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Background: Interstitial lung disease (ILD) is a significant cause of morbidity and mortality in patients with systemic sclerosis (SSc). To date, clinical practice guidelines regarding treatment for patients with SSc-ILD are primarily consensus based. Methods: An international expert guideline committee composed of 24 individuals with expertise in rheumatology, SSc, pulmonology, ILD, or methodology, and with personal experience with SSc-ILD, discussed systematic reviews of the published evidence assessed using the Grading of Recommendations, Assessment, Development, and Evaluation approach. Predetermined conflict-of-interest management strategies were applied, and recommendations were made for or against specific treatment interventions exclusively by the nonconflicted panelists. The confidence in effect estimates, importance of outcomes studied, balance of desirable and undesirable consequences of treatment, cost, feasibility, acceptability of the intervention, and implications for health equity were all considered in making the recommendations. This was in accordance with the American Thoracic Society guideline development process, which is in compliance with the Institute of Medicine standards for trustworthy guidelines. Results: For treatment of patients with SSc-ILD, the committee: 1) recommends the use of mycophenolate; 2) recommends further research into the safety and efficacy of (a) pirfenidone and (b) the combination of pirfenidone plus mycophenolate; and 3) suggests the use of (a) cyclophosphamide, (b) rituximab, (c) tocilizumab, (d) nintedanib, and (e) the combination of nintedanib plus mycophenolate. Conclusions: The recommendations herein provide an evidence-based clinical practice guideline for the treatment of patients with SSc-ILD and are intended to serve as the basis for informed and shared decision making by clinicians and patients.
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Enfermedades Pulmonares Intersticiales , Esclerodermia Sistémica , Humanos , Estados Unidos , Inmunosupresores/uso terapéutico , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Enfermedades Pulmonares Intersticiales/etiología , Ciclofosfamida/uso terapéutico , Rituximab/uso terapéutico , Esclerodermia Sistémica/complicaciones , PulmónRESUMEN
OBJECTIVE: To understand if autoantibodies account for racial variation in disease severity, we compared autoantibody distribution and associated phenotype between self-identified black and white systemic sclerosis (SSc) patients. METHODS: 803 black and 2178 white SSc patients had systematic testing for autoantibodies using Euroimmun (centromere (ACA), RNA-polymerase III (POLR3), Scl70, PM/Scl, NOR90, Th/To, Ku, U3RNP and Ro52) and commercial ELISA (U1RNP). In this observational study, logistic regression was performed to assess the association between self-identified race and outcomes, adjusting for autoantibodies. To estimate whether the effect of race was mediated by autoantibody status, race coefficients from multivariate models including and excluding autoantibodies were compared. RESULTS: Anti-Scl70, anti-U1RNP, anti-U3RNP, anti-Th/To, anti-Ku and anti-NOR90 were more common in the black cohort than in the white cohort, which was enriched for ACA, anti-POLR3 and anti-PM/Scl. Black individuals had a higher prevalence of severe Raynaud's, skin, lung, gastrointestinal and renal disease whereas white individuals had a higher prevalence of severe heart and muscle disease. Adjusting for autoantibodies decreased the effect of race on outcome for telangiectasias, forced vital capacity <70%, pulmonary hypertension and severe lung, heart, muscle and gastrointestinal disease by 11%-44% and increased the association between race and renal crisis and severe kidney disease by 37%-52%. CONCLUSIONS: This study is the largest systematic analysis of autoantibody responses in a geographically diverse population of black SSc patients. Black and white individuals with SSc have distinct autoantibody profiles. Autoantibodies explain only a fraction of the effect of race on clinical outcomes, suggesting other factors contribute to disparate outcomes between these groups.
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OBJECTIVE: To examine disease and target engagement biomarkers in the RISE-SSc trial of riociguat in early diffuse cutaneous systemic sclerosis and their potential to predict the response to treatment. METHODS: Patients were randomized to riociguat (n = 60) or placebo (n = 61) for 52 weeks. Skin biopsies and plasma/serum samples were obtained at baseline and week 14. Plasma cyclic guanosine monophosphate (cGMP) was assessed using radio-immunoassay. Alpha smooth muscle actin (αSMA) and skin thickness were determined by immunohistochemistry, mRNA markers of fibrosis by qRT-PCR in skin biopsies, and serum CXC motif chemokine ligand 4 (CXCL-4) and soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1) by enzyme-linked immunosorbent assay. RESULTS: By week 14, cGMP increased by 94 ± 78% with riociguat and 10 ± 39% with placebo (p < 0.001, riociguat vs placebo). Serum sPECAM-1 and CXCL-4 decreased with riociguat vs placebo (p = 0.004 and p = 0.008, respectively). There were no differences in skin collagen markers between the 2 groups. Higher baseline serum sPECAM-1 or the detection of αSMA-positive cells in baseline skin biopsies were associated with a larger reduction of modified Rodnan skin score from baseline at week 52 with riociguat vs placebo (interaction P-values 0.004 and 0.02, respectively). CONCLUSION: Plasma cGMP increased with riociguat, suggesting engagement with the nitric oxide-soluble guanylate cyclase-cGMP pathway. Riociguat was associated with a significant reduction in sPECAM-1 (an angiogenic biomarker) vs placebo. Elevated sPECAM-1 and the presence of αSMA-positive skin cells may help to identify patients who could benefit from riociguat in terms of skin fibrosis. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02283762.
