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OBJECTIVE: Autoantibodies and autoimmune diseases after SARS-CoV-2 infection are widely reported. Given evolving variants, milder infections, and increasing population vaccination, we hypothesized that SARS-CoV-2 infection earlier in the pandemic would be associated with more autoimmune connective tissue disease (CTD) symptoms and immunologic abnormalities. METHODS: Patients ≥18 years old with COVID-19 3/1/2020-8/15/2022 completed the CTD Screening Questionnaire and were tested for 27 autoimmune serologies, SARS-CoV-2 serologies, cell-bound complement activation products (CB-CAPs), and T and B lymphocyte immunophenotypes by flow cytometry. We assessed relationships between symptoms, serologies, and immunophenotypes in earlier (3/1/2020-1/31/2021) vs. later (2/1/2021-8/15/2022) periods, with different predominating SARS-CoV-2 viruses. RESULTS: 57 subjects had earlier and 23 had later pandemic COVID-19. 35 % of earlier vs. 17 % of later pandemic patients had CTD symptoms (p 0.18). More patients were antinuclear antibody (ANA) positive (44 % vs. 13 %, p 0.01) and had lupus anticoagulant (11 % vs. 4 %, p 0.67). After adjustment for age, race, and sex, earlier (vs. later) COVID-19 was associated with increased ANA positivity (OR 4.60, 95%CI 1.17, 18.15). No subjects had positive CB-CAPs. T and B cell immunophenotypes and SARS-CoV-2 serologies did not differ by group. In heatmap analyses, higher autoantibody variety was seen among those with infection in the early pandemic. CONCLUSION: In this sample, having COVID-19 infection in the earlier (pre-2/1/2021) vs. later pandemic was associated with more CTD symptoms, ANA positivity, and autoantibody reactivities. Earlier SARS-CoV-2 variants circulating in a less vaccinated population with less natural immunity may have been more immunogenic.
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Systemic lupus erythematosus (SLE) is prototypical autoimmune disease driven by pathological T cell-B cell interactions1,2. Expansion of T follicular helper (TFH) and T peripheral helper (TPH) cells, two T cell populations that provide help to B cells, is a prominent feature of SLE3,4. Human TFH and TPH cells characteristically produce high levels of the B cell chemoattractant CXCL13 (refs. 5,6), yet regulation of T cell CXCL13 production and the relationship between CXCL13+ T cells and other T cell states remains unclear. Here, we identify an imbalance in CD4+ T cell phenotypes in patients with SLE, with expansion of PD-1+/ICOS+ CXCL13+ T cells and reduction of CD96hi IL-22+ T cells. Using CRISPR screens, we identify the aryl hydrocarbon receptor (AHR) as a potent negative regulator of CXCL13 production by human CD4+ T cells. Transcriptomic, epigenetic and functional studies demonstrate that AHR coordinates with AP-1 family member JUN to prevent CXCL13+ TPH/TFH cell differentiation and promote an IL-22+ phenotype. Type I interferon, a pathogenic driver of SLE7, opposes AHR and JUN to promote T cell production of CXCL13. These results place CXCL13+ TPH/TFH cells on a polarization axis opposite from T helper 22 (TH22) cells and reveal AHR, JUN and interferon as key regulators of these divergent T cell states.
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Fatores de Transcrição Hélice-Alça-Hélice Básicos , Linfócitos T CD4-Positivos , Quimiocina CXCL13 , Interferon Tipo I , Lúpus Eritematoso Sistêmico , Proteínas Proto-Oncogênicas c-jun , Receptores de Hidrocarboneto Arílico , Feminino , Humanos , Masculino , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular , Quimiocina CXCL13/metabolismo , Epigenômica , Perfilação da Expressão Gênica , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Interleucina 22/imunologia , Interleucina 22/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Lúpus Eritematoso Sistêmico/genética , Proteínas Proto-Oncogênicas c-jun/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismoRESUMO
Granzymes are a family of serine proteases mainly expressed by CD8+ T cells, natural killer cells, and innate-like lymphocytes1,2. Although their major role is thought to be the induction of cell death in virally infected and tumor cells, accumulating evidence suggests some granzymes can regulate inflammation by acting on extracellular substrates2. Recently, we found that the majority of tissue CD8+ T cells in rheumatoid arthritis (RA) synovium, inflammatory bowel disease and other inflamed organs express granzyme K (GZMK)3, a tryptase-like protease with poorly defined function. Here, we show that GZMK can activate the complement cascade by cleaving C2 and C4. The nascent C4b and C2a fragments form a C3 convertase that cleaves C3, allowing further assembly of a C5 convertase that cleaves C5. The resulting convertases trigger every major event in the complement cascade, generating the anaphylatoxins C3a and C5a, the opsonins C4b and C3b, and the membrane attack complex. In RA synovium, GZMK is enriched in areas with abundant complement activation, and fibroblasts are the major producers of complement C2, C3, and C4 that serve as targets for GZMK-mediated complement activation. Our findings describe a previously unidentified pathway of complement activation that is entirely driven by lymphocyte-derived GZMK and proceeds independently of the classical, lectin, or alternative pathways. Given the widespread abundance of GZMK-expressing T cells in tissues in chronic inflammatory diseases and infection, GZMK-mediated complement activation is likely to be an important contributor to tissue inflammation in multiple disease contexts.
