The clinical outcomes and healthcare resource utilization in IgG4-related disease: a claims-based analysis of commercially insured adults in the United States.

OBJECTIVES: IgG4-related disease (IgG4-RD) can affect nearly any organ and is often treated with glucocorticoids, which contribute to organ damage and toxicity. Comorbidities and healthcare utilization in IgG4-RD are poorly understood. METHODS: We conducted a cohort study using claims data from a United States managed care organization. Incident IgG4-RD cases were identified using a validated algorithm; general population comparators were matched by age, sex, race/ethnicity, and index date. The frequency of 21 expert-defined clinical outcomes associated with IgG4-RD or its treatment and healthcare-associated visits and costs were assessed 12 months before and 36 months after the index date (date of earliest IgG4-RD-related claim). RESULTS: There were 524 cases and 5,240 comparators. Most cases received glucocorticoids prior to (64.0%) and after (85.1%) the index date. Nearly all outcomes, many being common glucocorticoid toxicities, occurred more frequently in cases vs comparators. During follow-up, the largest differences between cases and comparators were seen for gastroesophageal reflux disease (prevalence difference: +31.2%, p< 0.001); infections (+17.3%, p< 0.001); hypertension (+15.5%, p< 0.01); and diabetes mellitus (+15.0%, p< 0.001). The difference in malignancy increased during follow-up from +8.8% to + 12.5% (p< 0.001). 17.4% of cases used pancreatic enzyme replacement therapy during follow-up. Over follow-up, cases were more often hospitalized (57.3% vs 17.2%, p< 0.01) and/or had an ER visit (72.0% vs 36.7%, p< 0.01); all costs were greater in cases than comparators. CONCLUSIONS: Patients with IgG4-RD are disproportionately affected by adverse outcomes, some of which may be preventable or modifiable with vigilant clinician monitoring. Glucocorticoid-sparing treatments may improve these outcomes.

Machine learning insights into thrombo-ischemic risks and bleeding events through platelet lysophospholipids and acylcarnitine species.

Coronary artery disease (CAD) often leads to adverse events resulting in significant disease burdens. Underlying risk factors often remain inapparent prior to disease incidence and the cardiovascular (CV) risk is not exclusively explained by traditional risk factors. Platelets inherently promote atheroprogression and enhanced platelet functions and distinct platelet lipid species are associated with disease severity in patients with CAD. Lipidomics data were acquired using mass spectrometry and processed alongside clinical data applying machine learning to model estimates of an increased CV risk in a consecutive CAD cohort (n = 595). By training machine learning models on CV risk measurements, stratification of CAD patients resulted in a phenotyping of risk groups. We found that distinct platelet lipids are associated with an increased CV or bleeding risk and independently predict adverse events. Notably, the addition of platelet lipids to conventional risk factors resulted in an increased diagnostic accuracy of patients with adverse CV events. Thus, patients with aberrant platelet lipid signatures and platelet functions are at elevated risk to develop adverse CV events. Machine learning combining platelet lipidome data and common clinical parameters demonstrated an increased diagnostic value in patients with CAD and might improve early risk discrimination and classification for CV events.

Effectiveness of a fourth dose of COVID-19 mRNA vaccine in patients with systemic autoimmune rheumatic diseases using disease-modifying antirheumatic drugs: an emulated target trial.