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The goal of therapy for patients with essential thrombocythemia (ET) and polycythemia vera (PV) is to reduce thrombotic events by normalizing blood counts. Hydroxyurea (HU) and interferon-α (IFN-α) are the most frequently used cytoreductive options for patients with ET and PV at high risk for vascular complications. Myeloproliferative Disorders Research Consortium 112 was an investigator-initiated, phase 3 trial comparing HU to pegylated IFN-α (PEG) in treatment-naïve, high-risk patients with ET/PV. The primary endpoint was complete response (CR) rate at 12 months. A total of 168 patients were treated for a median of 81.0 weeks. CR for HU was 37% and 35% for PEG (P = .80) at 12 months. At 24 to 36 months, CR was 20% to 17% for HU and 29% to 33% for PEG. PEG led to a greater reduction in JAK2V617F at 24 months, but histopathologic responses were more frequent with HU. Thrombotic events and disease progression were infrequent in both arms, whereas grade 3/4 adverse events were more frequent with PEG (46% vs 28%). At 12 months of treatment, there was no significant difference in CR rates between HU and PEG. This study indicates that PEG and HU are both effective treatments for PV and ET. With longer treatment, PEG was more effective in normalizing blood counts and reducing driver mutation burden, whereas HU produced more histopathologic responses. Despite these differences, both agents did not differ in limiting thrombotic events and disease progression in high-risk patients with ET/PV. This trial was registered at www.clinicaltrials.gov as #NCT01259856.
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Policitemia Vera , Trombocitemia Esencial , Trombosis , Progresión de la Enfermedad , Humanos , Hidroxiurea/efectos adversos , Interferón-alfa/efectos adversos , Policitemia Vera/tratamiento farmacológico , Policitemia Vera/genética , Trombocitemia Esencial/tratamiento farmacológico , Trombocitemia Esencial/genética , Trombosis/inducido químicamente , Trombosis/prevención & controlRESUMEN
Primary myelofibrosis (PMF) is the most aggressive of the myeloproliferative neoplasms and patients require greater attention and likely require earlier therapeutic intervention. Currently approved treatment options are limited in their selective suppression of clonal proliferation resulting from driver- and coexisting gene mutations. Janus kinase inhibitors are approved for symptomatic patients with higher-risk PMF. Additionally, most ongoing clinical studies focus on patients with higher-risk disease and/or high rates of transfusion dependency. Optimal treatment of early/lower-risk PMF remains to be identified and needs randomized clinical trial evaluations. Pegylated interferon alfa is recommended for symptomatic lower-risk PMF patients based on phase 2 non-randomized studies and expert opinion. Ropeginterferon alfa-2b (ropeg) is a new-generation pegylated interferon-based therapy with favorable pharmacokinetics and safety profiles, requiring less frequent injections than prior formulations. This randomized, double-blind, placebo-controlled phase 3 trial will assess its efficacy and safety in patients with "early/lower-risk PMF", defined as pre-fibrotic PMF or PMF at low or intermediate-1 risk according to Dynamic International Prognostic Scoring System-plus. Co-primary endpoints include clinically relevant complete hematologic response and symptom endpoint. Secondary endpoints include progression- or event-free survival, molecular response in driver or relevant coexisting gene mutations, bone marrow response, and safety. Disease progression and events are defined based on the International Working Group criteria and well-published reports. 150 eligible patients will be randomized in a 2:1 ratio to receive either ropeg or placebo. Blinded sample size re-estimation is designed. Ropeg will be administered subcutaneously with a tolerable, higher starting-dose regimen. The study will provide important data for the treatment of early/lower-risk PMF for which an anti-clonal, disease-modifying agent is highly needed.
