bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of preventive substrate catheter ablation on implantable cardioverter-defibrillator interventions in patients with ischaemic cardiomyopathy and infarct-related coronary chronic total occlusion
Authors: Žižek David , Mrak Miha , Jan Matevž , Zupan Mežnar Anja , Ivanovski Maja , Žlahtič Tadej , Kajdič Nina , Antolič Bor , Klemen Luka , Skale Rafael , Avramovič Gregorič Jurij , Štublar Jernej , Pernat Andrej , Šinkovec Matjaž
Published: April 2024

Aims

Primary prevention patients with ischaemic cardiomyopathy and chronic total occlusion of an infarct-related coronary artery (CTO) are at a particularly high risk of implantable cardioverter-defibrillator (ICD) therapy occurrence. The trial was designed to evaluate the efficacy of preventive CTO-related substrate ablation strategy in ischaemic cardiomyopathy patients undergoing primary prevention ICD implantation.

Methods and results

The PREVENTIVE VT study was a prospective, multicentre, randomized trial including ischaemic patients with ejection fraction ≤40%, no documented ventricular arrhythmias (VAs), and evidence of scar related to the coronary CTO. Patients were randomly assigned 1:1 to a preventive substrate ablation before ICD implantation or standard therapy with ICD implantation only. The primary outcome was a composite of appropriate ICD therapy or unplanned hospitalization for VAs. Secondary outcomes included the primary outcome’s components, the incidence of appropriate ICD therapies, cardiac hospitalization, electrical storm, and cardiovascular (CV) mortality. Sixty patients were included in the study. During the mean follow-up of 44.7 ± 20.7 months, the primary outcome occurred in 5 (16.7%) patients undergoing preventive substrate ablation and in 13 (43.3%) patients receiving only ICD [hazard ratio (HR): 0.33; 95% confidence interval (CI): 0.12–0.94; P = 0.037]. Patients in the preventive ablation group also had fewer appropriate ICD therapies (P = 0.039) and the electrical storms (Log-rank: P = 0.01). While preventive ablation also reduced cardiac hospitalizations (P = 0.006), it had no significant impact on CV mortality (P = 0.151).

Conclusion

Preventive ablation of the coronary CTO-related substrate in patients undergoing primary ICD implantation is associated with the reduced risk of appropriate ICD therapy or unplanned hospitalization due to VAs.
Planned oocyte cryopreservation: a systematic review and meta-regression analysis
Authors: Hirsch Ayala , Hirsh Raccah Bruria , Rotem Reut , Hyman Jordana H , Ben-Ami Ido , Tsafrir Avi
Published: April 2024

BACKGROUND

Awareness of the age-related decline in fertility potential has increased the popularity of planned oocyte cryopreservation (POC). However, data regarding outcomes of POC, including rates of women returning to thaw oocytes, as well as pregnancy and live birth rates, are scarce and based mostly on small case series.

OBJECTIVE AND RATIONALE

POC was defined as cryopreservation exclusively for prevention of future age-related fertility loss. The primary outcome was live birth rate per patient. The secondary outcomes included the return to thaw rate and laboratory outcomes. A meta-regression analysis examining the association between live birth and age above 40 or below 35 was conducted.

SEARCH METHODS

We conducted a systematic database search from inception to August 2022. The search included PubMed (MEDLINE) and EMBASE. Our search strategies employed a combination of index terms (Mesh) and free text words to compile relevant concepts. The systematic review and meta-regression were undertaken following registration of systematic review (PROSPERO registration number CRD42022361791) and were reported following guidelines of Preferred Reporting Items for Systematic Review and Meta-Analyses 2020 (PRISMA 2020).

OUTCOMES

The database search yielded 3847 records. After the selection process, 10 studies, conducted from 1999 to 2020, were included. Overall, 8750 women underwent POC, with a mean cryopreservation age of 37.2 (±0.8). Of those, 1517 women returned to use their oocytes with a return rate of 11.1% (± 4.7%). The mean age at the time of cryopreservation for women who returned to use their oocytes was 38.1 (±0.4), with an average of 12.6 (±3.6) cryopreserved oocytes per woman. In a meta-analysis, the oocyte survival rate was 78.5% with a 95% CI of 0.74–0.83 (I2 = 93%). The live birth rate per patient was 28% with a 95% CI of 0.24–0.33 (I2 = 92%). Overall, 447 live births were reported. In a sub-group analysis, women who underwent cryopreservation at age ≥40 achieved a live birth rate per patient of 19% (95% CI 0.13–0.29, I2 = 6%), while women aged ≤35 years old or younger had a higher live birth rate per patient of 52% (95% CI 0.41–0.63, I2 = 7%).

WIDER IMPLICATIONS

POC emerges as a feasible option for women aiming to improve their chances of conceiving at a later reproductive age. Nonetheless, it must be acknowledged that the overall success rates of POC are limited and that the likelihood of successful live birth declines as the age at cryopreservation rises. With increasing interest in POC, the collation of comprehensive and high-quality data is imperative to clearly define the outcomes for various age groups.