BACKGROUND: Patients with systemic autoimmune rheumatic diseases using disease-modifying antirheumatic drugs (DMARDs) might have blunted responses to COVID-19 vaccines. The initial mRNA vaccine series is defined as three doses for this population and a fourth booster dose is recommended. The effectiveness of the fourth dose in patients with systemic autoimmune rheumatic diseases using DMARDs is not well established. We aimed to assess the effectiveness of receiving versus not receiving a fourth dose of COVID-19 mRNA vaccine using a target trial framework, in a cohort of patients with systemic autoimmune rheumatic diseases receiving DMARD therapy. METHODS: We conducted an emulated target trial using observational data from the Mass General Brigham health-care system to compare receiving versus not receiving a fourth mRNA vaccine dose. Analysed patients had systemic autoimmune rheumatic diseases, were prescribed DMARDs, and were eligible for a fourth dose of BNT162b2 or mRNA-1273 vaccines between Jan 16 and June 11, 2022. To account for temporal changes, the study period was divided into 1-week intervals. Fourth-dose-exposed patients were included in a 1-week interval if they received a fourth mRNA dose in that interval; fourth-dose-unexposed patients were eligible for but had not received the fourth dose of the vaccine. The primary outcome was a SARS-CoV-2 infection; the secondary outcome was severe SARS-CoV-2 infection (ie, admission to hospital or death within -3 to +14 days of a positive test). We assessed the effectiveness of the fourth dose using time-stratified, overlap propensity score-weighted Cox regression models. FINDINGS: We included 4305 patients, 3126 of whom received a fourth dose of vaccine and 1179 who had not. The median follow-up time was 135 days (IQR 112-154) among patients who had received a fourth dose and 65 days (30-156) among patients who had not received a fourth dose. After overlap weighting in both groups, 1863 (72·7%) of 2563 participants were women, 700 (27·3%) were men, and 2242 (87·5%) were White. Rheumatoid arthritis was present in 1392 (54·3%) of 2563 participants; the most frequent treatments were conventional synthetic DMARDs (1489 [58·1%]) or biological DMARDs (1007 [39·3%]). SARS-CoV-2 infection risk was lower among patients receiving versus not receiving a fourth dose of vaccine (HR 0·59 [95% CI 0·47-0·74]). A fourth dose reduced the risk of admission to hospital or death within -3 to +14 days of SARS-CoV-2 infection (0·35 [0·14-0·85]). INTERPRETATION: In this emulated target trial, a fourth dose of COVID-19 mRNA vaccine reduced the risk of SARS-CoV-2 infection and severe COVID-19 among patients with systemic autoimmune rheumatic diseases using DMARDs during the Omicron era. Patients with systemic autoimmune rheumatic diseases should be encouraged to remain up-to-date with COVID-19 vaccinations. FUNDING: The National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

cGMP modulates hemin-mediated platelet death.

BACKGROUND AND AIMS: Hemolysis is a known risk factor for thrombosis resulting in critical limb ischemia and microcirculatory disturbance and organ failure. Intravasal hemolysis may lead to life-threatening complications due to uncontrolled thrombo-inflammation. Until now, conventional antithrombotic therapies failed to control development and progression of these thrombotic events. Thus, the pathophysiology of these thrombotic events needs to be investigated to unravel underlying pathways and thereby identify targets for novel treatment strategies. METHODS: Here we used classical experimental set-ups as well as high-end flow cytometry, metabolomics and lipidomic analysis to in-depth analyze the effects of hemin on platelet physiology and morphology. RESULTS: Hemin does strongly and swiftly induce platelet activation and this process is modulated by the sGC-cGMP-cGKI signaling axis. cGMP modulation also reduced the pro-aggregatory potential of plasma derived from patients with hemolysis. Furthermore, hemin-induced platelet death evokes distinct platelet subpopulations. Typical cell death markers, such as ROS, were induced by hemin-stimulation and the platelet lipidome was specifically altered by high hemin concentration. Specifically, arachidonic acid derivates, such as PGE2, TXB2 or 12-HHT, were significantly increased. Balancing the cGMP levels by modulation of the sGC-cGMP-cGKI axis diminished the ferroptotic effect of hemin. CONCLUSION: We found that cGMP modulates hemin-induced platelet activation and thrombus formation in vitro and cGMP effects hemin-mediated platelet death and changes in the platelet lipidome. Thus, it is tempting to speculate that modulating platelet cGMP levels may be a novel strategy to control thrombosis and critical limb ischemia in patients with hemolytic crisis.

Genomic Analyses Uncover Evolutionary Features of Influenza A/H3N2 Viruses in Yunnan Province, China, from 2017 to 2022.

