bluuebunny/crossref_metadata_2025 huggingface dataset:
Morbidity and mortality risks associated with valproate withdrawal in young adults with epilepsy
Authors: Mbizvo Gashirai K , Bucci Tommaso , Lip Gregory Y H , Marson Anthony G
Published: April 2024

Valproate is the most effective treatment for idiopathic generalized epilepsy. Current guidance precludes its use in females of childbearing potential, unless other treatments are ineffective or not tolerated, because of high teratogenicity. This risk was recently extended to males. New guidance will limit use both in males and females aged <55 years, resulting in withdrawal of valproate from males already taking it, as occurs for females. Whether there are risks of personal harm (including injury or death) associated with valproate withdrawal has not yet been quantified for males or females ON valproate, meaning clinicians cannot reliably counsel either sex when discussing valproate withdrawal with them, despite that this concern may be at the forefront of patients’ and clinicians’ minds. We assessed whether there are any morbidity or mortality risks associated with valproate withdrawal in young males and females.

We performed a retrospective cohort study of internationally derived electronic health data within the TriNetX Global Collaborative Network. Included were males and females aged 16–54 years with ≥1 epilepsy disease or symptom code between 1 December 2017 and 1 December 2018, and ≥2 valproate prescriptions over the preceding 2 years (1 January 2015–30 November 2017). Five-year propensity-matched risks of mortality and a range of morbidity outcomes were compared between those remaining ON versus withdrawn from valproate during the 1 December 2017–1 December 2018 recruitment period, regardless of whether switched to another antiseizure medication. Survival analysis was undertaken using Cox-proportional hazard models, generating hazard ratios (HRs) with 95% confidence intervals (CIs).

In total, 8991 males and 5243 females taking valproate were recruited. Twenty-eight per cent of males and 36% of females were subsequently withdrawn from valproate. Valproate withdrawal was associated with significantly increased risks of emergency department attendance [HRs overall: 1.236 (CI 1.159–1.319), males: 1.181 (CI 1.083–1.288), females: 1.242 (CI 1.125–1.371)], hospital admission [HRs overall: 1.160 (CI 1.081–1.246), males: 1.132 (CI 1.027–1.249), females: 1.147 (CI 1.033–1.274)], falls [HRs overall: 1.179 (CI 1.041–1.336), males: 1.298 (CI 1.090–1.546)], injuries [HRs overall: 1.095 (CI 1.021–1.174), males: 1.129 (CI 1.029–1.239)], burns [HRs overall: 1.592 (CI 1.084–2.337)] and new-onset depression [HRs overall 1.323 (CI 1.119–1.565), females: 1.359 (CI 1.074–1.720)]. The risk of these outcomes occurring was 1%–7% higher in those withdrawn from valproate than in those remaining ON valproate. Overall, valproate withdrawal was not associated with increased mortality.

These results may help patients and clinicians have a more informed discussion about personal safety when considering valproate withdrawal.
Effect of using borax decahydrate as nanoparticles additive in blends of spirulina biodiesel/diesel on combustion characteristics and knock intensity
Authors: Singh Ajay Partap , Gautam Puneet Singh
Published: April 2024

In this extensive investigation, the impact of borax decahydrate as a fuel additive in a diesel single-cylinder engine was rigorously examined. Borax decahydrate was introduced at concentrations of 5, 15, 25 and 35 g in 500 ml of biodiesel, forming five unique fuel mixtures with conventional diesel: 90% diesel + 10% spirulina biodiesel (SB10), SB10 + 1 g borax decahydrate (SB10B1), SB10 + 3 g borax decahydrate (SB10B3), SB10 + 5 g borax decahydrate (SB10B5) and SB10 + 7 g borax decahydrate (SB10B7). The investigation encompassed four diverse loading conditions and yielded insightful findings. Notably, at full load, SB10B3 exhibited a higher cylinder peak pressure than diesel, reaching 69.25 bar. Heat release rate profiles demonstrated superior efficiency for SB10 at 50% load, with a cumulative heat release rate of 950 J/°CA, which is lower than the 1050 J/°CA of diesel. Knock intensity (KI) evaluations revealed that, although SB10 and SB10B1 exhibited higher KI than diesel at full load due to elevated peak pressure, SB10B7 showed no knocking across all loads, indicative of reduced in-cylinder combustion. This meticulous numerical analysis emphasizes the potential of borax decahydrate as a catalyst and enhancer, providing valuable insights into the combustion dynamics of these alternative fuel blends and their viability for sustainable and efficient engine performance. In summary, out of all the blends, SB10B3 could be a potential diesel fuel replacement fuel for compression-ignition engines.
The Dmc1 recombinase physically interacts with and promotes the meiotic crossover functions of the Mlh1–Mlh3 endonuclease
Authors: Pannafino Gianno , Chen Jun Jie , Mithani Viraj , Payero Lisette , Gioia Michael , Crickard J Brooks , Alani Eric
Published: April 2024