REGISTRATION NUMBER

CRD42022361791.
What Contributes to the Minimum Inhibitory Concentration? Beyond β-Lactamase Gene Detection in Klebsiella pneumoniae
Authors: Maclean Alyssa K W , Morrow Stacey , Niu Fang , Hanson Nancy D
Published: April 2024

Background

Klebsiella pneumoniae is capable of resistance to β-lactam antibiotics through expression of β-lactamases (both chromosomal and plasmid-encoded) and downregulation of outer membrane porins. However, the extent to which these mechanisms interplay in a resistant phenotype is not well understood. The purpose of this study was to determine the extent to which β-lactamases and outer membrane porins affected β-lactam resistance.

Methods

Minimum inhibitory concentrations (MICs) to β-lactams and inhibitor combinations were determined by agar dilution or Etest. Outer membrane porin production was evaluated by Western blot of outer membrane fractions. β-lactamase carriage was determined by whole genome sequencing and expression evaluated by real-time reverse-transcription polymerase chain reaction.

Results

Plasmid-encoded β­-lactamases were important for cefotaxime and ceftazidime resistance. Elevated expression of chromosomal SHV was important for ceftolozane-tazobactam resistance. Loss of outer membrane porins was predictive of meropenem resistance. Extended-spectrum β-lactamases and plasmid-encoded AmpCs (pAmpCs) in addition to porin loss were sufficient to confer resistance to the third-generation cephalosporins, piperacillin-tazobactam, ceftolozane-tazobactam, and meropenem. pAmpCs (CMY-2 and DHA) alone conferred resistance to piperacillin-tazobactam.

Conclusions

Detection of a resistance gene by whole genome sequencing was not sufficient to predict resistance to all antibiotics tested. Some β-lactam resistance was dependent on the expression of both plasmid-encoded and chromosomal β-lactamases and loss of porins.
Transient States and Timeless Ties: (In)Formality, Power Networks, and the EU Mission in Kosovo
Authors: Tripathi Siddharth , Richter Solveig
Published: April 2024

State-building by external actors can be understood as a practice of intervention in post-conflict spaces characterized by convergences and contestations between different actors striving for power and legitimacy. Informal non-state (armed) groups and clientele networks profit from the contingencies during transition and “capture” emerging formal state institutions to secure private gains and public positions. Order in this newly formed state is established through a dynamic process involving both external actors and domestic power networks. Most of the literature on intervention either focuses on top-down effects of external actors or resistance by local actors, thus falling short of describing the timeless ties of post-war networks and individuals in their day-to-day interaction patterns. How can we then understand the interaction and collusion between post-conflict power networks and external “statebuilders”? We use Bourdieu’s concept of the field to examine the local spaces of interventions and argue that interventions are social and relational practices characterized by day-to-day routines and overlapping, yet co-existing modes of formal and informal interactions. Empirically, we rely on qualitative social network analysis and interviews to visibilize these social practices and collusion between external actors and power networks in Kosovo and its impact on “state-building” efforts by the international community.
Plasma concentrations of antiretroviral drugs in a successful 4-days-a-week maintenance treatment strategy in HIV-1 patients (ANRS 170-Quatuor trial)
Authors: Abe Emuri , Landman Roland , Assoumou Lambert , Amat Karine , Lambert-Niclot Sidonie , Bellet Jonathan , Gibowski Séverine , Girard Pierre-Marie , Morand-Joubert Laurence , de Truchis Pierre , Alvarez Jean-Claude
Published: April 2024

Objectives

Charaterization of the plasma concentrations of antiretrovirals in a 4-days-a-week maintenance treatment strategy in the ANRS-170-QUATUOR study.

Methods

Patients were randomized in two groups receiving triple therapy taken 4-days-ON and 3-days-OFF (4/7) or continuous therapy (7/7). Plasma antiretroviral concentrations were monitored during the ‘ON-treatment period’ (Day 3 or 4 of the 4-day treatment block) and the ‘OFF-treatment period’ (Day 3 of the 3-day drug cessation) for the 4/7 group, or before the daily drug intake for the 7/7 group, until week-48 (W48). After W48, all patients switched to the 4/7 strategy and were followed until W96.

Results

W0 measured concentrations were comparable in both groups, except for raltegravir, concentrations of which were higher in the 4/7 group, and were all above the values usually recommended to be effective in therapeutic drug monitoring. Comparison of ON-period median concentrations between the two groups showed a statistical difference for rilpivirine [88 ng/mL (interquartile range (IQR) = 64–112) for 4/7 arm versus 130 ng/mL (82–160) for 7/7 arm, P < 0.001] and tenofovir [tenofovir disoproxil fumarate: 93 ng/mL (73–135) for 4/7 arm versus 117 ng/mL (83–160) for 7/7 arm, P < 0.001; tenofovir alafenamide: 11 ng/mL (7–15) for 4/7 arm versus 14 ng/mL (11–18) for 7/7 arm, P = 0.001]. Median OFF concentrations were significantly lower (P < 0.001) at the 48 week analysis for all medications except for raltegravir (P = 0.493) and atazanavir (P = 0.105), for which the numbers of patients were very small.