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Interferón alfa-2 , Interferón-alfa , Polietilenglicoles , Mielofibrosis Primaria , Proteínas Recombinantes , Humanos , Mielofibrosis Primaria/tratamiento farmacológico , Polietilenglicoles/uso terapéutico , Polietilenglicoles/administración & dosificación , Polietilenglicoles/efectos adversos , Proteínas Recombinantes/uso terapéutico , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/administración & dosificación , Método Doble Ciego , Interferón-alfa/uso terapéutico , Interferón-alfa/efectos adversos , Interferón-alfa/administración & dosificación , Interferón alfa-2/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Adulto , Resultado del Tratamiento , AncianoRESUMEN
We previously found IQ motif containing GTPase activating protein (IQGAP1) to be consistently elevated in lung fibroblasts (LF) isolated from patients with scleroderma (systemic sclerosis, SSc)-associated interstitial lung disease (ILD) and reported that IQGAP1 contributed to SSc by regulating expression and organization of α-smooth muscle actin (SMA) in LF. The aim of this study was to compare the development of ILD in the presence and absence of IQGAP1. Pulmonary fibrosis was induced in IQGAP1 knockout (KO) and wild-type (WT) mice by a single-intratracheal instillation of bleomycin. Two and three weeks later, mice were euthanized and investigated. We observed that the IQGAP1 KO mouse was characterized by a reduced rate of actin polymerization with reduced accumulation of actin in the lung compared to the WT mouse. After exposure to bleomycin, the IQGAP1 KO mouse demonstrated decreased contractile activity of LF, reduced expression of SMA, TGFß, and collagen, and lowered overall fibrosis scores compared to the WT mouse. The numbers of inflammatory cells and expression of pro-inflammatory cytokines in lung tissue were not significantly different between IQGAP1 KO and WT mice. We conclude that IQGAP1 plays an important role in the development of lung fibrosis induced by bleomycin, and the absence of IQGAP1 reduces the contractile activity of lung fibroblast and bleomycin-induced pulmonary fibrosis. Thus, IQGAP1 may be a potential target for novel anti-fibrotic therapies for lung fibrosis.
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Actinas , Bleomicina , Fibroblastos , Fibrosis Pulmonar , Proteínas Activadoras de ras GTPasa , Animales , Ratones , Actinas/metabolismo , Modelos Animales de Enfermedad , Fibroblastos/metabolismo , Fibroblastos/patología , Pulmón/patología , Pulmón/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Polimerizacion , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/patología , Proteínas Activadoras de ras GTPasa/metabolismo , Proteínas Activadoras de ras GTPasa/genéticaRESUMEN
BACKGROUND: Depression is one of the most common complications of childbirth, and is experienced by approximately 17% of pregnant women and 13% of postpartum women. An estimated 85% of these women go untreated-an alarming statistic given the serious consequences for the mother, her child, other family members, and society. Professional societies (the American College of Obstetricians and Gynecologists and American Academy of Pediatrics) have recommended improvements in screening and treatment. Meta-analyses indicate that cognitive behavioral therapy eHealth interventions are efficacious for depression, generally, and for perinatal depression, specifically. Earlier controlled trials have established the effectiveness and acceptability of MomMoodBooster (including an Australian version, MumMoodBooster), an eHealth program for ameliorating postpartum depression. OBJECTIVE: This study aimed to evaluate the effectiveness of a perinatal version of MomMoodBooster encompassing both prenatal and postpartum content in a healthcare delivery setting already providing universal screening and referral of at-risk patients as part of routine care. STUDY DESIGN: A practical effectiveness study randomly assigned 95 pregnant and 96 postpartum women screened as depressed and satisfying eligibility criteria to experimental groups: the healthcare organization's perinatal depression care program (routine-care group) and routine care+MomMoodBooster2 program (eHealth group). Eligibility criteria included: pregnant or <1 year postpartum, ≥18 years of age, no active suicidal ideation, access to broadband internet via desktop/laptop, tablet, or smartphone, and English language proficiency. RESULTS: Intent-to-treat analyses of group effects used fixed-effects growth models to assess 12-week posttest change in outcomes. Results showed that both groups had significantly decreased depression severity, anxiety, stress, and automatic thoughts, and increased behavioral activation and self-efficacy. Relative to the routine-care group, the eHealth group displayed significantly greater decreases in depression severity and stress. These group comparisons were not moderated by depression severity (screening or baseline), anxiety, stress, or pregnant/postpartum status. Almost all (93%; n=89) women in the eHealth group visited their program, of whom 99% visited program sessions (M sessions visited=4.3±2.0; M total session duration=73.0±70.2 minutes; 49% viewed all 6 sessions). Among confirmed eHealth program users who provided ratings, 96% (79/82) rated their program as easy to use, 83% rated it helpful, and 93% (76/82) indicated that they would recommend it. CONCLUSION: Results support the effectiveness of using MomMoodBooster2 as a treatment option for perinatal women with depression, especially when combined with universal depression screening and referral. Consequently, the eHealth program shows promise as a tool to increase the reach of treatment delivery and to potentially reduce the number of untreated perinatal women with depression.