The accurate segregation of homologous chromosomes during the Meiosis I reductional division in most sexually reproducing eukaryotes requires crossing over between homologs. In baker's yeast approximately 80% of meiotic crossovers result from Mlh1–Mlh3 and Exo1 acting to resolve double-Holliday junction intermediates in a biased manner. Little is known about how Mlh1–Mlh3 is recruited to recombination intermediates to perform its role in crossover resolution. We performed a gene dosage screen in baker's yeast to identify novel genetic interactors with Mlh1–Mlh3. Specifically, we looked for genes whose lowered dosage reduced meiotic crossing over using sensitized mlh3 alleles that disrupt the stability of the Mlh1–Mlh3 complex and confer defects in mismatch repair but do not disrupt meiotic crossing over. To our surprise we identified genetic interactions between MLH3 and DMC1, the recombinase responsible for recombination between homologous chromosomes during meiosis. We then showed that Mlh3 physically interacts with Dmc1 in vitro and in vivo. Partial complementation of Mlh3 crossover functions was observed when MLH3 was expressed under the control of the CLB1 promoter (NDT80 regulon), suggesting that Mlh3 function can be provided late in meiotic prophase at some functional cost. A model for how Dmc1 could facilitate Mlh1–Mlh3's role in crossover resolution is presented.
A Phase 1 Clinical Trial to Assess the Safety and Pharmacokinetics of a Tenofovir Alafenamide/Elvitegravir Insert Administered Rectally for HIV Prevention
Authors: Riddler Sharon A , Kelly Clifton W , Hoesley Craig J , Ho Ken S , Piper Jeanna M , Edick Stacey , Heard Faye , Doncel Gustavo F , Johnson Sherri , Anderson Peter L , Brand Rhonda M , Kunjara Na Ayudhya Ratiya Pamela , Bauermeister José A , Hillier Sharon L , Hendrix Craig W
Published: April 2024

Background

On-demand topical products could be an important tool for human immunodeficiency virus (HIV) prevention. We evaluated the safety, pharmacokinetics, and ex vivo pharmacodynamics of a tenofovir alafenamide/elvitegravir (TAF/EVG, 20 mg/16 mg) insert administered rectally.

Methods

MTN-039 was a phase 1, open-label, single-arm, 2-dose study. Blood, rectal fluid, and rectal tissue were collected over 72 hours following rectal administration of 1 and 2 TAF/EVG inserts for each participant.

Results

TAF/EVG inserts were safe and well tolerated. EVG and tenofovir (TFV) were detected in blood plasma at low concentrations: median peak concentrations after 2 inserts were EVG 2.4 ng/mL and TFV 4.4 ng/mL. Rectal tissue EVG peaked at 2 hours (median, 2 inserts = 9 ng/mg) but declined to below limit of quantification in the majority of samples at 24 hours, whereas tenofovir diphosphate (TFV-DP) remained high >2000 fmol/million cells for 72 hours with 2 inserts. Compared to baseline, median cumulative log10 HIV p24 antigen of ex vivo rectal tissue HIV infection was reduced at each time point for both 1 and 2 inserts (P < .065 and P < .039, respectively).

Discussion

Rectal administration of TAF/EVG inserts achieved high rectal tissue concentrations of EVG and TFV-DP with low systemic drug exposure and demonstrable ex vivo inhibition of HIV infection for 72 hours.

Clinical Trials Registration . NCT04047420.
Endocytic recycling in plants: pathways and regulation
Authors: Qi Wencai , Zhang Yu , Li Mengting , Zhang Peipei , Xing Jingjing , Chen Yanmei , Zhang Liang
Published: April 2024

Endocytic recycling is an intracellular trafficking pathway that returns endocytosed molecules to the plasma membrane via the recycling endosome. This pathway plays a crucial role in remodelling plasma membrane composition and is thus essential for cellular homeostasis. In plants, endocytic recycling regulates the localization and abundance of receptors, transporters, and channels at the plasma membrane that are involved in many aspects of plant growth and development. Despite its importance, the recycling endosome and the underlying sorting mechanisms for cargo recycling in plants remain understudied in comparison to the endocytic recycling pathways in animals. In this review, we focus on the cumulative evidence suggesting the existence of endosomes decorated by regulators that contribute to recycling in plant cells. We summarize the chemical inhibitors used for analysing cargo recycling and discuss recent advances in our understanding of how endocytic recycling participates in various plant cellular and physiological events.
World War I and the Thomas Splint: A Historical Review
Authors: Danford Joseph R , Stinner Daniel J
Published: April 2024

The Thomas splint, the first practical traction splint for femoral fractures, revolutionized the capabilities of military medicine. Its usage in WWI lowered the mortality rate from 80% to nearly 15%. Its development not only shaped modern orthopedics but also established the splint as standard equipment in hospitals worldwide.
The effect of thermal torques on AGN disc migration traps and gravitational wave populations
Authors: Grishin Evgeni , Gilbaum Shmuel , Stone Nicholas C
Published: April 2024