Conclusions

The 4/7-day treatment option led to antiretroviral blood levels close to continuous treatment after the four consecutive days of medication, and to low levels at the end of the non-treatment period.
Genomic estimated breeding values for bovine respiratory disease resistance in Angus feedlot cattle
Authors: Hayes Ben J , Duff Christian J , Hine Bradley C , Mahony Timothy J
Published: April 2024

Bovine respiratory disease (BRD) causes major losses in feedlot cattle worldwide. A genetic component for BRD resistance in feedlot cattle and calves has been reported in a number of studies, with heritabilities ranging from 0.04 to 0.2. These results suggest selection could be used to reduce the incidence of BRD. Genomic selection could be an attractive approach for breeding for BRD resistance, given the phenotype is not likely to be recorded on breeding animals. In this study, we derived GEBVs for BRD resistance and assessed their accuracy in a reasonably large data set recorded for feedlot treatment of BRD (1213 Angus steers, in two feedlots). In fivefold cross validation, genomic predictions were moderately accurate (0.23 ± 0.01) when a BayesR approach was used. Expansion of this approach to include more animals and a diversity of breeds is recommended to successfully develop a GEBV for BRD resistance in feedlots for the beef industry.
Simulation and analysis of the transient electromagnetic method response in double-layer water-filled goaf in coal mines
Authors: Yu Chuantao , Ma Jie , Xue Junjie
Published: April 2024

The resolution ability of the transient electromagnetic method (TEM) for double-layer water-filled goaf is affected by the low resistance shielding effect of the overlying strata. Currently, there is a lack of quantitative research on how the parameter changes of the upper water-filled goaf affect its resolution capability. In this study, through numerical and physical simulations, the relative error of the TEM response between single- and double-layer water-filled goafs was regarded as the evaluation index to analyse and summarize the resolution capability of the TEM for double-layer water-filled goaf under different burial depths, thicknesses, and areas of the upper water-filled goaf. The results are summarized as follows. (ⅰ) The resolution capability of the TEM for double-layer water-filled goaf decreased with the increasing burial depth, thickness, or area of the upper water-filled goaf. (ⅱ) The rate of decrease in resolution gradually accelerated as the burial depth increased. Conversely, as the thickness increased, the decrease rate in resolution gradually reduced. Furthermore, the resolution decreased rapidly and then tended towards a fixed value as the area increased. (ⅲ) The maximum value of the relative error curve moved towards the early stage with the increasing burial depth, resulting in a detection depth of the target body smaller than the actual value. Moreover, it moved towards the later stage with the increasing thickness or area, resulting in a detection depth of the target body greater than the actual value.
Spotted Hyena skull size variation across geography favors the energetic equivalence rule over Bergmann’s Rule
Authors: Cavalieri Cybil N , McElhinny Teresa L , Holekamp Kay E , Lundrigan Barbara L
Published: April 2024

Much historic work has focused on establishing geographical and ecological rules that broadly explain patterns in size variation. We examined geographic variation in Spotted Hyena skull size using geometric morphometrics and spatial statistics. We quantified size variation and sexual size dimorphism of the skull, and evaluated the influence of temperature, precipitation, land cover type, and population density on skull size. We found that female spotted hyenas are slightly larger on average than males. Our analysis of regional differences did not indicate geographic variation in sexual size dimorphism. Skull size of Spotted Hyenas varies with geography but does not adhere to Bergmann’s Rule. The smallest individuals of both sexes occur between −5.00° and 10.00° latitude and east of 28.50° longitude, with larger individuals being found elsewhere. Although Spotted Hyena skull size co-varies in some views with such variables as habitat type and climate indicators, skull size in this species most strongly co-varies with population density. The highest population densities are associated with the smallest skull size, possibly reflecting a relationship between high population density and access to resources. These results suggest that geographic variation in Spotted Hyena skull size is better explained by the energetic equivalence rule than Bergmann’s Rule.
Bayesian issues in the 1950s: an episode involving Karl Popper and Jimmie Savage
Authors: Stigler Stephen M
Published: April 2024

In the 1950s, the growing importance of Bayesian inference attracted both supporters and critics. In 1958, the philosopher Karl Popper published what he called a paradox that purported to show the foolishness of subjectivist Bayesian inference. In correspondence, Jimmie Savage pointed out what he considered an error in his reasoning, but Popper was unmoved and did not change his example when he reprinted it. It is argued that Popper did not acknowledge that the new subjectivists reasoned with distributions, not simply expected values. Excerpts from Jimmie Savage’s correspondence at the time with Popper and with Allen Wallis highlight the issues involved at this time when Bayesian statisticians were seeking general acceptance.
Expanding the Leibniz Hierarchy
Authors: Almeida Ugo C M , Pinto Darllan Conceição
Published: April 2024

In this work we present two new classes of logics determined by specific properties of the Leibniz operator that expand the Leibniz hierarchy. By doing so, we present a sufficient condition for the commutativity of the Leibniz operator with inverse substitutions/homomorphisms, which gives us a negative answer to the possibility of establishing a precise connection between Leibniz classes and the behavior of the Leibniz operator.
“Doesn’t Matter if It’s Crack or . . . Pesticides, AIDS, It’s All the Same Shit”: Body-Land Metonymies in Cherríe Moraga’s Heroes and Saints
Authors: Miller M A
Published: April 2024