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Depresión Posparto , Telemedicina , Humanos , Niño , Femenino , Embarazo , Depresión/diagnóstico , Depresión/terapia , Australia , Depresión Posparto/diagnóstico , Depresión Posparto/prevención & control , MadresRESUMEN
BACKGROUND: Perinatal depression affects an estimated 1 in 5 women in North America during the perinatal period, with annualized lifetime costs estimated at $20.6 billion CAD in Canada and over $45.9 billion USD in the US. Access to psychological treatments remains limited for most perinatal women suffering from depression and anxiety. Some barriers to effective care can be addressed through task-sharing to non-specialist providers and through telemedicine platforms. The cost-effectiveness of these strategies compared to traditional specialist and in-person models remains unknown. This protocol describes an economic evaluation of non-specialist providers and telemedicine, in comparison to specialist providers and in-person sessions within the ongoing Scaling Up Maternal Mental healthcare by Increasing access to Treatment (SUMMIT) trial. METHODS: The economic evaluation will be undertaken alongside the SUMMIT trial. SUMMIT is a pragmatic, randomized, non-inferiority trial across five North American study sites (N = 1,226) of the comparable effectiveness of two types of providers (specialist vs. non-specialist) and delivery modes (telemedicine vs. in-person) of a behavioural activation treatment for perinatal depressive and anxiety symptoms. The primary economic evaluation will be a cost-utility analysis. The outcome will be the incremental cost-effectiveness ratio, which will be expressed as the additional cost required to achieve an additional quality-adjusted life-year, as assessed by the EuroQol 5-Dimension 5-Level instrument. A secondary cost-effectiveness analysis will use participants' depressive symptom scores. A micro-costing analysis will be conducted to estimate the resources/costs required to implement and sustain the interventions; healthcare resource utilization will be captured via self-report. Data will be pooled and analysed using uniform price and utility weights to determine cost-utility across all trial sites. Secondary country-specific cost-utility and cost-effectiveness analyses will also be completed. Sensitivity analyses will be conducted, and cost-effectiveness acceptability-curves will be generated, in all instances. DISCUSSION: Results of this study are expected to inform key decisions related to dissemination and scale up of evidence-based psychological interventions in Canada, the US, and possibly worldwide. There is potential impact on real-world practice by informing decision makers of the long-term savings to the larger healthcare setting in services to support perinatal women with common mental health conditions.
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Trastorno Depresivo , Telemedicina , Humanos , Femenino , Salud Mental , Análisis Costo-Beneficio , Ansiedad/terapia , Telemedicina/métodosRESUMEN
Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens. We examined HLA associations in SSc and its autoantibody subsets in a large, newly recruited African American (AA) cohort and among European Americans (EA). In the AA population, the African ancestry-predominant HLA-DRB1*08:04 and HLA-DRB1*11:02 alleles were associated with overall SSc risk, and the HLA-DRB1*08:04 allele was strongly associated with the severe antifibrillarin (AFA) antibody subset of SSc (odds ratio = 7.4). These African ancestry-predominant alleles may help explain the increased frequency and severity of SSc among the AA population. In the EA population, the HLA-DPB1*13:01 and HLA-DRB1*07:01 alleles were more strongly associated with antitopoisomerase (ATA) and anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizing the importance of HLA in defining autoantibody subtypes. The association of the HLA-DPB1*13:01 allele with the ATA+ subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence and HLA-DPB1*13:01 allele frequency in multiple populations was observed (r = 0.98, P = 3 × 10-6). Conditional analysis in the autoantibody subsets of SSc revealed several associated amino acid residues, mostly in the peptide-binding groove of the class II HLA molecules. Using HLA α/ß allelic heterodimers, we bioinformatically predicted immunodominant peptides of topoisomerase 1, fibrillarin, and centromere protein A and discovered that they are homologous to viral protein sequences from the Mimiviridae and Phycodnaviridae families. Taken together, these data suggest a possible link between HLA alleles, autoantibodies, and environmental triggers in the pathogenesis of SSc.