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OBJECTIVE: To determine the incidence and baseline factors associated with breakthrough coronavirus disease 2019 (COVID-19) after preexposure prophylaxis (PrEP) with tixagevimab/cilgavimab among patients with systemic autoimmune rheumatic diseases (SARDs). METHODS: We performed a retrospective cohort study among patients with SARDs who received tixagevimab/cilgavimab between January 2, 2022, and November 16, 2022. The primary outcome was breakthrough COVID-19 after tixagevimab/cilgavimab. We performed multivariable Cox regression models adjusted for baseline factors to identify risk factors for breakthrough COVID-19. RESULTS: We identified 444 patients with SARDs who received tixagevimab/cilgavimab (mean age 62.0 years, 78.2% female). There were 83 (18.7%) breakthrough COVID-19 cases (incidence rate 31.5/1000 person-months, 95% CI 24.70-38.24), 7 (1.6%) hospitalizations, and 1 (0.2%) death. Older age was inversely associated with breakthrough COVID-19 (adjusted hazard ratio [aHR] 0.86/10 years, 95% CI 0.75-0.99). Higher baseline spike antibody levels were associated with lower risk of breakthrough COVID-19 (aHR 0.42, 95% CI 0.18-0.99 for spike antibody levels > 200 vs < 0.4 units). CD20 inhibitor users had a similar risk of breakthrough COVID-19 (aHR 1.05, 95% CI 0.44-2.49) compared to conventional synthetic disease-modifying antirheumatic drug (DMARD) users. CONCLUSION: We found that patients with SARDs had frequent breakthrough COVID-19, but the proportion experiencing severe COVID-19 was low. DMARD type, including CD20 inhibitors, did not significantly affect risk of breakthrough COVID-19. Evidence of prior humoral immunity was protective against breakthrough infection, highlighting the continued need for a multimodal approach to prevent severe COVID-19 as novel PrEP therapies are being developed.
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Anticorpos Monoclonais , Antirreumáticos , COVID-19 , Doenças Reumáticas , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Estudos Retrospectivos , Antirreumáticos/uso terapêutico , Doenças Reumáticas/complicações , Doenças Reumáticas/tratamento farmacológicoRESUMO
BACKGROUND: People with a severe mental illness (SMI) have shorter life expectancy and poorer quality of life compared to the general population. Most years lost are due to cardiovascular disease, respiratory disease, and various types of cancer. We co-designed an intervention to mitigate this health problem with key stakeholders in the area, which centred on an extended consultations for people with SMI in general practice. This study aimed to1) investigate general practitioners' (GPs) experience of the feasibility of introducing extended consultations for patients with SMI, 2) assess the clinical content of extended consultations and how these were experienced by patients, and 3) investigate the feasibility of identification, eligibility screening, and recruitment of patients with SMI. METHODS: The study was a one-armed feasibility study. We planned that seven general practices in northern Denmark would introduce extended consultations with their patients with SMI for 6 months. Patients with SMI were identified using practice medical records and screened for eligibility by the patients' GP. Data were collected using case report forms filled out by practice personnel and via qualitative methods, including observations of consultations, individual semi-structured interviews, a focus group with GPs, and informal conversations with patients and general practice staff. RESULTS: Five general practices employing seven GPs participated in the study, which was terminated 3 ½ month ahead of schedule due to the COVID-19 pandemic. General practices attempted to contact 57 patients with SMI. Of these, 38 patients (67%) attended an extended consultation, which led to changes in the somatic health care plan for 82% of patients. Conduct of the extended consultations varied between GPs and diverged from the intended conduct. Nonetheless, GPs found the extended consultations feasible and, in most cases, beneficial for the patient group. In interviews, most patients recounted the extended consultation as beneficial. DISCUSSION: Our findings suggest that it is feasible to introduce extended consultations for patients with SMI in general practice, which were also found to be well-suited for eliciting patients' values and preferences. Larger studies with a longer follow-up period could help to assess the long-term effects and the best implementation strategies of these consultations.