Accretion discs in active galactic nuclei (AGNs) foster black hole (BH) formation, growth, and mergers. Stellar mass BHs migrate inwards under the influence of hydrodynamical torques unless they encounter a region where the torque flips sign. At these migration traps, BHs accumulate and merge via dynamical or gas-assisted interactions, producing high-frequency LIGO/Virgo/KAGRA (LVK) gravitational wave (GW) sources and potentially cutting off the supply of extreme mass ratio inspirals that would otherwise make low-frequency, LISA-band GWs. In this paper, we study the interplay between different types of migration torques, focusing especially on the ‘thermal torques’ generated by the thermal response of the AGN to embedded stellar-mass BHs that accrete through their own mini-discs. In contrast to previous work, we find that Type I torques cannot produce migration traps on their own, but thermal torques often do, particularly in low-mass AGN. The migration traps produced by thermal torques exist at much larger distances (∼103−5 gravitational radii) than do previously identified Type I traps, carrying implications for GW populations at multiple frequencies. Finally, we identify a bifurcation of AGN discs into two regimes: migration traps exist below a critical AGN luminosity, and do not at higher luminosities. This critical luminosity is fit as $\log _{10} L_{\rm AGN}^c = 45 {\!-\!} 0.32 \log _{10}{(\alpha /0.01)}$ where α is the Shakura–Sunyaev viscosity parameter, a range compatible with recent claims that LVK GWs are not preferentially associated with high-luminosity AGN.
Whole-Blood PCR Preferred for Timely Diagnosis of Neuroinvasive West Nile Virus Infections: Lessons From the 2021 Arizona Outbreak
Authors: Kasule Sabirah , Fernholz Emily , Grant Leah , Kole Amy , Grys Thomas E , Kaleta Erin , Theel Elitza S , Pritt Bobbi , Graf Erin H
Published: April 2024

Background

In 2021, the state of Arizona experienced the largest focal outbreak of West Nile virus (WNV) in US history. Timely and accurate diagnostic testing remains a challenge for WNV due to transient viremia and limited immunoassay specificity. Recent studies have identified whole blood (WB) and urine as more sensitive specimen types for the detection of WNV RNA.

Methods

We evaluated ordering practices, test performance, and patient characteristics of probable and confirmed cases. In total, we identified 190 probable and proven cases, including 127 patients (66.8%) with neuroinvasive disease.

Results

Among all cases, only 29.5% had WNV polymerase chain reaction (PCR) testing ordered on WB, of which 80.3% resulted as positive, including 7 cases in which WNV serologic testing was negative and 5 cases for which serologic testing was not ordered. In comparison, only 23.7% of cases that had cerebrospinal fluid (CSF) PCR ordered had a positive result, including 3 cases that were negative by PCR on WB. In contrast, WNV PCR on WB detected 12 neuroinvasive cases that were CSF PCR negative. WNV PCR testing in urine was only ordered on 2 patients, both of whom were positive. Crossing cycle threshold (Ct) values were not significantly different between WB and CSF specimen types, nor was there a correlation between Ct value and days from symptom onset at the time of sample collection; all specimen types and time points had Ct values, with 98% above 30. WB was positive by WNV PCR in several patients for >7 days (range, 7–25 days) after symptom onset, as was the CSF PCR.

Conclusions

Taken together, these findings indicate that WNV PCR testing on WB may be the best initial test for timely diagnosis of WNV infection, irrespective of clinical manifestation; however, if negative in patients with suspected neuroinvasive disease, WNV PCR testing on CSF should be ordered.
Sex Differences in the Immunogenicity and Efficacy of Seasonal Influenza Vaccines: A Meta-analysis of Randomized Controlled Trials
Authors: Tadount Fazia , Kiely Marilou , Assi Ali , Rafferty Ellen , Sadarangani Manish , MacDonald Shannon E , Quach Caroline
Published: April 2024

Background

Sex impacts individuals’ response to vaccination. However, most vaccine studies do not report these differences disaggregated by sex. The aim of this study was to assess sex differences in the immunogenicity and efficacy of influenza vaccine.

Methods

We performed a meta-analysis using phase 3 randomized controlled trial data conducted between 2010 and 2018. Using hemagglutination inhibition antibody titers for each strain, differences in geometric mean ratios (GMRs) were calculated by sex. Risk ratios (RRs) comparing seroconversion proportions were pooled for females and males using random-effects models. Vaccine efficacy (VE) was assessed. Data were analyzed by age group (18–64 vs ≥65 years).

Results

A total of 33 092 healthy adults from 19 studies were included for immunogenicity analysis, and 6740 from 1 study for VE. Whereas no sex differences in immunogenicity were found in adults <65 years old, older females had a significantly greater chance to seroconvert compared to older males for all strains: RRH1N1 = 1.17 [95% confidence interval {CI}, 1.12–1.23]; RRH3N2 = 1.09 [95% CI, 1.05–1.14]; RRVictoria = 1.23 [95% CI, 1.14–1.31]; RRYamagata = 1.22 [95% CI, 1.14–1.30]. GMRs were also higher in older females for all strains compared to older males. VE in preventing laboratory-confirmed influenza was higher in older females compared to older males with VEs of 27.32% (95% CI, 1.15%–46.56%) and 6.06% (95% CI, −37.68% to 35.90%), respectively.

Conclusions

Our results suggest a higher immunogenicity and VE in females compared to males in older adults. These differences in immunogenicity and VE support the disaggregation of vaccine data by sex in clinical trials and observational studies.