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Autoanticuerpos/inmunología , Autoantígenos/genética , Antígenos HLA/genética , Imitación Molecular/inmunología , Esclerodermia Sistémica/genética , Negro o Afroamericano/genética , Alelos , Secuencia de Aminoácidos/genética , Antígenos Virales/genética , Antígenos Virales/inmunología , Autoantígenos/inmunología , Biología Computacional , Conjuntos de Datos como Asunto , Femenino , Predisposición Genética a la Enfermedad , Antígenos HLA/inmunología , Humanos , Masculino , Mimiviridae/inmunología , Phycodnaviridae/inmunología , Estructura Secundaria de Proteína/genética , Medición de Riesgo , Esclerodermia Sistémica/epidemiología , Esclerodermia Sistémica/inmunología , Homología de Secuencia de Aminoácido , Población Blanca/genéticaRESUMEN
OBJECTIVE: This study aimed to determine whether clinically integrated Breastfeeding Peer Counseling (ci-BPC) added to usual lactation care reduces disparities in breastfeeding intensity and duration for Black and Hispanic/Latine participants. STUDY DESIGN: This study is a pragmatic, randomized control trial (RCT) of ci-BPC care at two ci-BPC-naïve obstetrical hospital facilities in the greater Chicago area. Participants will include 720 patients delivering at Hospital Site 1 and Hospital Site 2 who will be recruited from eight prenatal care sites during midpregnancy. Participants must be English or Spanish speaking, planning to parent their child, and have no exposure to ci-BPC care prior to enrollment. Randomization will be stratified by race and ethnicity to create three analytic groups: Black, Hispanic/Latine, and other races. RESULTS: The primary outcome will be breastfeeding duration. Additional outcomes will include the proportion of breastmilk feeds during the delivery admission, at 6-week postdelivery, and at 6-month postdelivery. A process evaluation will be conducted to understand implementation outcomes, facilitators, and barriers to inform replication and scaling of the innovative ci-BPC model. CONCLUSION: This research will produce findings of relevance to perinatal patients and their families, the vast majority of whom desire to provide breastmilk to their infants and require support to succeed with their feeding goals. As the largest RCT of ci-BPC in the United States to date, this research will improve the quality of evidence available regarding the effectiveness of ci-BPC at reducing disparities. These findings will help patients and stakeholders determine the benefits of accepting and adopting the program and inform policies focused on improving perinatal care and reducing maternal/child health disparities. This study is registered with Clinical Trial (identifier: NCT05441709). KEY POINTS: · Ci-BPC can promote racial breastfeeding equity.. · Ci-BPC has not been tested as a generalized lactation strategy in prior trials and is underused.. · This RCT will identify if ci-BPC can reduce breastfeeding disparities for Black and Hispanic patients..
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OBJECTIVES: The Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial compared hematopoietic stem cell transplant to CYC treatment in patients with early SSc with progressive skin and lung or kidney involvement. Here we describe lymphocyte phenotype abnormalities at study entry and the relation to prior DMARD therapy. METHODS: Lymphocyte subsets (n = 26) measured by flow cytometry were compared in 123 heathy controls and 71 SCOT participants, including those given (n = 57) or not given (n = 14) DMARDs within 12 months of randomization. RESULTS: Compared with healthy controls, individuals with SSc showed significant reductions in central memory CD8 T cells, activated total and CD4 T cells, γ/δ T cells, memory B cells, myeloid and plasmacytoid dendritic cells and FOXP3+CD25+ Treg cells and increases in naïve CD4 T cells, effector memory CD4 T cells and effector CD8 T cells. A greater bias towards a IL-4+ Th2/T cytotoxic 2 (Tc2) phenotype based on the Th2:Th1 CD4 ratio and Tc2:Tc1 CD8 T cells was also found. Notably, no difference in any lymphocyte subset was observed between those given or not given prior DMARDs. CONCLUSIONS: In patients with early, severe SSc, significant lymphocyte subset abnormalities were observed. Prior treatment with immunosuppressive therapy did not impact the immunophenotype, suggesting that lymphocyte disturbances in scleroderma appeared to be due to the disease itself. TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov), NCT00114530.
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Antirreumáticos , Células TH1 , Linfocitos T CD8-positivos , Ciclofosfamida/uso terapéutico , Factores de Transcripción Forkhead , Terapia de Inmunosupresión , Inmunosupresores/uso terapéutico , Interleucina-4 , Subgrupos Linfocitarios , Fenotipo , Subgrupos de Linfocitos T , Células Th2RESUMEN
For patients with optimally treated chronic myeloid leukemia (CML), discontinuation of tyrosine kinase inhibitor (TKI) therapy can lead to treatment-free remission. In previous trials, TKI discontinuation has been associated with increased musculoskeletal pain in some patients ("withdrawal syndrome"), based on physician-reported adverse events (AE). Patient-reported pain has not been described. The Life After Stopping TKI study was a 14-site prospective, non-randomized clinical trial of TKI discontinuation. We defined increased pain after discontinuation as: (i) a physician-reported pain AE, (ii) a 2-level increase in self-reported musculoskeletal pain (4-level single item), or (iii) initiation of a medication for pain. We plotted the trajectory of patient-reported pain over time using a piecewise mixed-effects ordinal logistic model. Within 3 months of discontinuation, 35 of 172 patients (20.3%) had a physician-reported pain AE, 22 of 172 (12.8%) had an increase in self-reported pain, and 18 of 154 (11.7%) initiated a pain medication. Agreement among these measures was limited; overall, 60 of 172 patients (34.9%) had increased pain. Three patients (1.7%) restarted a TKI because of pain. The modelpredicted trajectory showed an increase in pain in the first 3 months followed by a decrease, returning to baseline levels by 6 months and further decreasing after that. This trajectory was similar among patients who did and did not restart TKI, suggesting that resuming a TKI for withdrawal syndrome may be necessary for some, but other approaches to manage pain should be tried so that patients can remain in treatment-free remission when possible.