Influenza A viruses evolve at a high rate of nucleotide substitution, thereby requiring continuous monitoring to determine the efficacy of vaccines and antiviral drugs. In the current study, we performed whole-genome sequencing analyses of 253 influenza A/H3N2 strains from Yunnan Province, China, during 2017-2022. The hemagglutinin (HA) segments of Yunnan A/H3N2 strains isolated during 2017-2018 harbored a high genetic diversity due to heterogeneous distribution across branches. The mutation regularity of the predominant antigenic epitopes of HA segments in Yunnan was inconsistent in different years. Some important functional mutations in gene segments associated with viral adaptation and drug tolerance were revealed. The rapid genomic evolution of Yunnan A/H3N2 strains from 2017 to 2022 mainly concentrated on segments, i.e., matrix protein 2 (M2), non-structural protein 1 (NS1), neuraminidase (NA), NS2, and HA, with a high overall non-synonymous/synonymous substitution ratio (dN/dS). Our results highlighted a decline in vaccine efficacy against the A/H3N2 circulating strains, particularly against the Yunnan 2021-2022 A/H3N2 strains. These findings aid our understanding of evolutionary characteristics and epidemiological monitoring of the A/H3N2 viruses and provide in-depth insights into the protective efficacy of influenza vaccines.

Comparative analysis of shotgun metagenomics and 16S rDNA sequencing of gut microbiota in migratory seagulls.

Background: Shotgun metagenomic and 16S rDNA sequencing are commonly used methods to identify the taxonomic composition of microbial communities. Previously, we analysed the gut microbiota and intestinal pathogenic bacteria configuration of migratory seagulls by using 16S rDNA sequencing and culture methods. Methods: To continue in-depth research on the gut microbiome and reveal the applicability of the two methods, we compared the metagenome and 16S rDNA amplicon results to further demonstrate the features of this animal. Results: The number of bacterial species detected by metagenomics gradually increased from the phylum to species level, consistent with 16S rDNA sequencing. Several taxa were commonly shared by both sequencing methods. However, Escherichia, Shigella, Erwinia, Klebsiella, Salmonella, Escherichia albertii, Shigella sonnei, Salmonella enterica, and Shigella flexneri were unique taxa for the metagenome compared with Escherichia-Shigella, Hafnia-Obesumbacterium, Catellicoccus marimammalium, Lactococcus garvieae, and Streptococcus gallolyticus for 16S rDNA sequencing. The largest differences in relative abundance between the two methods were identified at the species level, which identified many pathogenic bacteria to humans using metagenomic sequencing. Pearson correlation analysis indicated that the correlation coefficient for the two methods gradually decreased with the refinement of the taxonomic levels. The high consistency of the correlation coefficient was identified at the genus level for the beta diversity of the two methods. Conclusions: In general, relatively consistent patterns and reliability could be identified by both sequencing methods, but the results varied following the refinement of taxonomic levels. Metagenomic sequencing was more suitable for the discovery and detection of pathogenic bacteria of gut microbiota in seagulls. Although there were large differences in the numbers and abundance of bacterial species of the two methods in terms of taxonomic levels, the patterns and reliability results of the samples were consistent.

Resurgence of influenza during COVID-19 in Chongqing, China: A retrospective analysis.

To better understand the trends of influenza and the impact of public health and social measures (PHSMs) implemented during the coronavirus disease 2019 (COVID-19) period in Chongqing, China. Data from the China Influenza Surveillance Information System from January 2017 to June 2022 were extracted. Epidemiological characteristics (influenza-like illness [ILI] and ILI%) and virological characteristics (influenza positive rate and circulating (sub)types) of influenza were described and compared between the pre-COVID-19 period and the COVID-19 period. Our survey showed that the implementation of PHSMs during the COVID-19 period had a positive impact on reducing influenza transmission. However, influenza activity resurged in 2021-2022 as the PHSMs were eased. Children under 5 years old constituted the highest proportion of ILI cases. The overall influenza positive rate was 23.70%, with a higher rate observed during the pre-COVID-19 period (31.55%) compared to the COVID-19 period (13.68%). Influenza virus subtypes co-circulated and the predominant subtype varied each year, with influenza A subtypes predominated in 2018/2019, while influenza B/Victoria lineage dominated in 2020/2021. PHSMs are effective measures to mitigate the spread of influenza. The findings underscore the need for bolstering monitoring systems, advocating influenza vaccination, and implementing practical PHSMs to strengthen prevention and control measures against influenza.