Clinical Trials Registration

CRD42018112260.
Community-Based Services for Hospitalized Patients With Serious Injection-Related Infections in Alabama: A Brief Report
Authors: Gagnon Kelly W , Bradford William , Bassler John , Nassel Ariann , Kay Emma Sophia , Jeziorski Madison , Prados Myles , McCleskey Brandi , Kobie James , Eaton Ellen
Published: April 2024

Injection-related infections continue to rise, particularly in the South. People who inject drugs are increasingly utilizing hospital services for serious injection-related infections but may be discharged to areas without harm reduction services. We explored the availability and travel time to services for HIV and substance use in Alabama.
Automated Quantitative CD8+ Tumor-Infiltrating Lymphocytes and Tumor Mutation Burden as Independent Biomarkers in Melanoma Patients Receiving Front-Line Anti-PD-1 Immunotherapy
Authors: Fortman Dylan , Karunamurthy Arivarasan , Hartman Douglas , Wang Hong , Seigh Lindsey , Abukhiran Ibrahim , Najjar Yana G , Pantanowitz Liron , Zarour Hassane M , Kirkwood John M , Davar Diwakar
Published: April 2024

Background

CD8+ tumor-infiltrating lymphocyte (TIL) predicts response to anti-PD-(L)1 therapy. However, there remains no standardized method to assess CD8+ TIL in melanoma, and developing a specific, cost-effective, reproducible, and clinically actionable biomarker to anti-PD-(L)1 remains elusive. We report on the development of automatic CD8+ TIL density quantification via whole slide image (WSI) analysis in advanced melanoma patients treated with front-line anti-PD-1 blockade, and correlation immunotherapy response.

Methods

Seventy-eight patients treated with PD-1 inhibitors in the front-line setting between January 2015 and May 2023 at the University of Pittsburgh Cancer Institute were included. CD8+ TIL density was quantified using an image analysis algorithm on digitized WSI. Targeted next-generation sequencing (NGS) was performed to determine tumor mutation burden (TMB) in a subset of 62 patients. ROC curves were used to determine biomarker cutoffs and response to therapy. Correlation between CD8+ TIL density and TMB cutoffs and response to therapy was studied.

Results

Higher CD8+ TIL density was significantly associated with improved response to front-line anti-PD-1 across all time points measured. CD8+ TIL density ≥222.9 cells/mm2 reliably segregated responders and non-responders to front-line anti-PD-1 therapy regardless of when response was measured. In a multivariate analysis, patients with CD8+ TIL density exceeding cutoff had significantly improved PFS with a trend toward improved OS. Similarly, increasing TMB was associated with improved response to anti-PD-1, and a cutoff of 14.70 Mut/Mb was associated with improved odds of response. The correlation between TMB and CD8+ TIL density was low, suggesting that each represented independent predictive biomarkers of response.

Conclusions

An automatic digital analysis algorithm provides a standardized method to quantify CD8+ TIL density, which predicts response to front-line anti-PD-1 therapy. CD8+ TIL density and TMB are independent predictors of response to anti-PD-1 blockade.
Erasing marks: Functions of plant deubiquitylating enzymes in modulating the ubiquitin code
Authors: Vogel Karin , Isono Erika
Published: April 2024

Plant cells need to respond to environmental stimuli and developmental signals accurately and promptly. Ubiquitylation is a reversible posttranslational modification that enables the adaptation of cellular proteostasis to internal or external factors. The different topologies of ubiquitin linkages serve as the structural basis for the ubiquitin code, which can be interpreted by ubiquitin-binding proteins or readers in specific processes. The ubiquitylation status of target proteins is regulated by ubiquitylating enzymes or writers, as well as deubiquitylating enzymes (DUBs) or erasers. DUBs can remove ubiquitin molecules from target proteins. Arabidopsis (A. thaliana) DUBs belong to 7 protein families and exhibit a wide range of functions and play an important role in regulating selective protein degradation processes, including proteasomal, endocytic, and autophagic protein degradation. DUBs also shape the epigenetic landscape and modulate DNA damage repair processes. In this review, we summarize the current knowledge on DUBs in plants, their cellular functions, and the molecular mechanisms involved in the regulation of plant DUBs.
Sexual harassment and psychological distress experienced by women police: The role of embitterment and psychological contract breach
Authors: Drew Jacqueline M , Chevroulet Chantal
Published: April 2024

Despite decades of workplace interventions, often focussed on increasing women police numbers, women continue to be under-represented in policing. Understanding the experiences of women once they have entered policing has been an area of ongoing interest. Examination of the experiences of women police is often undertaken with reference to its masculinized culture. Stemming from these discussions, sexual harassment remains a persistent concern across many police agencies. This study involves 491 women police employed in one large Australian, state police organization. Derived from the study findings, the concepts of psychological contract breach (PCB) and embitterment, two factors that have been rarely studied in policing, are critical to understanding the relationship between sexual harassment and psychological distress. Using mediated regression analysis, the research found PCB and embitterment provide a more nuanced explanation of outcomes of sexual harassment experiences and in turn, provided insight into why sexual harassment is associated with greater psychological distress. This research positions police agencies and their leaders to develop and implement more effective support strategies for women police who have experienced sexual harassment and mitigate negative psychological health impacts that may result.
The normative property dualism argument
Authors: Hambly Jesse
Published: April 2024

In this paper, I develop an argument against a type of Non-Analytic Normative Naturalism. This argument, the Normative Property Dualism Argument, suggests that if Non-Analytic Normative Naturalists posit that normative properties are identical to natural properties and that such identities are a posteriori, they will be forced to posit that these properties that are both normative and natural have higher-order normative properties of their own.
Consensual discrimination
Authors: Bengtson Andreas , Munch Lauritz Aastrup
Published: April 2024

What makes discrimination morally bad? In this paper, we discuss the putative badness of a case of consensual discrimination to show that prominent accounts of the badness of discrimination—appealing, inter alia, to harm, disrespect, and inequality—fail to provide a satisfactory answer to this question. In view of this, we present a more promising account.
Do thematic funding instruments lead researchers in new directions? Strategic funding priorities and topic switching among British grant recipients
Authors: Madsen Emil Bargmann , Nielsen Mathias Wullum
Published: April 2024