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Leucemia Mielógena Crónica BCR-ABL Positiva , Dolor Musculoesquelético , Médicos , Humanos , Estudios Prospectivos , Dolor Musculoesquelético/inducido químicamente , Dolor Musculoesquelético/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
PURPOSE OF REVIEW: Telemedicine has transformed our ability to access and offer mental healthcare. There remain key questions to facilitate scalable, patient-centered solutions for perinatal mental health. We critically evaluate the recent literature and propose potential future directions. RECENT FINDINGS: The current literature highlights the promise of telemedicine in the prevention and treatment of perinatal depression, including the preference for and the potential efficacy of telemedicine-delivered mental healthcare when compared to in-person treatments. There remains a need for large, adequately powered randomized controlled trials; integration of trauma into depression and anxiety trials, transdiagnostic treatment of perinatal women, and scaling up these effective treatments into existing health and payer systems. Pragmatic, evidence-based solutions exist to effectively scale-up treatments for perinatal mental health. While research is underway to address the growing treatment gap, questions remain regarding who will deliver and pay for these treatments and how we can leverage telemedicine to treat perinatal mental health transdiagnostically.
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Trastorno Depresivo , Servicios de Salud Mental , Telemedicina , Embarazo , Humanos , Femenino , Atención a la Salud , Salud Mental , Depresión/terapiaRESUMEN
OBJECTIVE: The objective of the study was to evaluate whether patients with oxytocin discontinued during the second stage of labor (≥30 minutes prior to delivery) had a lower rate of postpartum hemorrhage (PPH) compared with those with oxytocin continued until delivery or discontinued <30 minutes prior to delivery. STUDY DESIGN: Retrospective cohort study was performed from August 1, 2014 to July 31, 2019. Singleton pregnancies of 24 to 42 weeks gestation were included if they reached the second stage of labor and received oxytocin during labor. Patients on anticoagulants were excluded. Patients with oxytocin discontinued ≥30 minutes prior to delivery represented STOPPED and those with oxytocin continued until delivery or discontinued <30 minutes prior to delivery represented CONTINUED. Patient data were abstracted from the electronic medical record. The primary outcome was PPH (≥1,000 mL blood loss). Univariable analyses were performed to compare groups. Multi-variable logistic regression was performed to adjust for prespecified confounders. Planned sub-group analyses by the route of delivery were performed. RESULTS: Of 10,421 total patients, 1,288 had oxytocin STOPPED and 9,133 had oxytocin CONTINUED. There were no significant differences in age, race, or ethnicity, body mass index, public insurance, gestational diabetes, or pregnancy-induced hypertension between STOPPED and CONTINUED. The PPH rate was 15.2 and 5.7% in STOPPED and CONTINUED, respectively (p < 0.001). After adjusting for confounders, STOPPED remained at higher odds for PPH (adjusted odds ratio 2.859, 95% confidence interval 2.394, 3.414, p < 0.001). Among cesarean deliveries only, there was no significant difference in the rate of PPH between STOPPED and CONTINUED (38.0 vs. 36.4%, respectively, p = 0.730). However, among vaginal deliveries, the rate of PPH was actually lower in STOPPED than CONTINUED (3.4 vs. 5.2%, respectively, p = 0.024). CONCLUSION: The rate of PPH was higher in patients with oxytocin STOPPED compared with CONTINUED. However, among vaginal deliveries, there was a significantly lower rate of PPH in STOPPED. These disparate findings may be explained by the variable impact of second-stage oxytocin on PPH as a function of delivery type. KEY POINTS: · It is unclear if oxytocin use in the second stage of labor may independently increase the risk of hemorrhage.. · Patients with oxytocin discontinued during the second stage of labor had a higher rate of PPH.. · PPH was significantly lower among vaginal deliveries in patients with oxytocin discontinued..
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BACKGROUND: Despite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma. METHODS: We randomly assigned adults (18 to 69 years of age) with severe scleroderma to undergo myeloablative autologous stem-cell transplantation (36 participants) or to receive cyclophosphamide (39 participants). The primary end point was a global rank composite score comparing participants with each other on the basis of a hierarchy of disease features assessed at 54 months: death, event-free survival (survival without respiratory, renal, or cardiac failure), forced vital capacity, the score on the Disability Index of the Health Assessment Questionnaire, and the modified Rodnan skin score. RESULTS: In the intention-to-treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P=0.01). In the per-protocol population (participants who received a transplant or completed ≥9 doses of cyclophosphamide), the rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P=0.02). At 72 months, Kaplan-Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P=0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease-modifying antirheumatic drugs (DMARDs) by 54 months, as compared with 44% of those in the cyclophosphamide group (P=0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group. CONCLUSIONS: Myeloablative autologous hematopoietic stem-cell transplantation achieved long-term benefits in patients with scleroderma, including improved event-free and overall survival, at a cost of increased expected toxicity. Rates of treatment-related death and post-transplantation use of DMARDs were lower than those in previous reports of nonmyeloablative transplantation. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health; ClinicalTrials.gov number, NCT00114530 .).