This article closely examines Mario Valle, the seroconverted Chicano gay male minor protagonist in Cherríe Moraga’s play Heroes and Saints (1992) as a case study of Chicanx environmentalism informed by a materially metonymic body-land relationship. The article addresses Mario Valle’s HIV+ status not as a peripheral aberration but as integral to the play. The play renders legible the entangled impact of environmental toxins—pesticide poisoning and AIDS—as necessary to understanding the soothing metonymic acts of substitution queer care makes possible. AIDS and pesticide poisoning, this article argues, are mutually reinforcing and intra-acting embodied parts of an environmental, soil, and land-based whole. Through Moraga’s recuperative lens of “Queer Aztlán,” AIDS can finally be understood as its own unique environmental issue alongside agrochemical usage rather than as a separately delineated social concern of individualized risky behavior. The poetic potential of metonymy does not solely focus on individual human actors in service of one another. Rather, such a literary device considers the environmental nesting potential of part/whole substitutability: human, non/human, and more-than-human parts continuously generate connection and care beyond the borders of skin and soil. There is no membrane of separation between toxic bodies and toxic lands. Characters in the play often fulfill alternative roles, abilities, and bodily parts—a sister acting as a substitute child, lesbian lover, nourishing/nourished mouth for a sibling—in order to alleviate the suffering caused by acts of environmental degradation. Although truncated by enforced forms of toxicity, such contaminated bodies negate negation, producing canceling forms of negativity that are neither anti-relational nor driven toward death. Rather, these body-land relationships reinscribe the possibility for toxic bodies to perform acts of emotional labor and alleviate suffering in the face of forcibly foreclosed futurity.
New evidence of binarity in young α-rich turn-off and subgiant stars: fast rotation and strong magnetic activity
Authors: Yu Jie , Casagrande Luca , Ciucă Ioana , Ting Yuan-Sen , Murphy Simon J , Chen Boquan
Published: April 2024

Young α-rich (YAR) stars within the old Galactic thick disc exhibit a dual characteristic of relative youth determined with asteroseismology and abundance enhancement in α elements measured from high-resolution spectroscopy. The youth origin of YAR stars has been proposed to be binary evolution via mass transfer or stellar mergers. If that is the case, YAR stars should spin rapidly and thus be magnetically active, because they are mass and angular momentum gainers. In this study, to seek this binary footprint, we select YAR stars on the main-sequence turn-off or the subgiant branch (MSTO-SGB) from APOGEE DR17, whose ages and projected rotation velocities (vsin i) can be precisely measured. With APOGEE vsin i and LAMOST spectra, we find that YAR stars are indeed fast rotators and magnetically active. In addition, we observe low [C/N] ratios and high Gaia RUWE in some YAR stars, suggesting that these MSTO-SGB stars probably have experienced mass transfer from red-giant companions. Our findings underscore that magnetic activity can serve as a valuable tool for probing the binary evolution for other chemically peculiar stars, such as red giants with lithium anomalies and carbon-enhanced metal-poor stars.
MaNGA DynPop – V. The dark-matter fraction versus stellar velocity dispersion relation and stellar initial mass function variations in galaxies: dynamical models and full spectrum fitting of integral-field spectroscopy
Authors: Lu Shengdong , Zhu Kai , Cappellari Michele , Li Ran , Mao Shude , Xu Dandan
Published: April 2024

Using the final Mapping Nearby Galaxies at Apache Point Observatory sample of 10K galaxies, we investigate the dark matter (DM) fraction fDM within one half-light radius Re for about 6K galaxies with good kinematics spanning a wide range of morphologies and stellar velocity dispersion. We employ two techniques to estimate fDM: (i) Jeans anisotropic modelling (JAM), which performs DM decomposition based on stellar kinematics and (ii) comparing the total dynamical mass-to-light ratios (M/L)JAM and (M*/L)SPS from stellar population synthesis (SPS). We find that both methods consistently show a significant trend of increasing fDM with decreasing σe and low fDM at larger σe. For 235 early-type galaxies with the best models, we explore the variation of stellar initial mass function (IMF) by comparing the stellar mass-to-light ratios from JAM and SPS. We confirm that the stellar mass excess factor αIMF increases with σe, consistent with previous studies that reported a transition from Chabrier-like to Salpeter IMF among galaxies. We show that the αIMF trend cannot be driven by M*/L or IMF gradients as it persists when allowing for radial gradients in our model. We find no evidence for the total M/L increasing toward the centre. We detect weak positive correlations between αIMF and age, but no correlations with metallicity. We stack galaxy spectra according to their αIMF to search for differences in IMF-sensitive spectral features (e.g. the $\rm Na_{\rm I}$ doublet). We only find marginal evidence for such differences, which casts doubt on the validity of one or both methods to measure the IMF.
Alteration of mechanical stresses in the murine brain by age and hemorrhagic stroke
Authors: Zheng Siyi , Banerji Rohin , LeBourdais Rob , Zhang Sue , DuBois Eric , O’Shea Timothy , Nia Hadi T
Published: April 2024