Characteristics of laser-induced steel plasmas generated with different focusing conditions.

Laser focusing is an important parameter that affects the characteristics of laser-induced plasma. Focusing lenses with different F-numbers form different energy density distributions near the surface of a sample, thus affecting the characteristics of plasma. In this study, the plasma generated by a nanosecond laser ablation of a micro-alloy steel certified sample at 1 atm of air was investigated. We compare the spectrally integrated plasma images obtained at different defocusing distances for short- and long-focus lenses and investigate the optical emission spectra of laser-induced plasma on steel alloy by using focusing lenses with different F-numbers. With an increase in the defocusing distance, the plasma plume changes from flat to hemispherical and then splitting occurs. The spectral line intensity increases first and then decreases, then increases slightly, and finally decreases gradually. For the long-focus lens, when the focal point is above the sample surface, the laser beam strongly interacts with air over a longer distance, leading to longer air plasma and weaker sample plasma compared with the short-focus lens. Thus, the relative intensity of the second peak in the spectral line intensity, according to the defocusing distance, gradually decreases with increasing F-number. We also obtain two-dimensional spatial distributions of the spectral line intensity according to the F-number and defocusing distance. The optimal defocusing distances for all focusing lenses occur when the focal point is below the sample surface. The relation between the optimal defocusing distance and F-number follows a single- exponential decay function.

Assessment of patient-reported symptoms and distress in IgG4-related disease (IgG4-RD): Development, clinical validation, and content validation of the IgG4-RD Symptom Severity Index.

OBJECTIVE: IgG4-related disease (IgG4-RD), a multi-organ autoimmune disease, causes diverse manifestations that can lead to symptoms and distress. We developed and validated the Symptom Severity Index (SSI) to assess symptom burden. METHODS: A pilot SSI was tested in n = 5; several gaps were identified. Twenty semi-structured qualitative interviews were performed to expand the item set and identify missing symptoms. Subsequent changes resulted in the current SSI; it was administered with quality of life (QOL) measures to n = 136. We assessed symptom burden and the construct validity of the SSI. A distress score for each symptom is calculated by multiplying symptom frequency ("Never" [0 points] to "Every Day" [3 points]) by associated distress ("None" [0 points] to "Very Much" [4 points]). Each distress score is summed to calculate a total SSI score. RESULTS: The SSI assesses the frequency and distress of 24 symptoms. Among n = 136 with ≥ 1 SSI, 90% experienced ≥ 1 symptom and 88% had distress. The median SSI score was 6.5 (IQR 3.0, 18.0). Fear of more severe disease was observed in 49%. The SSI inversely correlated with the SF-36 (r= - 0.51, p<0.001), the feeling thermometer (r= - 0.28, p<0.001), and the EQ-5D (r= - 0.28, p<0.001). The median SSI score was higher during active vs non-active disease among n = 52 who completed >1 SSI (15 [6, 26] vs. 3 [2, 14], p = 0.008). CONCLUSIONS: Symptoms and distress are common in IgG4-RD and associated with worse health-related QOL. The SSI has face, content, and construct validity; it corresponds with QOL measures.

Drug allergy in older adults: A study from the United States Drug Allergy Registry.

BACKGROUND: Older adults have an increased risk of adverse drug reactions and negative effects associated with alternative antibiotic use. Although the number of antibiotic allergies reported increases with age, the characteristics and outcomes of older adults receiving drug allergy assessment are unknown. OBJECTIVE: To assess the characteristics and outcomes of drug allergy evaluations in older adults. METHODS: We considered patients aged above or equal to 65 years enrolled in the United States Drug Allergy Registry (USDAR), a US multisite prospective cohort (January 16, 2019 to February 28, 2022). Data were summarized using descriptive statistics. RESULTS: Of 1678 USDAR participants from 5 sites, 406 older adults aged above or equal to 65 years (37% 65-69 years, 37% 70-74 years, 16% 75-79 years, and 10% ≥80 years) received 501 drug allergy assessments. USDAR older adults were primarily of female sex (69%), White (94%), and non-Hispanic (98%). Most USDAR older adults reported less than or equal to 1 infections per year (64%) and rated their general health as good, very good, or excellent (80%). Of 296 (59%) penicillin allergy assessments in USDAR older adults, 286 (97%) were disproved. Other drug allergy assessments included sulfonamide (n = 41, 88% disproved) and cephalosporin (n = 20, 95% disproved) antibiotics. All 41 drug allergy labels in USDAR participants aged above or equal to 80 years and all 80 penicillin allergy labels in USDAR men aged above or equal to 65 years were disproved. CONCLUSION: Older adults represented a quarter of USDAR participants but were neither racially nor ethnically diverse and were generally healthy without considerable antibiotic need. Most older adults presented for antibiotic allergy assessments, the vast majority of which were disproved. Drug allergy assessments may be underutilized in the older adults who are most vulnerable to the harms of unconfirmed antibiotic allergy labels.