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COVID-19 , Medicina Geral , Transtornos Mentais , Humanos , Estudos de Viabilidade , Pandemias , Qualidade de Vida , COVID-19/epidemiologia , Transtornos Mentais/diagnóstico , Transtornos Mentais/epidemiologia , Transtornos Mentais/terapia , Encaminhamento e ConsultaRESUMO
Immune checkpoint inhibitor (ICI) therapies used to treat cancer, such as anti-PD-1 antibodies, can induce autoimmune conditions in some individuals. The T cell mechanisms mediating such iatrogenic autoimmunity and their overlap with spontaneous autoimmune diseases remain unclear. Here, we compared T cells from the joints of 20 patients with an inflammatory arthritis induced by ICI therapy (ICI-arthritis) with two archetypal autoimmune arthritides, rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Single-cell transcriptomic and antigen receptor repertoire analyses highlighted clonal expansion of an activated effector CD8 T cell population in the joints and blood of patients with ICI-arthritis. These cells were identified as CD38hiCD127- CD8 T cells and were uniquely enriched in ICI-arthritis joints compared with RA and PsA and also displayed an elevated interferon signature. In vitro, type I interferon induced CD8 T cells to acquire the ICI-associated CD38hi phenotype and enhanced cytotoxic function. In a cohort of patients with advanced melanoma, ICI therapy markedly expanded circulating CD38hiCD127- T cells, which were frequently bound by the therapeutic anti-PD-1 drug. In patients with ICI-arthritis, drug-bound CD8 T cells in circulation showed marked clonal overlap with drug-bound CD8 T cells from synovial fluid. These results suggest that ICI therapy directly targets CD8 T cells in patients who develop ICI-arthritis and induces an autoimmune pathology that is distinct from prototypical spontaneous autoimmune arthritides.
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Artrite Psoriásica , Artrite Reumatoide , Linfócitos T CD8-Positivos , Humanos , Artrite Psoriásica/metabolismo , Líquido Sinovial/metabolismo , Linfócitos T Citotóxicos/metabolismoRESUMO
Rheumatoid arthritis (RA) is an autoimmune disease initiated by antigen-specific T cells and B cells, which promote synovial inflammation through a complex set of interactions with innate immune and stromal cells. To better understand the phenotypes and clonal relationships of synovial T and B cells, we performed single-cell RNA and repertoire sequencing on paired synovial tissue and peripheral blood samples from 12 donors with seropositive RA ranging from early to chronic disease. Paired transcriptomic-repertoire analyses highlighted 3 clonally distinct CD4 T cells populations that were enriched in RA synovium: T peripheral helper (Tph) and T follicular helper (Tfh) cells, CCL5+ T cells, and T regulatory cells (Tregs). Among these cells, Tph cells showed a unique transcriptomic signature of recent T cell receptor (TCR) activation, and clonally expanded Tph cells expressed an elevated transcriptomic effector signature compared to non-expanded Tph cells. CD8 T cells showed higher oligoclonality than CD4 T cells, and the largest CD8 T cell clones in synovium were highly enriched in GZMK+ cells. TCR analyses revealed CD8 T cells with likely viral-reactive TCRs distributed across transcriptomic clusters and definitively identified MAIT cells in synovium, which showed transcriptomic features of TCR activation. Among B cells, non-naive B cells including age-associated B cells (ABC), NR4A1+ activated B cells, and plasma cells, were enriched in synovium and had higher somatic hypermutation rates compared to blood B cells. Synovial B cells demonstrated substantial clonal expansion, with ABC, memory, and activated B cells clonally linked to synovial plasma cells. Together, these results reveal clonal relationships between functionally distinct lymphocyte populations that infiltrate RA synovium.