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Ciclofosfamida/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Inmunosupresores/uso terapéutico , Esclerodermia Sistémica/terapia , Adolescente , Adulto , Anciano , Ciclofosfamida/efectos adversos , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Inmunosupresores/efectos adversos , Infecciones/etiología , Análisis de Intención de Tratar , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Esclerodermia Sistémica/tratamiento farmacológico , Esclerodermia Sistémica/mortalidad , Acondicionamiento Pretrasplante , Trasplante Autólogo , Adulto JovenRESUMEN
Prior studies have reported high response rates with recombinant interferon-α (rIFN-α) therapy in patients with essential thrombocythemia (ET) and polycythemia vera (PV). To further define the role of rIFN-α, we investigated the outcomes of pegylated-rIFN-α2a (PEG) therapy in ET and PV patients previously treated with hydroxyurea (HU). The Myeloproliferative Disorders Research Consortium (MPD-RC)-111 study was an investigator-initiated, international, multicenter, phase 2 trial evaluating the ability of PEG therapy to induce complete (CR) and partial (PR) hematologic responses in patients with high-risk ET or PV who were either refractory or intolerant to HU. The study included 65 patients with ET and 50 patients with PV. The overall response rates (ORRs; CR/PR) at 12 months were 69.2% (43.1% and 26.2%) in ET patients and 60% (22% and 38%) in PV patients. CR rates were higher in CALR-mutated ET patients (56.5% vs 28.0%; P = .01), compared with those in subjects lacking a CALR mutation. The median absolute reduction in JAK2V617F variant allele fraction was -6% (range, -84% to 47%) in patients achieving a CR vs +4% (range, -18% to 56%) in patients with PR or nonresponse (NR). Therapy was associated with a significant rate of adverse events (AEs); most were manageable, and PEG discontinuation related to AEs occurred in only 13.9% of subjects. We conclude that PEG is an effective therapy for patients with ET or PV who were previously refractory and/or intolerant of HU. This trial was registered at www.clinicaltrials.gov as #NCT01259856.
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Antineoplásicos/uso terapéutico , Interferón-alfa/uso terapéutico , Policitemia Vera/tratamiento farmacológico , Polietilenglicoles/uso terapéutico , Trombocitemia Esencial/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Humanos , Hidroxiurea , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/uso terapéutico , Resultado del TratamientoRESUMEN
Tuberculosis (TB) remains a worldwide public health threat. Development of a more effective vaccination strategy to prevent pulmonary TB, the most common and contagious form of the disease, is a research priority for international TB control. A key to reaching this goal is improved understanding of the mechanisms of local immunity to Mycobacterium tuberculosis, the causative organism of TB. In this study, we evaluated global M. tuberculosis-induced gene expression in airway immune cells obtained by bronchoalveolar lavage (BAL) of individuals with latent TB infection (LTBI) and M. tuberculosis-naive controls. In prior studies, we demonstrated that BAL cells from LTBI individuals display substantial enrichment for M. tuberculosis-responsive CD4+ T cells compared with matched peripheral blood samples. We therefore specifically assessed the impact of the depletion of CD4+ and CD8+ T cells on M. tuberculosis-induced BAL cell gene expression in LTBI. Our studies identified 12 canonical pathways and a 47-gene signature that was both sensitive and specific for the contribution of CD4+ T cells to local recall responses to M. tuberculosis In contrast, depletion of CD8+ cells did not identify any genes that fit our strict criteria for inclusion in this signature. Although BAL CD4+ T cells in LTBI displayed polyfunctionality, the observed gene signature predominantly reflected the impact of IFN-γ production on a wide range of host immune responses. These findings provide a standard for comparison of the efficacy of standard bacillus Calmette-Guérin vaccination as well as novel TB vaccines now in development at impacting the initial response to re-exposure to M. tuberculosis in the human lung.
