blooming, buzzing, confusion of the microphysical level? I suggest an approach to the puzzle. The easy part of the approach involves arguing that properties are so abundant that there will always be higher-level regularities, if there are no restrictions on the properties involved. However, the high-level regularities we care about are formulated using only relatively natural, non-gerrymandered properties. Why is this the case? I approach this question by considering what makes for natural properties in the higher-level sciences. Is there something about high-level naturalness that implies that there will be regularities about those properties? Many accounts of higher-level naturalness imply that there is not. But some accounts reduce the notion of high-level naturalness to patterns of facts at the fundamental level. Such reductive accounts can be formulated so the existence of high-level regularities that are formulated using only natural properties flows directly from the account. This provides a kind of answer to the question about high-level regularities—they exist because of the nature of high-level naturalness. I illustrate this using a version of Loewer’s package deal account of naturalness and my own favored account of high-level naturalness.
Ingenuity in Natural Philosophy and Medicine
Authors: Garrod Raphaële
Published: January 2025

This chapter explores natural-philosophical and medical accounts of ingenuity Rabelais would have encountered as a medical student in Montpellier, then as a working physician and an editor for Gryphius in Lyon: those of Galen in medicine, those of Aristotle in faculty psychology. It tracks the Galenic meanings of the ingenium: intelligent design and artfulness in anatomy, idiosyncratic natures or temperaments and their cognitive expressions as wit in physiology. It then investigates their medieval Arabic and Renaissance Latin receptions in Avicenna edited by the physician Symphorien Champier, Rabelais’s contemporary, before turning to Melanchthon’s De anima edited by Gryphius, and to two of Melanchthon’s sources: Johannes Velcurio and Juan-Luis Vivès. This chapter discloses the sedimentation of a classical medical and philosophical doxa on ingenuity, but also its transformations and adaptations required for the cognitive operations at stake in embodied thinking to accommodate the philosophical and theological dogma of the immaterial, rational soul.