Residual mechanical stresses, also known as solid stresses, emerge during rapid differential growth or remodeling of tissues, as observed in morphogenesis and tumor growth. While residual stresses typically dissipate in most healthy adult organs, as the growth rate decreases, high residual stresses have been reported in mature, healthy brains. However, the origins and consequences of residual mechanical stresses in the brain across health, aging, and disease remain poorly understood. Here, we utilized and validated a previously developed method to map residual mechanical stresses in the brains of mice across three age groups: 5–7 days, 8–12 weeks, and 22 months. We found that residual solid stress rapidly increases from 5–7 days to 8–12 weeks and remains high in mature 22 months mice brains. Three-dimensional mapping revealed unevenly distributed residual stresses from the anterior to posterior coronal brain sections. Since the brain is rich in negatively charged hyaluronic acid, we evaluated the contribution of charged extracellular matrix (ECM) constituents in maintaining solid stress levels. We found that lower ionic strength leads to elevated solid stresses, consistent with its unshielding effect and the subsequent expansion of charged ECM components. Lastly, we demonstrated that hemorrhagic stroke, accompanied by loss of cellular density, resulted in decreased residual stress in the murine brain. Our findings contribute to a better understanding of spatiotemporal alterations of residual solid stresses in healthy and diseased brains, a crucial step toward uncovering the biological and immunological consequences of this understudied mechanical phenotype in the brain.
OA29 Epigenetic regulation of IL-4 promoter targeting p300 attenuating intervertebral disc degeneration and pain by inhibiting IL-1β
Authors: Cui Haowen , Zheng Zhaomin
Published: April 2024

Background/Aims

Low back pain (LBP) is a prevalent condition primarily caused by intervertebral disc degeneration (IVDD), which imposes a substantial social and medical burden. Effective targeted treatments to prevent the progression of IVDD and alleviate LBP are still lacking. p300, a critical member of the histone acetyltransferase (HAT) family, is involved in the regulation of inflammation. This study aims to investigate the role of p300/IL-4 in IVDD and pain and elucidate the underlying molecular mechanism.

Methods

Human intervertebral disc samples were collected and graded based on the Pfirrmann grading scheme. A rat model of IVDD was established through posterior disc puncture, and various treatments were administered. Human nucleus pulposus cells (NPCs) were isolated and cultured, followed by assessments including qRT-PCR, Western blotting, immunofluorescence, and histopathological analyses. The mechanical and thermal hyperalgesia were assessed using von Frey hair tests and the plantar test, respectively. Chromatin immunoprecipitation (ChIP) and ChIP-qPCR were performed, and lentivirus transduction was used for p300 knockdown.

Results

We investigated the role of CREB binding protein (CBP)/p300 in IVDD. Degenerated nucleus pulposus (NP) tissues from IVDD patients exhibited a significant downregulation of p300 at both nucleic acid and protein levels, while CBP levels remained unchanged. Manipulating p300 expression in NPCs regulated matrix production, with p300 overexpression enhancing aggrecan and collagen II expression and knockdown leading to increased matrix-degrading proteins. In a rat IVDD model, activating p300 function with CTPB (p300-specific activator) alleviated IVDD and pain, while inhibiting p300 with C646 exacerbated IVDD and pain. Transcriptome analysis implicated IL-4 as a downstream effector of p300, and IL-4 demonstrated protective effects against IVDD and pain. Mechanistically, p300 was found to acetylate H3K27 at the IL-4 promoter, promoting its expression.

Conclusion

The novel findings of this study suggest that the p300/IL-4/IL-1β axis may represent a promising therapeutic target for IVDD and LBP. These results propose a hypothesis that, early in the inflammatory phase, NPCs may initiate a self-protective mechanism through p300, aiding itself in preserving a favourable metabolic microenvironment. This mechanism is primarily mediated by the expression of IL-4, which has the capacity to counteract IL-1β, rather than TNF-α.

Disclosure

H. Cui: None. Z. Zheng: None.
OA30 Primary osteoarthritis chondrocyte map of chromatin conformation reveals novel effector genes
Authors: Bittner Norbert , Shi Chenfu , Zhao Danyun , Ding James , Southam Lorraine , Swift Diane , Kreitmaier Peter , Tutino Mauro , Hankinson Jenny , Wilkinson Mark , Orozco Gisela , Zeggini Eleftheria
Published: April 2024

Background/Aims

Osteoarthritis is a complex disease with a huge public health burden. Genome-wide association studies (GWAS) have identified hundreds of osteoarthritis-associated sequence variants, but the effector genes underpinning these signals remain largely elusive. Understanding chromosome organisation in 3D space is essential for identifying long-range contacts between distant genomic features (e.g., between genes and regulatory elements), in a tissue-specific manner. Here, we generate the first whole genome chromosome conformation analysis (Hi-C) map of primary osteoarthritis chondrocytes and identify novel effector genes for the disease.

Methods

Primary chondrocytes collected from eight knee osteoarthritis patients underwent Hi-C analysis to link chromosomal structure to genomic sequence. The identified loops were then combined with osteoarthritis GWAS results to identify variants involved in gene regulation via enhancer-promoter interactions.

Results

We identified 36 genetic variants residing within chromatin loop anchors that are associated with 13 osteoarthritis GWAS signals. Five of these variants reside directly in enhancer regions of 3 enhancer-promoter loops newly described in chondrocytes, pointing to high-confidence effector genes: PAPPA, NSD2 and NCOA6. PAPPA is directly associated with the turnover of IGF-1 transport proteins, and IGF-1 is an important factor in the repair of damaged chondrocytes.