Research agencies increasingly use thematic funding schemes to steer scientists toward issues of political interest. Funders set strategic priorities and expect scientists to follow the money. Using statistical-matching methods, we paired 10,475 UK-based recipients of thematic grants (with aims proposed by the funding agency) and responsive-mode grants (with aims proposed by researchers) in Physics, Engineering, and Bioscience to investigate the relation between funding-type and shifts in scientists’ research interests. We applied citation-based community detection to create individual time-series of topic distributions based on the grantees’ publications, and used these to estimate funding-related shifts in research focus. Our analysis, which estimates the similarity of the grantees’ research focus before, during and after a grant, suggests that scientists acquiring thematic funding alter their research interests more than comparable scientists funded through responsive-mode schemes. However, recipients of both types of grants tend to revert toward their original research interests when the funding expires. We find no evidence that thematic funding increases the level of diversity in a recipient’s research portfolio. Our study thus highlights an ambiguous link between thematic funding mechanisms and researchers’ orientations.
OA07 Is the SPADE tool a suitable way of screening patients for possible axial spondyloarthropathy
Authors: Nadin Thomas , Crompton Samuel , Chopra Annu , Kotnis Nikhil , Dunkley Lisa
Published: April 2024

Background/Aims

There are often significant delays to the diagnosis of axial spondyloarthritis (AxSpA). The imaging modality of choice to investigate for AxSpA is an MRI with a specific AxSpA protocol (MRI AS protocol). A common route of referral for MRI scans looking for AxSpA is via the community physiotherapy team. The Spondyloarthritis Diagnosis Evaluation (SPADE) tool has been designed to estimate the probability of patients having AxSpA. This study aimed to look at the relationship between SPADE tool probability score and MRI AS protocol results in patients who were referred from community physiotherapy.

Methods

This was a retrospective service evaluation. The sample was obtained from 200 MRI AS protocol requests between 6 January 2020 and 15 December 2021. For each patient, the MRI result was obtained from ICE electronic results software. MRI results were categorised as AxSpA, not AxSpA, or equivocal. For equivocal results, electronic patient notes were reviewed to identify whether patients went on to be diagnosed with AxSpA. The patient SPADE score (improbable, additional tests necessary, probable diagnosis, or definite diagnosis) was recorded for each patient. Information was obtained from the electronic physiotherapy notes to determine a SPADE score.

Results

Of the 200 scans requested, 21 scans were excluded (eight due to AS protocol not being performed; six due to duplicate requests; four not investigating for AxSpA; two where radiology had suggested MRI AS protocol; one patient awaiting recall for a repeat scan). Of the 179 patients who had MRI scans, 9.5% (n = 17) showed AxSpA, 8.9% were equivocal (n = 16) and 81.6% (n = 146) were negative. A SPADE score was determined for 177 patients (two had insufficient data to determine a score). 30% (n = 53) of patients were ‘improbable’, 56% (n = 99) were ‘additional tests necessary’, 8% (n = 14) were ‘probable’ and 6% (n = 11) were ‘definite’. Of the ‘improbable’ cases, three had MRI demonstrating AxSpA and one was equivocal (4/53 [7.5%]). 49 patients had no MRI evidence of AxSpA. Of the patients with MRI positive scans, 3/17 (17.6%) were ‘improbable’ using the SPADE tool.

Conclusion

Having a tool to screen patients in the community may help to better identify those who warrant further investigation for AxSpA. The SPADE tool may be a useful aid to identify who to refer for further investigation of inflammatory back pain. Many patients identified as ‘improbable’ by the SPADE tool did not have evidence of AxSpA. If the tool was applied prospectively, this may lead to large reduction in the number of MRI AS protocol scans performed. However, there were a small number of ‘improbable’ cases who had MRI evidence of AxSpA and could therefore be misdiagnosed as non-inflammatory back pain.

Disclosure

T. Nadin: None. S. Crompton: None. A. Chopra: None. N. Kotnis: None. L. Dunkley: Honoraria; Abbvie, UCB, Pfizer and Novartis. Other; Speakers fees from Abbvie, UCB, Pfizer and Novartis.
OA13 Alkaptonuria: a big mimic
Authors: Shah Meera , Kumar Upadhyaya Sundeep
Published: April 2024

Background/Aims

Alkaptonuria is a rare metabolic disorder, often misdiagnosed as spondyloarthritis or degenerative musculoskeletal disease. The population most affected are young males in their 30s with characteristic arthritis involving the spine and large joints. The patient may notice their urine turning dark on standing and pigmentation over the skin and connective tissues (ochronosis); however, these subtle features may sometimes go unnoticed.

Methods

A 38-year-old-male with long standing back pain presented with right knee swelling. With a diagnosis of spondyloarthritis, he was previously treated with DMARDS but did not have any relief. There was a history of urine turning dark on standing. On examination, there was subtle hyperpigmentation over left ear concha and a spot on the sclera. An x-ray of the thoracic spine showed flattening and calcification of intervertebral disc spaces at multiple levels. Aspiration of synovial fluid showed suspended fragments of articular cartilage. His inflammatory markers were negative. We performed gas chromatography mass spectrometry which showed elevated excretion of homogentisic acid (HGA). A homozygous pathogenic variant in the homogentisate 1,2-dioxygenase gene associated with alkaptonuria was reported on whole genome sequencing.