Large-scale lipidomics profiling reveals characteristic lipid signatures associated with an increased cardiovascular risk.

BACKGROUND AND AIMS: Patients with cardiovascular disease (CVD) are at high risk to develop adverse events. The distinct risk of developing adverse cardiovascular (CV) events is not solely explained by traditional risk factors. Platelets are essentially involved in progression of CVD including coronary artery disease (CAD) and platelet hyperreactivity leads to development of adverse CV events. Alterations in the platelet lipidome lead to platelet hyperresponsiveness and thus might alter the individual risk profile. In this study, we investigate the platelet lipidome of CAD patients by untargeted lipidomics and elucidate alterations in the lipid composition of patients with adverse CV events. METHODS: We characterized the platelet lipidome in a large consecutive CAD cohort (n = 1057) by an untargeted lipidomics approach using liquid chromatography coupled to mass spectrometry. RESULTS: The platelet lipidome in this study identified 767 lipids and characteristic changes occurred in patients with adverse CV events. The most prominent upregulated lipids in patients with cardiovascular events primarily belong to the class of phospholipids and fatty acyls. Further, upregulated platelet lipids are associated with an increased cardiovascular or bleeding risk and independently associated with adverse events. In addition, alterations of the platelet lipidome are associated with modulation of in vitro platelet functions. CONCLUSIONS: Our results reveal that the composition of the platelet lipidome is altered in CVD patients with an increased cardiovascular risk and distinct platelet lipids may indicate adverse events. Results of this study may contribute to improved risk discrimination and classification for cardiovascular events in patients with CVD. Main findings of this study and hypothetical impact of altered platelet lipid signatures in patients with adverse cardiovascular events on platelet function and clinical outcome. LPE lysophosphatidylethanolamines, CAR acylcarnitines, FA fatty acids.

Profiling of branched chain and straight chain saturated fatty acids by ultra-high performance liquid chromatography-mass spectrometry.

Branched chain fatty acids (BCFAs) are one of the important sub categories of fatty acids (FAs) which have unique functions in nature. They are commonly analyzed by GC-MS after derivatization to methyl esters (FAMEs). On the other hand, there is a lack of isomer-selective LC-MS methods which allow the distinction of different isomers with wide coverage of carbon chain length. In this work, a systematic retention and isomer selectivity study on seven commercially available UHPLC columns (six polysaccharide columns Chiralpak IA-U, IB-U, IC-U, ID-U, IG-U and IH-U; one Acquity UPLC CSH C18 column) was performed. Various experimental factors were evaluated including column temperatures, gradient profiles and flow rates to elucidate their effects on the separation ability of homologous series of BCFAs with distinct chain lengths, different branching types and branching positions. In general, IG-U outperformed the other columns in terms of isomer selectivity especially for the short and medium-chain BCFA isomers while RP C18 showed good potential in terms of selectivity for long-chain BCFA isomers. Furthermore, after the evaluation of the chromatographic retention pattern on the various columns and method optimization, we report a methodology for untargeted isomer-selective BCFA profiling without precolumn derivatization with UHPLC-ESI-MS/MS by quadrupole-time-of-flight instrument with SWATH acquisition. The best method provides selectivity for constitutional isomers of BCFAs covering distinct chain length (C5-C20) with different branching types (methyl or ethyl) and branching positions (2Me, 3Me, 4Me, 6Me, anteiso and iso-BCFAs) with an optimized LC condition on Acquity UPLC CSH C18 column. Finally, the optimized method was applied for the BCFAs profiling in lipid extracts of Staphylococcus aureus samples. Besides, pooled human platelets and pooled human plasma were evaluated as mammalian samples for presence of BCFAs as well. The new method showed strong potential for BCFA profiling in bacterial samples including different isomers anteiso and iso-BCFAs, which could be a useful tool for related subdisciplines in metabolomics and lipidomics in particular in combination with electron-activated dissociation MS. Compared to GC, the presented isomer selective LC methods can be also of great utility for preparative purposes. Equivalent (carbon) chain length numbers were calculated for RP18 and Chiralpak IG-U and compared to those of FAMEs obtained by GC.