Conclusion

We have constructed the first Hi-C map of primary human chondrocytes and have made it available as a resource for the scientific community. By integrating 3D-genomics with large-scale genetic association data, we identify high-confidence osteoarthritis effector genes which enhance our understanding of disease and can serve as putative high-value novel targets.

Disclosure

N. Bittner: None. C. Shi: None. D. Zhao: None. J. Ding: None. L. Southam: None. D. Swift: None. P. Kreitmaier: None. M. Tutino: None. J. Hankinson: None. M. Wilkinson: None. G. Orozco: None. E. Zeggini: None.
P001 An audit to assess whether patients who had a delayed or missed denosumab dose during the covid-19 pandemic came to any harm or suffered a subsequent fracture
Authors: Rehman Sumaiya , Sultan Shabina
Published: April 2024

Background/Aims

Denosumab is licensed by NICE for the secondary prevention of osteoporosis in patients who are unable to comply, have an intolerance, or contraindication to bisphosphonates. With the outbreak of Covid-19, denosumab appointments were delayed. A delay of denosumab doses by more than 16 weeks is associated with an increased risk of vertebral fractures. This audit was carried out to see if the Pandemic caused a delayed (>1 month) or missed (>6 months) dose in patients receiving their denosumab injection and whether this delay/missed dose resulted in patients coming to any harm such as a subsequent fracture.

Methods

We included 166 patients of which 95% were female. We stratified data utilising the Oberoi consulting clinical audit services which provided a database of patients who were on six monthly repeat prescriptions for Denosumab. Retrospective data was collected including indications for denosumab, start date, duration, missed or delayed doses, reasons for delayed doses and whether a fracture of a pathological nature was sustained. We later reviewed if the missed or delayed doses occurred during the covid pandemic (2020-22) and subsequently, if the fracture occurred as a result of the pandemic.

Results

34/166(21%) patients did not receive their Denosumab dose on time during Covid-19. 21/166(12.6%) patients had a delayed dose (6 pre-Covid and 15 post-Covid) and 13/166 (7.8%) patients missed a dose entirely (3 pre-Covid and 10 post-Covid) showing more delays/missed doses occurred during the pandemic. Reasons as to why patients did not receive timely doses include, clinical reasons (7/34 20.6%), patient safety decisions made by clinicians in patients’ best interest 12/34(35.3%) and patient choice related factors 15/34 (44.1%). Reasons for delays include not wanting repeat bloods, being on holiday, chest infection low Vitamin D levels, pre dose bloods delayed, patient had covid, and isolating. Whilst on Denosumab, 8/166(4.8%) patients sustained a fracture of which 6/8(75%) also experienced a delayed/missed dose during Covid-19.

Conclusion

Of the 34/166 patients that had a delayed/missed dose, eight suffered a fracture bringing the fracture risk to 23.5% which is an increase from baseline (6.6%) confirming that a missed Denosumab dose does increase fracture risk. We can conclude a greater proportion of patients endured a missed or delayed dose as a consequence of the Covid-19 pandemic. 8/166(4.8%) patients sustained a fracture of which six had a missed/delayed dose as a result of the pandemic. The conclusions drawn are in keeping with the MHRA4 alert, a missed dose of Denosumab does increase the risk of pathological treatment discontinuation fractures. This highlights to clinicians the significance of timely doses and uninterrupted treatment.

Disclosure

S. Rehman: None. S. Sultan: None.
P002 A comparison between radiologically reported osteopenia and the FRAX score as an indication for bone densitometry
Authors: Srinivas Sourabh , Hood Katharine , Sapkota Hem
Published: April 2024

Background/Aims

Osteopenia is defined as a bone mineral density score between -1 and -2.5 standard deviations compared to a young adult reference mean (T-score) based on dual energy x-ray absorptiometry (DXA). Radiologists continue to use the term in a generic and qualitative manner to mean decreased bone mineral density, but they cannot distinguish between osteopenia and osteoporosis which means patients then go on to have a DXA. We would like to see if a FRAX (fracture risk assessment tool) can safely replace osteopenia as an indication for a DXA.

Methods

We retrospectively identified 2276 patients to have had a DXA scan from October 2022 to March 2023 according to the departmental database. Their referral forms were obtained from the Electronic Medical Record (EMR). Out of these, 150 patients were referred with a sole indication being radiologically reported osteopenia. Out of 150 patients, 22 were excluded as they were found to have other indications not reported on their referral from and seven more were excluded as three had bilateral hip replacement, three were below 40 and one was undergoing gender reassignment and was on oestrogen. The remaining 121 patients were included in the study and their post BMD ( bone mineral density) FRAX score was obtained from patient EMR. Pre BMD FRAX was also calculated using clinical information available on patient’s EMR retrospectively. NOGG ( National Osteoporosis Guideline Group) recommendation of treatment based on the fracture risk as per the FRAX were then compared between pre and post BMD retrospectively to see if there would be any change in treatment plan.