Results

Ochronotic arthropathy is defined as progressive degenerative joint disease mainly affecting the spine and large joints. Most patients require at least one joint replacement by age 55. Small joints of hands and feet and sacroiliac joints are usually spared. Arthroscopy of the joint may reveal dark brown to black pigmented cartilage defects. The synovium may show fragments of pigmented cartilage suspended in the fluid (ground pepper sign). Plain spine radiographs may show flattening and calcifications of the intervertebral discs with a characteristic vacuum phenomenon (radiolucent gas collection). Periarticular structures like tendons and ligaments are also affected, leading to rupture in around 20-30% of patients. Alkaptonuria is also associated with decreased bone mineral density and subsequent risk for fragility fracture.

Conclusion

Alkaptonuria often mimics ankylosing spondylitis. A triad of ochronosis, dark urine and ochronotic arthropathy is the key to diagnosis. Definitive diagnosis is through biochemical or genetic testing. Nitisinone has proved to be effective but shows significant side effects. Management mainly involves physiotherapy and palliative care.

Disclosure

M. Shah: None. S. Upadhyaya: None.
OA33 Factors associated with systemic lupus erythematosus patient concordance to medication: does nurse initiated therapy make a difference?
Authors: Salerno Rosaria , Ali Sasha Saadia , Dell’Accio Flora , Lapham Heather , Dobson Joanne , Gordon Patrick , Wincup Chris
Published: April 2024

Background/Aims

Medication non-concordance in systemic lupus erythematosus (SLE) is associated with a higher risk of flares, hospitalisations and mortality. Patient non-concordance involves a complex interplay of both patient and physician factors including communication, the nature and severity of disease, treatment and the clinician-patient relationship. We hypothesise that patients starting medication initiated by a specialist nurse would achieve better rates of medication concordance.

Methods

A retrospective analysis of patients attending the tertiary lupus clinic at King’s College Hospital was undertaken. Inclusion criteria included patients with a diagnosis of lupus being initiated on conventional DMARD therapy (mycophenolate, methotrexate or azathioprine) who had their medication prescribed and dispensed by the hospital pharmacy. Those starting biologics or receiving medication via shared care agreements were excluded. Patients were defined as concordant if they renewed all 3-monthly prescriptions over a 12 month period. Demographics, disease activity, employment status and ethnicity were recorded. We sought to assess differences in concordance between those initiated by nurse specialists vs doctors, and between those given written vs online information about the drug. Statistical analyses was performed using t-tests and Chi square.

Results

45 patients were included in the analysis. The median age was 41.52 ± 12.04 years old with 86.9% females. 65% of patients were of black ethnicity, 56.5% of patients were employed and the median SLEDAI-2K score was 6 (6,8). 65% of patients were on mycophenolate, 26% on azathioprine and 6.5% on methotrexate. Concordance is summarised in the attached Table. In total, 64% (29/45) were concordant with medications over 12 months. All patients initiated by a nurse were concordant for the full 12 months, compared to only 6% (1/17) if initiated by a doctor. Interestingly, concordance was significantly higher if patients were given an online link to an information leaflet compared to when a paper leaflet was provided.

Conclusion

These findings suggest that patients with SLE who are initiated on DMARD therapy by a nurse specialist are markedly more likely to be concordant at 12 months when compared with those initiated by doctors, emphasising the vital role of nurse specialists in the care of patients with SLE.

Disclosure

R. Salerno: None. S. Ali: None. F. Dell’Accio: None. H. Lapham: None. J. Dobson: None. P. Gordon: None. C. Wincup: None.
P011 Time to diagnosis for different types of inflammatory arthritis
Authors: Jeyaratnam Sangeeta , Fish Sarah , Horton Sarah , Madan Ayesha , Rao Chandini , MacPhie Elizabeth
Published: April 2024

Background/Aims

Timely diagnosis of inflammatory arthritis (IA) is crucial for optimising patient outcomes. However, it is appreciated that some types of inflammatory arthritis may be more challenging to diagnose as they present very differently. The National Early Inflammatory Arthritis Audit (NEIAA) provides the opportunity for rheumatology services to benchmark the care they provide. This project used NEIAA to investigate if there is a difference in time to diagnosis for rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (AxSpA).

Methods

Lancashire and South Cumbria Foundation Trust (LSCFT) recruited patients diagnosed with an IA to NEIAA over a five-year period (May 2018 to March 2023). Information on demographics, duration of symptoms prior to referral, GP referral time and rheumatology waiting time were analysed.

Results

A total of 393 patients with either RA, PsA or AxSpA were included in the analysis. There was a higher proportion of patients from minority ethnic backgrounds in the AxSpA group. The ratio of female to male was >1 in RA and PSA but approximately 1:1 in AxSpA. The mean ages of patients in the RA, PsA and AxSpA groups were 60, 49 and 40 years, respectively. Table 1: Difference in time to diagnosis for the different types of IA, highlights the median time to diagnosis. Median was used due to outliers in data. Patients with AxSpA had the longest average duration of symptoms prior to presenting to the GP, with nearly 80% having symptoms for over a year. GP referral time was significantly shorter in the AxSpA group. Time to first rheumatology appointment was similar across the three groups.

Conclusion

There is a difference in time to diagnosis for the different types of IA. Further work is needed to understand why patients with AxSpA are presenting so late to their GP before being referred. We recognise the importance of exploring whether patients with AxSpA have been referred to other specialities or healthcare professionals. Investment in clinical triage and education sessions for primary care may help explain these results. More focus is needed on raising public awareness locally.

