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OBJECTIVE: To assess effects of iron supplementation, 66 mg elemental iron daily as ferrous fumarate, on iron status markers during normal pregnancies. METHODS: Randomized, double-blind, placebo-controlled study of 119 women (62 iron-, 57 placebo -treated) and their newborns. Hemoglobin (Hb), serum (S)-ferritin, S-transferrin saturation percentage (TSAT) and S-erythropoietin (S-EPO) were measured at 14–18, 24–27 weeks of gestation, prepartum, 1 and 8 weeks postpartum. RESULT: From 24–27 weeks gestation to 8 weeks postpartum, the iron group had higher Hb, S-ferritin and TSAT than the placebo group; prepartum, 11% had iron deficiency (ID) and 0% iron deficiency anemia (IDA) in the iron group, vs 60% and 18% in the placebo group; 8 weeks postpartum 1.6% in the iron group had ID and 1.6% IDA vs 14% and 7% in the placebo group. S-EPO levels in the iron group were lower than in the placebo group (p < 0.001). Mothers prepartum S-EPO values were correlated to newborns cord S-EPO values (p < 0.001). Newborns to iron treated mothers had higher cord S-ferritin levels than those to placebo treated mothers (p = 0.02). Newborn girls had higher cord S-ferritin levels than boys (p < 0.01). There was no impact of iron supplementation on the length of gestation, placental weight, or newborns birth weight. Birth weight was correlated only with mothers' body weight, length of gestation and placental weight. CONCLUSION: Iron supplementation had a "positive" impact on iron status and Hb both during pregnancy and postpartum, with a low frequency of ID/IDA and also a "positive" influence on newborns iron status. [ABSTRACT FROM AUTHOR]

Background: Around the world, individuals are living longer, but an increased average lifespan does not always equate to an increased healthspan. With advancing age, the increased prevalence of ageing-related diseases can have a significant impact on health status, functional capacity, and quality of life. It is therefore vital to develop comprehensive classification and staging systems for ageing-related pathologies, diseases and syndromes. This will allow societies to better identify, quantify, understand, and meet the healthcare, workforce, wellbeing, and socioeconomic needs of ageing populations, while supporting the development and utilisation of interventions to prevent or to slow, halt or reverse the progression of ageing-related pathologies., Methods: The foundation for developing such classification and staging systems is to define the scope of what constitutes an ageing-related pathology, disease or syndrome. To this end, a consensus meeting was hosted by the International Consortium to Classify Ageing-Related Pathologies (ICCARP), on February 19 th , 2024, in Cardiff, UK, and was attended by 150 recognised experts. Discussions and voting were centred on provisional criteria that had been distributed prior to the meeting. The participants debated and voted on these. Each criterion required a consensus agreement of ≥70% for approval., Results: The accepted criteria for an ageing-related pathology, disease or syndrome were: Develops and/or progresses with increasing chronological age.Should be associated with, or contribute to, functional decline, or an increased susceptibility to functional decline.Evidenced by studies in humans., Conclusions: Criteria for an ageing-related pathology, disease or syndrome have been agreed by an international consortium of subject experts. These criteria will now be used by the ICCARP for the classification and ultimately staging of ageing-related pathologies, diseases and syndromes.