Results

Of total 121 patients included, 94 were female. Mean age was 68 years. Retrospective review of the case notes revealed that using a FRAX with BMD, total 34 (28.1%) patients needed treatment for osteoporosis while 87 (71.9%) did not. Of 87 patients not requiring treatment, 55 would not have received DXA scan if FRAX assessment was done without BMD. Of the 34 who did need treatment, 32 would still be recommended for a DXA while only two patients wouldn’t. However, these two patients had other clinical indications for osteoporosis assessment and would still have required a specialist referral such that a decision can be made about DXA.

Conclusion

If radiologically reported osteopenia as an indication for a DXA is replaced by FRAX, DXA would not be needed in nearly half of the patients. This will have potential to save scarce DXA resource without compromising patient safety, treatment plan, and will reduce waiting times.

Disclosure

S. Srinivas: None. K. Hood: None. H. Sapkota: None.
P007 Successful use of patient initiated follow-up in a tertiary paediatric rheumatology service
Authors: Calvert William , Spinty Jean , McCann Liza J , Cleary Gavin
Published: April 2024

Background/Aims

Patient initiated follow-up (PIFU) is a national strategy enabling patients or carers to initiate contact with a service rather than a traditional model of routine scheduled appointments. PIFU enables patient empowerment and elective recovery after the Covid-19 pandemic. NHSE identified Paediatrics as appropriate for PIFU, but specific measures are needed to ensure safeguarding of paediatric patients is maintained.

Methods

With NHSE & I support and extrapolating guidance implementing PIFU in adult rheumatology services, we developed a clinical pathway that included safeguarding/governance structures within Paediatric Rheumatology at Alder Hey Children’s Hospital. Two strategies were developed - PIFU culminating with either a timed return (PEND) or discharge (DISCHARGE) model. A PIFU feasibility study in paediatric rheumatology initially targeted three index conditions (arthritis, mechanical pain and primary Raynaud’s) in March 2022. This was extended within a Plan-Do-Study-Act model of Quality Improvement.

Results

We placed 536 patients within PIFU pathways (PEND = 297, DISCHARGE = 239). The monthly usage of PIFU increased from <10 patients per month in March 2022 to > 40 patients per month in August 2023 with expansion of PIFU conditions. Within this time frame the number of patients put through the DISCHARGE model increased steadily to 60% of the monthly proportion as clinician confidence in PIFU increased. We demonstrate an 11% (total Rheumatology patients) PIFU rate over the study time frame, with a 2.7% (15/536) reactivation rate. Where calculable, timescale for review following activation was <48 hours. In our experience, patients/families are comfortable with PIFU and feel reassured by the safety-net provided. Decision for PIFU PEND/DISCHARGE is made in partnership with patients/families. As well as increased use within Rheumatology, PIFU use has extended to 80% of clinical teams across Alder Hey. The Trust-wide PIFU rate of 10% in September 2023 is double the original NHS England guidance target of 5%.

Conclusion

We advocate safety of PIFU in the correct population and its ability to empower patients. Table 1 shows the significant impact that correct use of PIFU can have on increasing capacity for seeing new patients, decreasing time to review and matching the number of patient reviews to referrals.

Disclosure

W. Calvert: None. J. Spinty: None. L.J. McCann: None. G. Cleary: None.
P017 Planned infliximab use during pregnancy for pakistani patients with immune-mediated inflammatory disease - case series of 12 patients
Authors: Tayyab Zaid , Haroon Mohammad
Published: April 2024

Background/Aims

Immune-mediated inflammatory diseases (IMIDs) affect mostly young females during their reproductive age. Therefore, a better understanding is needed about the possible disease effects in pregnancy, as well as the risks of fetal exposure to the medications used. Studies have shown that anti-TNF are considered safe and do not increase the risk of adverse events during pregnancy. Nevertheless, the data is quite limited, hence fall in FDA pregnancy category B. We wish to report a series of 12 pregnant women with IMIDs who were intentionally being treated with infliximab for the treatment of active intractable IMIDs.

Methods

The study included pregnant patients with IMIDs who were treated using anti-TNF between January 2021 to July 2023 at Fatima Memorial Hospital and Doctors Hospital & Medical Centre, Lahore. All patients receiving infliximab were reviewed by a dedicated medical team, who maintained a detailed medical record of each visit. The patients were prospectively followed up and the neonatal outcome was also recorded.

Results

12 pregnant women with IMIDs received Infliximab during this study. All these patients required >7.5mg of deltacortil to control their arthritis and hence decision was made to add bDMARDs. 10 patients successfully completed their pregnancies uneventfully and two additional patients are in the later stages of pregnancy. Seven patients had complete remission of their underlying IMIDs and the rest had overall good improvement but continued to have low grade active disease. All our patients presented a satisfactory response to treatment and the pregnancy progressed without any complications. Median gestational week of birth was 38 with a median birth weight of 3490 grams.

Conclusion

This is the first reported series from Pakistan of intentional infliximab use throughout pregnancy. Our data, combined with many other studies, suggests that anti-TNF is safe during pregnancy and its benefits in achieving control of IMIDs may outweigh the risk of foetal exposure to the drug. This is further supported by the available data suggesting the inflammatory activity as the main risk factor for unfavourable outcome. However, the benefits and risks must be discussed with the patient and management decisions should be taken on individual basis.