Disclosure

S. Jeyaratnam: None. S. Fish: None. S. Horton: None. A. Madan: None. C. Rao: None. E. MacPhie: None.
P015 Nodular skin rash associated with relapsing polychondritis, a challenging diagnostic journey to VEXAS syndrome
Authors: Gunawardena Methsala , Yalakki Leena , Moitra Rupak , Williams Emma L , Wong Henna , D'Cruz David
Published: April 2024

Background/Aims

VEXAS syndrome, first described in 2020, is a haemato-inflammatory disease caused by a mutation in the gene-UBA1.This syndrome can coexist with or without Myelodysplastic syndrome. What makes this case interesting is its long and challenging diagnostic journey and the involvement of different clinical specialties such as dermatology, ophthalmology, rheumatology, respiratory, haematology, and stroke teams. Ultimately, two years after the initial presentation, this appeared to be the first case of VEXAS with confirmed genetic mutation in the region. VEXAS being a relatively new entity, treating clinician/s were not aware of the possibility initially. Therefore, spreading awareness regarding the clinical picture of VEXAS is prudent. This case report highlights rheumatological and dermatological manifestations of the disease to aid in the timely diagnosis and management of future cases.

Methods

We report a 74-year-old previously healthy male presented in 2021 with a rash on his legs, arms, and torso since October 2019. It was progressive, painful, palpable, erythematous, non-pruritic, intermittent rash, cleared with hyperpigmentation. He also had oligoarticular arthritis, constitutional symptoms, recurrent episodes of polychondritis, uveitis, bibasal lung fibrosis, and an ESR and CRP above 100. He also had lymphadenopathy above the diaphragm, but the biopsy only showed necrotic material, and the bone marrow biopsy did not show any features of haematological malignancy. After excluding infections, he was started on high-dose oral prednisolone for relapsing polychondritis. The skin and inflammatory markers improved immediately following high doses of steroids. However, whenever steroids were weaned down, even with the help of Methotrexate, his skin was flaring. He also had unprovoked DVT and, while on anticoagulation, developed occipital infarction. He had extensive skin involvement when he had to stop Methotrexate following a chest infection.

Results

The skin biopsy was inconclusive. There was no significant cytopenia but persistent macrocytosis even after stopping Methotrexate. As a result, he underwent a repeat bone marrow biopsy, which showed Vacuoles and gene UBA1 mutation in 2023.

Conclusion

The heterogeneity and complexity of the disease are due to multi-organ involvement, including skin, joints, eyes, lungs, blood vessels, and cartilage, simultaneously or cumulatively. Skin involvement in VEXAS can also be vast, ranging from neutrophilic dermatosis, erythema nodosum-like lesions, leukocytoclastic, or urticarial vasculitis. Cutaneous manifestations develop in the majority with VEXAS syndrome and can be the first presenting symptom in this new rare syndrome.

Disclosure

M. Gunawardena: None. L. Yalakki: None. R. Moitra: None. E.L. Williams: None. H. Wong: None. D. D'Cruz: None.
P019 Comparison of newly proposed chronic nonbacterial osteomyelitis classification criteria to previous diagnostic criteria
Authors: Patel Aarat M , Lee Kelley S , Kim Ashley J
Published: April 2024

Background/Aims

Chronic nonbacterial osteomyelitis (CNO) is an aseptic autoinflammatory bone disease of unknown etiology. This diagnosis can be delayed due to the non-specific nature of symptoms and normal imaging studies. New classification criteria were proposed in 2022. This study seeks to validate these new classification criteria by comparing them to previous diagnostic criteria in a cohort of known CNO patients.

Methods

This is a retrospective case-series of pediatric patients diagnosed with CNO (n = 39) between 2012 and 2023 in Virginia, USA. The newly proposed classification criteria (Table 1) was applied to this cohort. The entry criteria of chronic bone pain, age <18 years, abnormal radiograph and/or MRI were used prior to applying the newly proposed classification criteria. The 2008 Jansson diagnostic criteria and 2016 Bristol diagnostic criteria were also applied to the cohort for comparison and further validation. The clinical manifestations, laboratory results, and imaging studies that lead to a diagnosis of CNO were reviewed.

Results

The average age of diagnosis was 10 (range 2-17) years-old with the average time between onset of symptoms to confirmed clinical diagnosis being 24 (range 1-120) months. The most common presenting symptoms were bone pain (100%) and arthritis (49%). Evidence of radiographic abnormalities leading to CNO diagnosis was found with regional MRI (64%), bone scan (44%) with some requiring full body MRI (31%). Only one patient did not meet the new classification criteria (1/39; 3%) because of age <3 years, fever and elevated ESR which together gave less than the required 55 points for criteria fulfillment. One different patient (1/39; 3%) did not meet both the Bristol and Jansson criteria because of unifocal disease and lack of bone biopsy.

Conclusion

This retrospective chart review validates the newly proposed classification criteria for CNO. Older diagnostic criteria (Jansson and Bristol) both require advanced imaging and at times bone biopsy for fulfillment. We conclude that the newly proposed criteria is easy to apply even in the absence of a bone biopsy or advanced imaging studies. The newly proposed criteria will aid in the development of a homogeneous cohort for future studies about CNO.