Supply chain disruption recovery in the evolving crisis-Evidence from the early COVID-19 outbreak in China.

The speed of recovery from supply chain disruption has been identified as the predominant factor in building a resilient supply chain. However, COVID-19 as an example of an evolving crisis may challenge this assumption. Infection risk concerns may influence production resumption decision-making because any incidents of infection may lead to further shutdowns of production lines and undermine firms' long-term cash flows. Sampling 244 production resumption announcements by Chinese manufacturers in the early COVID-19 crisis (February-March 2020), our analysis shows that, generally, investors react positively to production resumptions. However, investors perceived the earlier production resumptions were higher risk (indicated by declined stock price). Such concerns were exacerbated by more locally confirmed cases of COVID-19 but were less salient for manufacturers with high debts (liquidity pressure). This study calls for a reassessment of the current disruption management mindset in response to new evolving crises (e.g., COVID-19) and provides theoretical, practical, and policy implications for building resilient supply chains.

Incidence, prevalence and mortality of IgG4-related disease in the USA: a claims-based analysis of commercially insured adults.

BACKGROUND: IgG4-related disease (IgG4-RD) is an immune-mediated condition that can affect nearly any organ or anatomic site. We sought to describe the epidemiology of IgG4-RD in the USA. METHODS: We used Optum's deidentified Clinformatics Data Mart Database from 1 January 2009 to 31 December 2021 to identify IgG4-RD cases using a validated algorithm. We estimated the incidence rate and prevalence between 2015 and 2019 (when rates stabilised), standardised to the US population by age and sex. We compared mortality rates among patients with IgG4-RD to the non-IgG4-RD population matched in a 1:10 ratio on age, sex, race/ethnicity and encounter date. We used Cox proportional hazards models to estimate HRs and 95% CIs. RESULTS: We identified 524 IgG4-RD cases. The mean age was 56.5 years with 57.6% female and 66% White. The incidence of IgG4-RD increased during the study period from 0.78 to 1.39 per 100 000 person-years in 2015 and 2019, respectively. The point prevalence on 1 Janury 2019 was 5.3/100 000 persons. During follow-up, there were 39 and 164 deaths among 515 IgG4-RD cases and 5160 comparators, resulting in a mortality rate of 3.42 and 1.46/100 person-years, respectively, and adjusted HR of 2.51 (95% CI 1.76 to 3.56). CONCLUSIONS: The incidence of IgG4-RD is similar to that of systemic rheumatic diseases such as ANCA-associated vasculitis and systemic sclerosis but may be increasing as familiarity with this diagnosis grows. Clinicians should be aware of this condition, especially given the excess risk of death. Identification of effective therapies is an important research agenda.

Metagenomics of gut microbiome for migratory seagulls in Kunming city revealed the potential public risk to human health.