Rationale & Objective: Research in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) has focused on reducing treatment toxicities, notably through reduction of exposure to glucocorticoids. Glucocorticoid-sparing therapies such as avacopan are not widely available in many countries, and patients are exposed to high glucocorticoid doses. There is little data concerning what clinicians should accept as the lowest glucocorticoid dosing that can be used in induction therapy for AAV., Study Design: International, online survey., Setting & Participants: Clinicians in various countries with experience in managing vasculitis., Exposure and Outcomes: Survey questions to gauge interest and preferences in studying an induction of remission regimen for severe AAV using only 2 or 4 weeks of glucocorticoids without avacopan. Data collected included general opinions about standard of care for induction agents, glucocorticoids, and avacopan. Respondents were presented with 3 candidate trial designs, 2 of which proposed a combination of cyclophosphamide and rituximab induction., Analytical Approach: Using a 10-point Likert scale, respondents ranked each candidate trial on its usefulness in demonstrating whether a minimal glucocorticoid regimen would be safe and effective and their willingness to randomize into the trial., Results: There were 210 respondents to the survey. The candidate trials were rated moderate-to-high for usefulness to demonstrate safety and efficacy (scores 6-7/10), and moderate (scores 5-6/10) for willingness to randomize. Four-week glucocorticoid duration was preferred to 2 weeks, and combination cyclophosphamide-rituximab with 4-week glucocorticoids was the most preferred design. Forty-two percent of respondents felt avacopan had to be incorporated into a minimal GC trial design to want to recruit patients., Limitations: Representativeness of survey sample and generalizability of findings., Conclusions: Combination cyclophosphamide-rituximab may be the ideal way of studying minimal glucocorticoid use in severe AAV. Given its increasing uptake, incorporating avacopan into a potential trial design is important., (© 2024 The Authors.)

Personalized treatment of complex diseases has been mostly predicated on biomarker identification of one drug-disease combination at a time. Here, we use a computational approach termed Disruption Networks to generate a data type, contextualized by cell-centered individual-level networks, that captures biology otherwise overlooked when performing standard statistics. This data type extends beyond the "feature level space", to the "relations space", by quantifying individual-level breaking or rewiring of cross-feature relations. Applying Disruption Networks to dissect high-dimensional blood data, we discover and validate that the RAC1-PAK1 axis is predictive of anti-TNF response in inflammatory bowel disease. Intermediate monocytes, which correlate with the inflammatory state, play a key role in the RAC1-PAK1 responses, supporting their modulation as a therapeutic target. This axis also predicts response in rheumatoid arthritis, validated in three public cohorts. Our findings support blood-based drug response diagnostics across immune-mediated diseases, implicating common mechanisms of non-response., Competing Interests: Declaration of interests These authors disclose the following: Y.C. received consulting fees from AbbVie, Janssen, Takeda, Pfizer, and CytoReason; speaker fees from AbbVie, Janssen, and Takeda; and grants from AbbVie, Takeda and Janssen. S.S.S.-O. received grant fees from Takeda. S.S.S.-O., E.S., R.G., and Y.C. declare CytoReason equity. S.S.S.-O. declares CytoReason advisory fees. Y.C., N.Maimon, and A.K. are employees at CytoReason. S.G.V. declares CytoReason advisory fees. S.S.S.-O., Y.C., S.G.V., A.B., E.S., R.G., and N.Maimon, have a National Phase Patent: WO2022/264134 A1 (METHOD FOR DETERMINING SUITABILITY TO ANTI-TNF ALPHA THERAPY, published as of December 22, 2022). The grant support did not affect study design at any stage., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Diseases change over time, both phenotypically and in their underlying molecular processes. Though understanding disease progression dynamics is critical for diagnostics and treatment, capturing these dynamics is difficult due to their complexity and the high heterogeneity in disease development between individuals. We present TimeAx, an algorithm which builds a comparative framework for capturing disease dynamics using high-dimensional, short time-series data. We demonstrate the utility of TimeAx by studying disease progression dynamics for multiple diseases and data types. Notably, for urothelial bladder cancer tumorigenesis, we identify a stromal pro-invasion point on the disease progression axis, characterized by massive immune cell infiltration to the tumor microenvironment and increased mortality. Moreover, the continuous TimeAx model differentiates between early and late tumors within the same tumor subtype, uncovering molecular transitions and potential targetable pathways. Overall, we present a powerful approach for studying disease progression dynamics-providing improved molecular interpretability and clinical benefits for patient stratification and outcome prediction., (© 2023. The Author(s).)