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OBJECTIVE: Disease-modifying anti-rheumatic drugs (DMARDs) that treat rheumatoid arthritis (RA) may reduce immune responses to COVID-19 vaccination. We compared humoral and cell-mediated immunity before and after a 3rd dose of mRNA COVID vaccine in RA subjects. METHODS: RA patients that received 2 doses of mRNA vaccine enrolled in an observational study in 2021 before receiving a 3rd dose. Subjects self-reported holding or continuing DMARDs. Blood samples were collected pre- and 4 weeks after the 3rd dose. 50 healthy controls provided blood samples. Humoral response was measured with in-house ELISA assays for anti-Spike IgG (anti-S) and anti-receptor binding domain IgG (anti-RBD). T cell activation was measured after stimulation with SARS-CoV-2 peptide. Spearman's correlations assessed the relationship between anti-S, anti-RBD, and frequencies of activated T cells. RESULTS: Among 60 subjects, mean age was 63 years and 88% were female. 57% of subjects held at least 1 DMARD around the 3rd dose. 43% (anti-S) and 62% (anti-RBD) had a normal humoral response at week 4, defined as ELISA within 1 standard deviation of the healthy control mean. No differences in antibody levels were observed based on holding DMARDs. Median frequency of activated CD4 T cells was significantly greater post- vs. pre-3rd dose. Changes in antibody levels did not correlate with change in frequency of activated CD4 T cells. CONCLUSION: Virus-specific IgG levels significantly increased in RA subjects using DMARDs after completing the primary vaccine series, though fewer than two-thirds achieved a humoral response like healthy controls. Humoral and cellular changes were not correlated.
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Antirreumáticos , Artrite Reumatoide , COVID-19 , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Vacinas contra COVID-19 , SARS-CoV-2 , Imunidade Celular , RNA Mensageiro , Imunoglobulina GRESUMO
BACKGROUND: Pro-inflammatory fibroblasts are critical for pathogenesis in rheumatoid arthritis, inflammatory bowel disease, interstitial lung disease, and Sjögren's syndrome and represent a novel therapeutic target for chronic inflammatory disease. However, the heterogeneity of fibroblast phenotypes, exacerbated by the lack of a common cross-tissue taxonomy, has limited our understanding of which pathways are shared by multiple diseases. METHODS: We profiled fibroblasts derived from inflamed and non-inflamed synovium, intestine, lungs, and salivary glands from affected individuals with single-cell RNA sequencing. We integrated all fibroblasts into a multi-tissue atlas to characterize shared and tissue-specific phenotypes. FINDINGS: Two shared clusters, CXCL10+CCL19+ immune-interacting and SPARC+COL3A1+ vascular-interacting fibroblasts, were expanded in all inflamed tissues and mapped to dermal analogs in a public atopic dermatitis atlas. We confirmed these human pro-inflammatory fibroblasts in animal models of lung, joint, and intestinal inflammation. CONCLUSIONS: This work represents a thorough investigation into fibroblasts across organ systems, individual donors, and disease states that reveals shared pathogenic activation states across four chronic inflammatory diseases. FUNDING: Grant from F. Hoffmann-La Roche (Roche) AG.
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Artrite Reumatoide , Membrana Sinovial , Animais , Artrite Reumatoide/genética , Fibroblastos/metabolismo , Fenótipo , Células Estromais/metabolismoRESUMO
T cell-derived pro-inflammatory cytokines are a major driver of rheumatoid arthritis (RA) pathogenesis. Although these cytokines have traditionally been attributed to CD4 T cells, we have found that CD8 T cells are notably abundant in synovium and make more interferon (IFN)-γ and nearly as much tumor necrosis factor (TNF) as their CD4 T cell counterparts. Furthermore, using unbiased high-dimensional single-cell RNA-seq and flow cytometric data, we found that the vast majority of synovial tissue and synovial fluid CD8 T cells belong to an effector CD8 T cell population characterized by high expression of granzyme K (GzmK) and low expression of granzyme B (GzmB) and perforin. Functional experiments demonstrate that these GzmK+ GzmB+ CD8 T cells are major cytokine producers with low cytotoxic potential. Using T cell receptor repertoire data, we found that CD8 GzmK+ GzmB+ T cells are clonally expanded in synovial tissues and maintain their granzyme expression and overall cell state in blood, suggesting that they are enriched in tissue but also circulate. Using GzmK and GzmB signatures, we found that GzmK-expressing CD8 T cells were also the major CD8 T cell population in the gut, kidney, and coronavirus disease 2019 (COVID-19) bronchoalveolar lavage fluid, suggesting that they form a core population of tissue-associated T cells across diseases and human tissues. We term this population tissue-enriched expressing GzmK or TteK CD8 cells. Armed to produce cytokines in response to both antigen-dependent and antigen-independent stimuli, CD8 TteK cells have the potential to drive inflammation.