BACKGROUND: Seagull as a migratory wild bird has become most popular species in southwest China since 1980s. Previously, we analyzed the gut microbiota and intestinal pathogenic bacteria configuration for this species by using 16S rRNA sequencing and culture methods. To continue in-depth research on the gut microbiome of migratory seagulls, the metagenomics, DNA virome and RNA virome were both investigated for their gut microbial communities of abundance and diversity in this study. RESULTS: The metagenomics results showed 99.72% of total species was bacteria, followed by viruses, fungi, archaea and eukaryota. In particular, Shigella sonnei, Escherichia albertii, Klebsiella pneumonia, Salmonella enterica and Shigella flexneri were the top distributed taxa at species level. PCoA, NMDS, and statistics indicated some drug resistant genes, such as adeL, evgS, tetA, PmrF, and evgA accumulated as time went by from November to January of the next year, and most of these genes were antibiotic efflux. DNA virome composition demonstrated that Caudovirales was the most abundance virus, followed by Cirlivirales, Geplafuvirales, Petitvirales and Piccovirales. Most of these phages corresponded to Enterobacteriaceae and Campylobacteriaceae bacterial hosts respectively. Caliciviridae, Coronaviridae and Picornaviridae were the top distributed RNA virome at family level of this migratory animal. Phylogenetic analysis indicated the sequences of contigs of Gammacoronavirus and Deltacoronavirus had highly similarity with some coronavirus references. CONCLUSIONS: In general, the characteristics of gut microbiome of migratory seagulls were closely related to human activities, and multiomics still revealed the potential public risk to human health.

Comparative Effectiveness of Rituximab- Versus Cyclophosphamide-Based Remission Induction Strategies in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis for the Risk of Kidney Failure and Mortality.

OBJECTIVE: To compare rituximab- versus cyclophosphamide-based remission induction strategies for the long-term risks of kidney failure and death in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in a real-world cohort. METHODS: We performed a cohort study using the Mass General Brigham AAV Cohort, which includes proteinase 3-ANCA+ and myeloperoxidase (MPO)-ANCA+ AAV patients diagnosed from January 1, 2002 to December 31, 2019. We included cases in which the initial remission induction strategy was based either on rituximab or cyclophosphamide. The primary outcome was the composite outcome of kidney failure or death. We used multivariable Cox proportional hazards models and propensity score-matched analyses to assess the association of rituximab- versus cyclophosphamide-based treatment strategies with the composite outcome of kidney failure or death. RESULTS: Of 595 included patients, 352 patients (~60%) received rituximab-based and 243 patients (~40%) received cyclophosphamide-based regimens. The mean age was 61 years, 58% of patients were female, 70% of patients were MPO-ANCA+, and 69% of patients had renal involvement (median estimated glomerular filtration rate 37.3 ml/minute/1.73 m2 ). There were 133 events at 5 years, and the incidence rates in rituximab- and cyclophosphamide-based regimens were 6.8 and 6.1 per 100 person-years, respectively. The risk of kidney failure or death was similar in both groups in multivariable-adjusted analyses (hazard ratio [HR] 1.03 [95% confidence interval (95% CI) 0.55-1.93]) and in propensity score-matched analyses (HR 1.05 [95% CI 0.55-1.99]) at 5 years. Our findings were similar when outcomes were assessed at 1 and 2 years as well as in subgroups stratified according to renal involvement and severity as well as major organ involvement. CONCLUSION: Rituximab- and cyclophosphamide-based remission induction strategies for AAV are associated with similar risks of kidney failure and death.

The Subtilisin-Like Protease Furin Regulates Hemin-Dependent Ectodomain Shedding of Glycoprotein VI.

INTRODUCTION: Hemolysis results in release of free hemoglobin and hemin liberation from erythrocytes. Hemin has been described to induce platelet activation and to trigger thrombosis. METHODS: We evaluated the effect of hemin on platelet function and surface expression of the platelet collagen receptor glycoprotein VI (GPVI). Isolated platelets were stimulated with increasing concentrations of hemin. RESULTS: We found that hemin strongly enhanced platelet activation, aggregation, and aggregate formation on immobilized collagen under flow. In contrast, we found that surface expression of GPVI was significantly reduced upon hemin stimulation with high hemin concentrations indicating that hemin-induced loss of surface GPVI does not hinder platelet aggregation. Loss of hemin-induced surface expression of GPVI was caused by shedding of the ectodomain of GPVI as verified by immunoblotting and is independent of the GPVI or CLEC-2 mediated ITAM (immunoreceptor-tyrosine-based-activation-motif) signaling pathway as inhibitor studies revealed. Hemin-induced GPVI shedding was independent of metalloproteinases such as ADAM10 or ADAM17, which were previously described to regulate GPVI degradation. Similarly, concentration-dependent shedding of CD62P was also induced by hemin. Unexpectedly, we found that the subtilisin-like proprotein convertase furin controls hemin-dependent GPVI shedding as shown by inhibitor studies using the specific furin inhibitors SSM3 and Hexa-D-arginine. In the presence of SSM3 and Hexa-D-arginine, hemin-associated GPVI degradation was substantially reduced. Further, SSM3 inhibited hemin-induced but not CRP-XL-induced platelet aggregation and thrombus formation, indicating that furin controls specifically hemin-associated platelet functions. CONCLUSION: In summary, we describe a novel mechanism of hemin-dependent GPVI shedding and platelet function mediated by furin.