Objective: In 2020, the Canadian Vasculitis Research Network (CanVasc) published their updated recommendations for the management of ANCA-associated vasculitides (AAV). The current addendum provides further recommendations regarding the use of avacopan in AAV based on a review of newly available evidence., Methods: An updated systematic literature review on avacopan (formerly, CCX168) using Medline, Embase, and the Cochrane Library was performed for publications up to September 2022. New recommendations were developed and categorized according to the EULAR grading levels, as done for previous CanVasc recommendations. A modified Delphi procedure and videoconferences were used to reach ≥80% consensus on the inclusion, wording and grading of each recommendation., Results: Three new recommendations were developed. They focus on avacopan therapy indication and duration, as well as timely glucocorticoid tapering., Conclusion: These 2022 addended recommendations provide rheumatologists, nephrologists and other specialists caring for patients with AAV with guidance for the use of avacopan, based on current evidence and consensus from Canadian experts., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Systemic sclerosis (SSc) is a rare and chronic autoimmune disease characterized by a pathogenic triad of immune dysregulation, vasculopathy, and progressive fibrosis. Clinical tools commonly used to assess patients, including the modified Rodnan skin score, difference between limited or diffuse forms of skin involvement, presence of lung, heart or kidney involvement, or of various autoantibodies, are important prognostic factors, but still fail to reflect the large heterogeneity of the disease. SSc treatment options are diverse, ranging from conventional drugs to autologous hematopoietic stem cell transplantation, and predicting response is challenging. Genome-wide technologies, such as high throughput microarray analyses and RNA sequencing, allow accurate, unbiased, and broad assessment of alterations in expression levels of multiple genes. In recent years, many studies have shown robust changes in the gene expression profiles of SSc patients compared to healthy controls, mainly in skin tissues and peripheral blood cells. The objective analysis of molecular patterns in SSc is a powerful tool that can further classify SSc patients with similar clinical phenotypes and help predict response to therapy. In this review, we describe the journey from the first discovery of differentially expressed genes to the identification of enriched pathways and intrinsic subsets identified in SSc, using machine learning algorithms. Finally, we discuss the use of these new tools to predict the efficacy of various treatments, including stem cell transplantation. We suggest that the use of RNA gene expression-based classifications according to molecular subsets may bring us one step closer to precision medicine in Systemic Sclerosis., Competing Interests: Declaration of Competing Interest All authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: To define criteria based on iron status parameters for the identification of healthy women who do need/do not need iron supplementation during normal pregnancy., Methods: Randomized, double-blind, placebo-controlled study of 113 women (62 iron-, 51 placebo treated) and their newborns. Iron dose was 66 mg elemental iron as ferrous fumarate daily from 14-18 weeks gestation to delivery. Hemoglobin (Hb), serum (S)-ferritin, S-transferrin saturation percentage, and S-erythropoietin were measured during gestation, prepartum, one week and 8 weeks postpartum. The women were divided in groups according to S-ferritin levels at inclusion:<30,≥30,≥40,≥50 and≥60μg/L. Iron deficiency (ID) was defined as S-ferritin < 15μg/L; iron deficiency anemia (IDA) as S-ferritin < 15μg/L and Hb < 110 g/L., Results: Placebo treated women with S-ferritin levels < 30μg/L at inclusion had a much higher incidence of ID/IDA than placebo treated women with S-ferritin levels≥30,≥40,≥50, and≥60μg/L. S-ferritin levels≥40μg/L were associated with a very low risk of ID/IDA and none of the women with levels≥50 and≥60μg/L displayed ID/IDA., Conclusions: Women having S-ferritin < 30μg/L in early pregnancy, have a high risk of ID/IDA and should be recommended ferrous iron supplements in appropriate doses. With increasing iron reserves, i.e., increasing S-ferritin, the need for iron supplements diminishes, and placebo treated women having S-ferritin ≥40μg/L seldom develop IDA. Women with S-ferritin levels≥50 and≥60μg/L or higher, have adequate iron reserves and do not need routine iron prophylaxis in pregnancy. The results support the arguments for an individual iron supplementation guided by iron status, to avoid unwanted side effects of unnecessary iron intake.