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COVID-19 , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Citocinas/metabolismo , Granzimas/metabolismo , HumanosRESUMO
Macrophages regulate protective immune responses to infectious microbes, but aberrant macrophage activation frequently drives pathological inflammation. To identify regulators of vigorous macrophage activation, we analyzed RNA-seq data from synovial macrophages and identified SLAMF7 as a receptor associated with a superactivated macrophage state in rheumatoid arthritis. We implicated IFN-γ as a key regulator of SLAMF7 expression and engaging SLAMF7 drove a strong wave of inflammatory cytokine expression. Induction of TNF-α after SLAMF7 engagement amplified inflammation through an autocrine signaling loop. We observed SLAMF7-induced gene programs not only in macrophages from rheumatoid arthritis patients but also in gut macrophages from patients with active Crohn's disease and in lung macrophages from patients with severe COVID-19. This suggests a central role for SLAMF7 in macrophage superactivation with broad implications in human disease pathology.
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Inflamação/imunologia , Ativação de Macrófagos/imunologia , Família de Moléculas de Sinalização da Ativação Linfocitária/imunologia , Transcriptoma/imunologia , Doença Aguda , Adulto , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , COVID-19/genética , COVID-19/imunologia , COVID-19/metabolismo , COVID-19/virologia , Células Cultivadas , Doença Crônica , Doença de Crohn/genética , Doença de Crohn/imunologia , Doença de Crohn/metabolismo , Feminino , Humanos , Inflamação/genética , Inflamação/metabolismo , Ativação de Macrófagos/genética , RNA-Seq/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Análise de Célula Única/métodos , Membrana Sinovial/imunologia , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Transcriptoma/genéticaRESUMO
BACKGROUND: People with severe mental illness (SMI) have an increased risk of premature mortality, predominantly due to somatic health conditions. Evidence indicates that primary and tertiary prevention and improved treatment of somatic conditions in patients with SMI could reduce this excess mortality. This paper reports a protocol designed to evaluate the feasibility of a coordinated co-produced care program (SOFIA model, a Danish acronym for Severe Mental Illness and Physical Health in General Practice) in the general practice setting to reduce mortality and improve quality of life in patients with severe mental illness. METHODS: The SOFIA pilot trial is designed as a cluster randomized controlled trial targeting general practices in two regions in Denmark. We aim to include 12 practices, each of which is instructed to recruit up to 15 community-dwelling patients aged 18 and older with SMI. Practices will be randomized by a computer in a ratio of 2:1 to deliver a coordinated care program or usual care during a 6-month study period. A randomized algorithm is used to perform randomization. The coordinated care program includes educational training of general practitioners and their clinical staff educational training of general practitioners and their clinical staff, which covers clinical and diagnostic management and focus on patient-centered care of this patient group, after which general practitioners will provide a prolonged consultation focusing on individual needs and preferences of the patient with SMI and a follow-up plan if indicated. The outcomes will be parameters of the feasibility of the intervention and trial methods and will be assessed quantitatively and qualitatively. Assessments of the outcome parameters will be administered at baseline, throughout, and at end of the study period. DISCUSSION: If necessary the intervention will be revised based on results from this study. If delivery of the intervention, either in its current form or after revision, is considered feasible, a future, definitive trial to determine the effectiveness of the intervention in reducing mortality and improving quality of life in patients with SMI can take place. Successful implementation of the intervention would imply preliminary promise for addressing health inequities in patients with SMI. TRIAL REGISTRATION: The trial was registered in Clinical Trials as of November 5, 2020, with registration number NCT04618250 . Protocol version: January 22, 2021; original version.