Disclosure

A.M. Patel: Member of speakers’ bureau; ABBVIE, AMGEN, SANOFI. K.S. Lee: None. A.J. Kim: None.
P028 Progressive multifocal leukoencephalopathy in a patient with systemic lupus erythematosus
Authors: Babla Deep , Suleman Yasir , Whittington Ashley , Hamdulay Shahir
Published: April 2024

Background/Aims

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease that develops following the reactivation of the John Cunningham virus (JCV) that in rare circumstances can occur in autoimmune disorders such as systemic lupus erythematosus (SLE). We present a 75-year-old female with SLE who had been treated with immunosuppressive therapy (mycophenylate and steroids) for one year.

Methods

A 75 year-old female presented with sub-acute deterioration of physical and cognitive function over the course of a few months including memory loss, ataxia, dysgraphia, word finding difficulty, confusion, low mood and reduced oral intake. Neurological examination revealed receptive and expressive aphasia, gaze fixation, unilateral weakness, brisk reflexes with positive plantar reflex and rigidity. A diagnosis of PML was made due to the detection of JC virus in the cerebrospinal fluid (234 copies/ml) and brain MRI findings consistent with the disease. Haematology results showed a profound lymphopenia (0.1x109 ). Mycophenolate was held and she was commenced on increasing doses of Mirtazapine up to 45mg. Clinical review at four months found marked improvement in her cognitive and physical abilities. Repeat CSF analysis found JC virus to be undetectable.

Results

PML has a 20-fold greater incidence in SLE when compared with the general population. Lymphopenia is a common finding in patients with SLE and has been found to correlate with both the risk and severity of opportunistic infections. The cause of this can be multifactorial and immunosuppressive drugs are often implicated however SLE in isolation can cause severe CD4+ lymphopenia leading to an increased risk of PML reactivation. This case demonstrates the importance of monitoring lymphocyte counts in SLE. Current guidance suggests adjusting regimes of immunosuppressive therapy if lymphocyte counts fall below 1x109 however further guidance on its management may be warranted. The heterogenous manifestation of SLE can make differentiating between the neurological syndromes associated with rheumatic disease and PML challenging. Given the management of PML is vastly different to that of SLE in regards to introduction or withdrawal of immunosuppressive therapies, there should be a high index of clinical suspicion in the early stages of investigation. In vitro studies have explored the possibility of mirtazapine (a 5-HT2A antagonist) providing a low-risk treatment option for those with SLE and this warrants further research into its efficacy in treating or preventing PML in this cohort. Our patient had improved symptomology after cessation of mycophenolate and the commencement of Mirtazapine.

Conclusion

PML is a rare complication of SLE but should be considered in patients admitted with neuropsychiatric presentations, the use of Mirtazapine may provide a low-risk treatment strategy.

Disclosure

D. Babla: None. Y. Suleman: None. A. Whittington: None. S. Hamdulay: None.
P039 A systematic review and meta analysis of anti rheumatic drugs and pneumococcal vaccine immunogenicity in inflammatory arthritis
Authors: Nagra Deepak , Bechman Katie , Adas Maryam , Yang Zijing , Alveyn Edward , Patel Samir , Russell Mark , Norton Sam , Wincup Chris , Baldwin Christopher , Galloway James
Published: April 2024

Background/Aims

Pneumococcal pneumonia is an important cause of morbidity and mortality amongst patients with inflammatory arthritis. Vaccination is recommended by the National Institute of Clinical Excellence (NICE) but it remains unclear how vaccine efficacy is impacted by different immunosuppressive agents. Our objective was to compare the chance of a seroconversion following vaccination against pneumococcus in patients with inflammatory arthritis to the general population as well as to compare the chance of seroconversion across different targeted therapies.

Methods

We searched MEDLINE, Embase and the Cochrane library databases from inception until 20th June 2023. We included randomised controlled trials and observational studies. Aggregate data were used to undertake pairwise meta-analysis. Our primary outcome of interest was vaccine seroconversion. We accepted the definition of serological response reported by the authors of each study.

Results

20 studies identified in the systematic review (2,807 patients) with 10 reporting sufficient data to be included in the meta-analysis (1,443 patients). The odds of seroconversion in patients receiving targeted therapies, relative to the general population, was 0.61 (95% CI 0.35 to 1.08). The reduced odds of response was skewed strongly by the effects of abatacept and rituximab with no difference between patients on TNF inhibitors or IL6 inhibition and healthy controls. In the analysis comparing within inflammatory arthritis populations the findings remained consistent with rituximab having the strongest negative impact on vaccine response. TNF inhibition monotherapy associated with a greater odds of vaccine response compared with methotrexate (2.25 (95% CI 1.28 to 3.96)). JAK inhibitor studies were few in number and did not present comparable vaccine response endpoints to include in meta-analysis. The information available does not suggest a significant detrimental effects of JAK inhibitor on vaccine response.

Conclusion

This updated meta-analysis confirms that for the majority of patients with inflammatory arthritis, pneumococcal vaccine can be administered with confidence that it will achieve comparable seroconversion rates to the healthy population. Patients on rituximab were the group least likely to achieve a response and further research is needed to explore the value of multiple course pneumococcal vaccination schedules in this population.

Disclosure

D. Nagra: Honoraria; Abbvie, Galapagos, UCB. K. Bechman: None. M. Adas: None. Z. yang: None. E. Alveyn: None. S. Patel: None. M. Russell: None. S. Norton: None. C. Wincup: None. C. Baldwin: None. J. Galloway: None.