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Lavado Broncoalveolar , Linfocitos T CD4-Positivos/inmunología , Interferón gamma/biosíntesis , Tuberculosis Latente/genética , Mycobacterium tuberculosis/inmunología , Adolescente , Adulto , Femenino , Humanos , Interferón gamma/inmunología , Tuberculosis Latente/inmunología , Masculino , Persona de Mediana Edad , Vacunas contra la Tuberculosis/inmunología , Adulto JovenRESUMEN
OBJECTIVES: Riociguat is approved for pulmonary arterial hypertension and has antiproliferative, anti-inflammatory and antifibrotic effects in animal models of tissue fibrosis. We evaluated the efficacy and safety of riociguat in patients with early diffuse cutaneous systemic sclerosis (dcSSc) at high risk of skin fibrosis progression. METHODS: In this randomised, double-blind, placebo-controlled, phase IIb trial, adults with dcSSc of <18 months' duration and a modified Rodnan skin score (mRSS) 10-22 units received riociguat 0.5 mg to 2.5 mg orally three times daily (n=60) or placebo (n=61). The primary endpoint was change in mRSS from baseline to week 52. RESULTS: At week 52, change from baseline in mRSS units was -2.09±5.66 (n=57) with riociguat and -0.77±8.24 (n=52) with placebo (difference of least squares means -2.34 (95% CI -4.99 to 0.30; p=0.08)). In patients with interstitial lung disease, forced vital capacity declined by 2.7% with riociguat and 7.6% with placebo. At week 14, average Raynaud's condition score had improved ≥50% in 19 (41.3%)/46 patients with riociguat and 13 (26.0%)/50 patients with placebo. Safety assessments showed no new signals with riociguat and no treatment-related deaths. CONCLUSIONS: Riociguat did not significantly benefit mRSS versus placebo at the predefined p<0.05. Secondary and exploratory analyses showed potential efficacy signals that should be tested in further trials. Riociguat was well tolerated.
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Activadores de Enzimas/administración & dosificación , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , Esclerodermia Difusa/tratamiento farmacológico , Adulto , Biopsia con Aguja , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Internacionalidad , Masculino , Persona de Mediana Edad , Pruebas de Función Respiratoria , Medición de Riesgo , Esclerodermia Difusa/patología , Índice de Severidad de la Enfermedad , Insuficiencia del TratamientoRESUMEN
Fedratinib is an oral, selective Janus kinase 2 (JAK2) inhibitor. The phase II JAKARTA2 study assessed fedratinib in patients with intermediate- or high-risk myelofibrosis (MF) who were resistant or intolerant to prior ruxolitinib per investigator assessment. Patients received fedratinib 400 mg/day in 28-day cycles. The JAKARTA2 outcomes were initially reported using a last-observation-carried forward (LOCF) analysis in a "Per Protocol" population. This updated analysis of JAKARTA2 employs intention-to-treat analysis principles without LOCF for all treated patients (ITT Population; N = 97), and for a patient subgroup who met more stringent definitions of prior ruxolitinib failure (Stringent Criteria Cohort; n = 79). Median duration of prior ruxolitinib exposure was 10.7 months. The primary endpoint was spleen volume response rate (SVRR; ≥35% spleen volume decrease from baseline to end of cycle 6 [EOC6]). The SVRR was 31% in the ITT Population and 30% in the Stringent Criteria Cohort. Median duration of spleen volume response was not reached. Symptom response rate (≥50% reduction from baseline to EOC6 in total symptom score [TSS] on the modified Myelofibrosis Symptom Assessment Form [MFSAF]) was 27%. Grade 3-4 anemia and thrombocytopenia rates were 38% and 22%, respectively. Patients with advanced MF substantially pretreated with ruxolitinib attained robust spleen responses and reduced symptom burden with fedratinib.
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Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/patología , Pirrolidinas/administración & dosificación , Bazo/patología , Sulfonamidas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nitrilos , Tamaño de los Órganos/efectos de los fármacos , Pirazoles/administración & dosificación , PirimidinasRESUMEN
Screens and adjunctive treatments for perinatal mood are available, but barriers prevent many women from receiving them. Mobile technology may help bypass barriers. The purpose of this study was to evaluate the feasibility of screening and texting perinatal women via their personal smartphones. This prospective cohort study enrolled 203 pregnant and postpartum women receiving obstetric care at a Midwestern US academic medical center. Participants received one electronic mood screen and three text messages per week for two weeks. Texts were based on the Mothers and Babies Course, a CBT-based preventative program that addresses limited social support, lack of pleasant activities, and harmful thought patterns. Feasibility was defined as the ability to take the mood screen and receive texts without technical difficulties. Demographic variables were paired with results. Insurance type (private or public) was used as a proxy for socioeconomic status. Pearson chi-squared tests were used to analyze the data. A text-based satisfaction survey was also administered. The sample was 72% privately insured and 28% publicly insured. Sixty-seven percent completed electronic screening. Screen completion was significantly associated with private insurance (OR = 3.8, 95% CI 2.00-7.30) and "married" status (OR = 1.93, 95% CI 1.01-3.70). Most survey respondents (92%) found it easy to receive the texts, and 76% responded with very favorable comments about the texts. Smartphone mood screening and supportive texting were technically feasible. Screen completion was lower among single women with public insurance.