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OBJECTIVE: To develop a Core Outcome Set (COS) for treatment of perinatal depression. DESIGN: Systematic overview of outcomes reported in the literature and consensus development study. SETTING: International. POPULATION: Two hundred and twenty-two participants, mainly patients, healthcare professionals and researchers, representing 13 countries. METHODS: A systematic overview of outcomes reported in recently published research, a two-round Delphi survey and a consensus meeting at which the final COS was decided using modified nominal group technique. MAIN RESULTS: In the literature search, 1772 abstracts were identified and evaluated, and 165 studies were finally included in the review. In all, 106 outcomes were identified and included in the Delphi survey. In all, 222 participants registered for the first round of the Delphi survey and 151 (68%) responded. In the second round, 123 (55%) participants responded. Thirteen participants attended the consensus meeting, where the following nine outcomes were agreed upon for inclusion in the final COS: self-assessed symptoms of depression, diagnosis of depression by a clinician, parent to infant bonding, self-assessed symptoms of anxiety, quality of life, satisfaction with intervention, suicidal thoughts, attempted or committed suicide, thoughts of harming the baby, and adverse events. CONCLUSIONS: The relevant stakeholders prioritised outcomes and reached consensus on a COS comprising nine outcomes. We expect that this COS will contribute to the consistency and uniformity of outcome selection and reporting in future clinical trials involving treatment of perinatal depression. TWEETABLE ABSTRACT: Development of a core outcome set regarding treatment for perinatal depression by @SBU_en.
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Ansiedade/psicologia , Depressão/tratamento farmacológico , Assistência Perinatal/normas , Gestantes/psicologia , Qualidade de Vida/psicologia , Consenso , Técnica Delphi , Depressão/diagnóstico , Depressão Pós-Parto/diagnóstico , Depressão Pós-Parto/tratamento farmacológico , Determinação de Ponto Final/métodos , Feminino , Humanos , Avaliação de Resultados em Cuidados de Saúde/métodos , Gravidez , Resultado do TratamentoRESUMO
[This corrects the article DOI: 10.1007/s10680-020-09570-0.].
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Objectives: The study aimed to evaluate the feasibility of a blood flow restriction (BFR) training regimen in patients with rheumatoid arthritis (RA); and to compare the effects of 4 weeks of BFR training with low-intensity strength training on muscle strength, muscle endurance, and joint pain in patients with RA.Method: In this non-blinded pilot randomized controlled trial, 18 women with RA aged 18-65 years performed low-intensity strength training for the lower limbs three times a week for 4 weeks, and were randomized to train with or without occlusion bands. The primary outcomes were registration of the recruitment process, compliance with training sessions, side effects, perceived pain, and a satisfaction survey. The secondary outcomes were changes in muscle strength, muscle endurance, and joint pain.Results: The findings of this pilot study included a challenging recruitment process, well tolerated training and test protocols, overall good patient satisfaction, no serious side effects, and high compliance. Both groups achieved significant improvements in knee extensor strength from baseline to follow-up, with a change of 11.5 kg [interquartile range (IQR) 9.8;13.0] in the intervention group and 8.4 kg (IQR 5.5;12.4) in the control group, and a significant between-group difference in favour of the intervention group (p = 0.0342).Conclusions: The feasibility results of this study indicated a challenging recruitment process, general satisfaction with the BFR and exercises, good compliance, and only expected non-serious side effects. BFR training may improve knee extensor strength in women with RA, compared low-intensity strength training without BFR.
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Artrite Reumatoide/terapia , Terapia por Exercício/métodos , Articulação do Joelho/fisiopatologia , Força Muscular/fisiologia , Fluxo Sanguíneo Regional/fisiologia , Adulto , Idoso , Artrite Reumatoide/fisiopatologia , Estudos de Viabilidade , Feminino , Humanos , Pessoa de Meia-Idade , Projetos Piloto , Treinamento Resistido/métodos , Resultado do TratamentoRESUMO
During the 2010s, fertility rates fell across the Nordic region. The onset of these declines seems linked to the Great Recession of 2008-2009, but their continuation cannot easily be linked to subsequent economic change. The 1990s, too, brought episodes of economic crises to the Nordic region that were followed by different degrees of fertility decline. In this study, we provide an empirical overview of parity-, age- and education-specific fertility developments in the five Nordic countries in the wake of the economic recessions in 2008 and the early 1990s, respectively. We demonstrate a high degree of heterogeneity in fertility developments across countries after 1990, whereas after 2008, the trends are much more similar across the five countries. Likewise, the educational differences in birth hazards that characterized the developments after 1990 were much smaller in the initial years after 2008-2009. This reversal from heterogeneity to homogeneity in the fertility response to recessions calls for an expansion of theories on the cyclicality of fertility in relation to uncertainty and economic and social change. In our discussion, we consider the role of a set of factors that also incorporates the state, crisis management, and perceptions of economic and welfare uncertainty.