The aim was to evaluate patient satisfaction with virtual care, and identify factors associated with level of satisfaction. Surveys were mailed to all patients who had a phone visit at The Ottawa Hospital Rheumatology division. Patients' satisfaction with various aspects of the phone visits was assessed on a 5-point scale and analyzed according to demographic variables using chi-square and regression analyses. Of 2423 surveys mailed, we received 742 responses (31%). Eighty-nine percent of patients were satisfied overall with the phone visit. Statistically significant less satisfaction was seen in patients who spoke to a resident compared to their rheumatologist (p < 0.001), were not called on time (p < 0.001), had difficulty using a telephone (p < 0.001), needed assistance of a second person (p < 0.01), or had new consultations (versus routine follow-up, p = 0.01), the former 3 factors being significant in a multivariate regression analysis. Rheumatology patients expressed a high level of satisfaction with virtual care; however, areas of improvement were identified. Patients' satisfaction will be important to inform future decisions regarding the sustainability of virtual care. Further research is required to understand the impacts of virtual care on patients' Key Points • Patients in rheumatology practice were satisfied with phone visits and preferred this method to in-person visits during the pandemic. • Speaking directly to the rheumatologist, being phoned on time, and the capability of using the telephone were the major determinants of high patient satisfaction. • Based on the identified factors, further improvement of the quality of and satisfaction with phone visits can be pursued given that virtual care may continue longer, beyond the pandemic., (© 2022. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Background: Much remains unknown regarding the response of the immune system to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination., Methods: We employed circulating cell-free DNA (cfDNA) to assess the turnover of specific immune cell types following administration of the Pfizer/BioNTech vaccine., Findings: The levels of B cell cfDNA after the primary dose correlated with development of neutralizing antibodies and memory B cells after the booster, revealing a link between early B cell turnover-potentially reflecting affinity maturation-and later development of effective humoral response. We also observed co-elevation of B cell, T cell, and monocyte cfDNA after the booster, underscoring the involvement of innate immune cell turnover in the development of humoral and cellular adaptive immunity. Actual cell counts remained largely stable following vaccination, other than a previously demonstrated temporary reduction in neutrophil and lymphocyte counts., Conclusions: Immune cfDNA dynamics reveal the crucial role of the primary SARS-CoV-2 vaccine in shaping responses of the immune system following the booster vaccine., Funding: This work was supported by a generous gift from Shlomo Kramer. Supported by grants from Human Islet Research Network (HIRN UC4DK116274 and UC4DK104216 to R.S. and Y.D.), Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine, The Alex U Soyka Pancreatic Cancer Fund, The Israel Science Foundation, the Waldholtz/Pakula family, the Robert M. and Marilyn Sternberg Family Charitable Foundation, the Helmsley Charitable Trust, Grail, and the DON Foundation (to Y.D.). Y.D. holds the Walter and Greta Stiel Chair and Research Grant in Heart Studies. I.F.-F. received a fellowship from the Glassman Hebrew University Diabetes Center., Competing Interests: Declaration of interests I.F.-F., B.G., R.S., and Y.D. have filed patents related to DNA methylation markers., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Disease recovery dynamics are often difficult to assess, as patients display heterogeneous recovery courses. To model recovery dynamics, exemplified by severe COVID-19, we apply a computational scheme on longitudinally sampled blood transcriptomes, generating recovery states, which we then link to cellular and molecular mechanisms, presenting a framework for studying the kinetics of recovery compared with non-recovery over time and long-term effects of the disease. Specifically, a decrease in mature neutrophils is the strongest cellular effect during recovery, with direct implications on disease outcome. Furthermore, we present strong indications for global regulatory changes in gene programs, decoupled from cell compositional changes, including an early rise in T cell activation and differentiation, resulting in immune rebalancing between interferon and NF-κB activity and restoration of cell homeostasis. Overall, we present a clinically relevant computational framework for modeling disease recovery, paving the way for future studies of the recovery dynamics in other diseases and tissues., Competing Interests: Declaration of interests F.J.T. reports receiving consulting fees from ImmunAI and ownership interest in Dermagnostix. S.S.S.-O. holds equity and is a consultant of CytoReason., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)