Disclosure

Z. Tayyab: None. M. Haroon: None.
P051 Trends in consultations for musculoskeletal pain in children and young people presenting to United Kingdom primary care: an electronic health record study
Authors: Mason Kayleigh J , Jordan Kelvin P , Bailey James , Jöud Anna , Jowett Sue , Protheroe Joanne , Mughal Faraz , Snell Kym I E , Thomas Martin , Dunn Kate M
Published: April 2024

Background/Aims

Musculoskeletal pain in childhood increases the risk of such pain in adulthood but there is an absence of management guidance for this group, not helped by a lack of evidence on the extent and nature of pain in children. The aim was to determine the extent and patterns of consultations for musculoskeletal pain in children and young people (CYP) presenting to UK primary care.

Methods

Data were obtained from an anonymised nationally representative UK primary care electronic health record database (Clinical Practice Research Datalink, CPRD). The study population was patients aged 8-18 years between 2005-2021 with consultations for musculoskeletal pain. Consultation prevalence was calculated per 10,000 registered population for each calendar year, and by age (8-11, 12-15 and 16-18 years), gender and body site (prevalence presented for 2019 prior to COVID-19 pandemic).

Results

1.12 million children and young people (48% female; median age 14 years) were recorded with musculoskeletal pain, with an annual consultation prevalence of over 9% (932/10,000, 95% CI 928-937). Consultation prevalence increased until 2015, stabilised until 2019, and was lower during 2020 due to the COVID-19 pandemic, but climbed slightly in 2021. Consultation prevalence in 2019 was highest for those aged 12-15 years (1105/10,000 vs 8-11 years 736/10,000 and 16-18 years 984/10,000) and for females. Age and gender differences were observed by body site with foot/ankle the most common site of pain in younger children (ages 8-11: females 277/10,000, males 229/10,000,), back the most common site in older females (ages 16- 18: 247/10,000) and knee the most common site in older males (ages 16-18: 178/10,000).

Conclusion

Musculoskeletal pain in CYP is common with almost one in ten consulting primary care annually, but pain sites vary by age and gender. Understanding the extent and nature of musculoskeletal pain in CYP presenting to primary care can help inform targeted and effective care, and underpin much needed intervention studies, potentially reducing risk of continued pain into adulthood.

Disclosure

K.J. Mason: None. K.P. Jordan: None. J. Bailey: None. A. Jöud: None. S. Jowett: None. J. Protheroe: None. F. Mughal: None. K.I.E. Snell: None. M. Thomas: None. K.M. Dunn: None.
P102 Should Fibromyalgia be Diagnosed in Primary or Secondary Care?
Authors: Sykes Mark P
Published: April 2024

Background/Aims

Both the Rheumatology Getting It Right First Time (GIRFT) report, published in February 2021, and the British Society for Rheumatology (BSR) referral guidelines from October 2021 recommend not referring patients with suspected Fibromyalgia to Rheumatology services. In contrast the Royal College of Physicians (RCP) guidelines on Fibromyalgia from 2022 recommend that for unequivocal cases, referral is not necessary, but that referral is appropriate if there is diagnostic uncertainty. We undertook an evaluation of our Rheumatology service to assess whether following either of these guidelines would be appropriate.

Methods

A prospective analysis of all patients referred to one general Rheumatologist over 18 months to assess the accuracy of suspected fibromyalgia diagnoses from primary care. The included cases were all patients referred with possible fibromyalgia on the referral letter, along with patients with an end diagnosis of fibromyalgia.

Results

Seventy-two patients were referred to one consultant with possible fibromyalgia on the referral letter. Of these, only 44 (61%) were confirmed as having fibromyalgia. Common other problems felt by the GP to be fibromyalgia included 2+ areas of localised soft tissue rheumatism (seven patients), localised chronic back pain (six patients) and biomechanical lower limb pains due to flat feet (three patients). Another 39 patients were diagnosed as fibromyalgia when not considered by primary care; nine of these patients were referred on the early arthritis pathway and two patients to the axial spondyloarthritis clinic. Overall this workload only constituted approximately 9% of new patients to the service, with patients with an end diagnosis of fibromyalgia making up approximately 7% of the overall new referrals.

Conclusion

The problems with diagnosing fibromyalgia in primary care are likely multifactorial - general practitioners (GP’s) are very busy and there is an increasing use of allied health professionals (AHP) in primary care, who do not always have the experience or training to diagnose fibromyalgia or other common musculoskeletal conditions. Some GP’s do not feel comfortable diagnosing fibromyalgia and some patients are just not happy with a primary care opinion. Overall, we do not feel that the diagnosis of fibromyalgia can be left solely in the hands of primary care; if the patients in this review had not been referred, then a significant number would have been incorrectly labelled as fibromyalgia, with all the problems that may bring. In view of this, the RCP guidelines would appear more appropriate than the BSR referral guidelines, but even then some of the patients in this review may still have ended up with an incorrect diagnosis, so overall Rheumatology departments should be very cautious about declining referrals for possible fibromyalgia and we continue to see these referrals in our department.

Disclosure

M.P. Sykes: None.