Longitudinal Patterns of Renal Function in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

OBJECTIVE: A spectrum of chronic kidney disease (CKD) and end-stage renal disease (ESRD) may occur in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). The longitudinal trajectory of renal function in AAV is poorly understood. METHODS: Patients with ≥2 creatinine measurements, including at baseline (±30 days of treatment initiation), were included from the Mass General Brigham AAV Cohort. We calculated estimated glomerular filtration rate (eGFR). We incorporated longitudinal changes in eGFR into a group-based trajectory model to identify patients with similar patterns of change in renal function. The chi-square test and the Kruskal-Wallis test were used to evaluate differences between groups in categorical variables and non-normally distributed continuous variables, respectively. RESULTS: In 255 AAV patients, we identified 4 renal trajectory groups: rapid decline (n = 20), impaired (n = 82), preserved (n = 129), and recovery (n = 24). The rapid decline and impaired groups had greater baseline comorbidity (P = 0.01) and lower prevasculitis eGFR (P = 0.02). Clinically significant CKD (eGFR <60 ml/minute/1.73 m2 ) persisted over 5 years in >75% of the impaired group, compared to <40% of patients in the preserved group (P < 0.001). ESRD occurred most frequently in the rapid decline (100%), followed by the impaired and preserved groups (7% each). Baseline AAV renal involvement was present prior to 95% of ESRD. However, ESRD etiology varied, with 90% of rapid-onset ESRD attributed to vasculitis, versus 17-44% in impaired or preserved groups (P = 0.001). CONCLUSION: We identified 4 longitudinal patterns of renal function after AAV diagnosis. Our findings highlight the burden of CKD in AAV and provide a framework for future research into personalized care in this vulnerable population.

Statin Treatment Is Associated with Alterations in the Platelet Lipidome.

BACKGROUND: Platelets are key players in the pathophysiology of coronary artery disease (CAD) and platelet hyperreactivity leads to increased risk of developing adverse cardiovascular events. Further, significant changes in the platelet lipidome occur in patients with acute coronary syndrome (ACS) and critically regulated lipids lead to platelet hyperresponsiveness. Statin treatment is crucial in the treatment and prevention of patients with CAD by remodeling lipid metabolism. OBJECTIVE: In this study, we investigate the platelet lipidome of CAD patients by untargeted lipidomics, highlighting significant changes between statin-treated and naïve patients. METHODS: We characterized the platelet lipidome in a CAD cohort (n = 105) by an untargeted lipidomics approach using liquid chromatography coupled to mass spectrometry. RESULTS: Among the annotated lipids, 41 lipids were significantly upregulated in statin-treated patients, whereas 6 lipids were downregulated compared to naïve patients. The most prominent upregulated lipids in statin-treated patients belong to the class of triglycerides, cholesteryl esters, palmitic acid, and oxidized phospholipids, whereas mainly glycerophospholipids were downregulated compared to untreated patients. A more pronounced effect of statin treatment on the platelet lipidome was observed in ACS patients. We further highlight a dose-dependent influence on the platelet lipidome. CONCLUSION: Our results reveal that the platelet lipidome is altered in CAD patients with statin treatment and upregulated lipids embody mainly characteristic triglycerides, whereas downregulated lipids mostly compromise glycerophospholipids, which may play a role in the pathophysiology of CAD. Results of this study may contribute to the understanding of statin treatment softening the lipid phenotype.