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BACKGROUND: Multilevel anterior cervical discectomy and fusion (mACDF) is the gold standard for multilevel spinal disease; although safe and effective, mACDF can limit regular spinal motion and contribute to adjacent segment disease (ASD). Hybrid surgery, composed of ACDF and cervical disc arthroplasty, has the potential to reduce ASD by retaining spinal mobility. This study examined the safety of hybrid surgery by utilizing administrative claims data to compare real-world rates of subsequent surgery and post-procedural hospitalization within populations of patients undergoing hybrid surgery versus mACDF for multilevel spinal disease. METHODS: This observational, retrospective analysis used the MarketScan Commercial and Medicare Database from July 2013 through June 2020. Propensity score matched cohorts of patients who received hybrid surgery or mACDF were established based on the presence of spinal surgery procedure codes in the claims data and followed over a variable post-period. Rates of subsequent surgery and post-procedural hospitalization (30- and 90-day) were compared between hybrid surgery and mACDF cohorts. RESULTS: A total of 430 hybrid surgery patients and 2,136 mACDF patients qualified for the study; average follow-up was approximately 2 years. Similar rates of subsequent surgery (Hybrid: 1.9 surgeries/100 patient-years; mACDF: 1.8 surgeries/100 patient-years) were observed for the two cohorts. Hospitalization rates were also similar across cohorts at 30 days post-procedure (Hybrid: 0.67% hospitalized/patient-year; mACDF: 0.87% hospitalized/patient-year). At 90 days post-procedure, hybrid surgery patients had slightly lower rates of hospitalization compared to mACDF patients (0.23% versus 0.42% hospitalized/patient-year; p < 0.05). CONCLUSIONS: Findings of this real-world, retrospective cohort study confirm prior reports indicating that hybrid surgery is a safe and effective intervention for multilevel spinal disease which demonstrates non-inferiority in relation to the current gold standard mACDF. The use of administrative claims data in this analysis provides a unique perspective allowing the inclusion of a larger, more generalizable population has historically been reported on in small cohort studies.
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Degeneração do Disco Intervertebral , Fusão Vertebral , Estados Unidos/epidemiologia , Humanos , Idoso , Degeneração do Disco Intervertebral/cirurgia , Estudos Retrospectivos , Vértebras Cervicais/cirurgia , Medicare , Discotomia/efeitos adversos , Discotomia/métodos , Artroplastia/métodos , Fusão Vertebral/efeitos adversos , Fusão Vertebral/métodos , Resultado do TratamentoRESUMO
Differentiation of CD4(+) helper and CD8(+) cytotoxic αß T cells from CD4(+)CD8(+) thymocytes involves upregulation of lineage-specifying transcription factors and transcriptional silencing of CD8 or CD4 coreceptors, respectively, in MHC class II or I (MHCII or I)-restricted thymocytes. In this study, we demonstrate that inactivation of the Dicer RNA endonuclease in murine thymocytes impairs initiation of Cd4 and Cd8 silencing, leading to development of positively selected MHCI- and MHCII-restricted mature CD4(+)CD8(+) thymocytes. Expression of the antiapoptotic BCL2 protein or inactivation of the p53 proapoptotic protein rescues these thymocytes from apoptosis, increasing their frequency and permitting accumulation of CD4(+)CD8(+) αß T cells in the periphery. Dicer-deficient MHCI-restricted αß T cells fail to normally silence Cd4 and display impaired induction of the CD8 lineage-specifying transcription factor Runx3, whereas Dicer-deficient MHCII-restricted αß T cells show impaired Cd8 silencing and impaired induction of the CD4 lineage-specifying transcription factor Thpok. Finally, we show that the Drosha RNA endonuclease, which functions upstream of Dicer in microRNA biogenesis, also regulates Cd4 and Cd8 silencing. Our data demonstrate a previously dismissed function for the microRNA biogenesis machinery in regulating expression of lineage-specifying transcription factors and silencing of Cd4 and Cd8 during αß T cell differentiation.
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RNA Helicases DEAD-box/genética , MicroRNAs/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Ribonuclease III/genética , Linfócitos T Citotóxicos/citologia , Linfócitos T Auxiliares-Indutores/citologia , Animais , Apoptose/imunologia , Antígenos CD4/genética , Antígenos CD4/imunologia , Antígenos CD8/genética , Antígenos CD8/imunologia , Diferenciação Celular/imunologia , Linhagem da Célula/imunologia , Subunidade alfa 3 de Fator de Ligação ao Core/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Camundongos , Camundongos Knockout , MicroRNAs/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Linfócitos T Citotóxicos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Fatores de Transcrição/imunologia , Proteína Supressora de Tumor p53/metabolismo , Regulação para CimaRESUMO
The Dicer nuclease generates small RNAs that regulate diverse biological processes through posttranscriptional gene repression and epigenetic silencing of transcription and recombination. Dicer-deficient cells exhibit impaired differentiation, activity, proliferation, and survival. Dicer inactivation in developing mouse lymphocytes impairs their proliferation and survival and alters Ag receptor gene repertoires for largely undefined reasons. To elucidate functions of Dicer in lymphocyte development and Ag receptor locus transcription and recombination, we analyzed mice with conditional Dicer deletion in thymocytes containing unrearranged or prerearranged TCRß loci. Expression of either a preassembled functional TCRß gene (Vß1(NT)) or the prosurvival BCL2 protein inhibited death and partially rescued proliferative expansion of Dicer-deficient thymocytes. Notably, combined expression of Vß1(NT) and BCL2 completely rescued proliferative expansion of Dicer-deficient thymocytes and revealed that Dicer promotes survival of cells attempting TCRß recombination. Finally, inclusion of an endogenous preassembled DJß complex that enhances Vß recombination increased death and impaired proliferative expansion of Dicer-deficient thymocytes. These data demonstrate a critical role for Dicer in promoting survival of thymocytes experiencing DNA double-strand breaks (DSBs) during TCRß recombination. Because DSBs are common and ubiquitous in cells, our findings indicate that impaired cellular survival in response to DSBs should be considered when interpreting Dicer-deficient phenotypes.
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Quebras de DNA de Cadeia Dupla , Ribonuclease III/metabolismo , Timócitos/metabolismo , Animais , Sobrevivência Celular/genética , Camundongos , Camundongos Knockout , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Recombinação Genética , Ribonuclease III/genética , Timócitos/imunologiaRESUMO
AIMS: To investigate real-world treatment adherence and persistence in people with type 2 diabetes newly initiating oral semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), or a dipeptidyl peptidase-4 inhibitor (DPP-4i). METHODS: This retrospective cohort study used the Merative™ MarketScan® Commercial and Medicare databases. Index date was the first fill for the cohort medication. Adherence was defined as proportion of days covered (PDC) over the 12-month post-index period ('adherent' = ≥0.8). Persistence was number of days until discontinuation, based on a 45-day gap. Results were compared between cohorts using inverse probability treatment weighting. RESULTS: Oral semaglutide (n=5485) and DPP-4i (n=4980) cohorts had similar percentages of people who were adherent (PDC ≥0.8; 41.6â¯% vs. 42.9â¯%; P = 0.182) and persistent for ≥9 months (45.0â¯% vs. 46.3â¯%; P = 0.185). The DPP-4i cohort used significantly more anti-diabetic medication (ADM) classes over the post-index period (mean±SD: 2.6±1.0 vs. 2.9±1.1, P < 0.001), with 23.2â¯% filling a GLP-1 RA in the post-period. CONCLUSIONS: Adherence and persistence were similar between cohorts. However, there are potential benefits to prescribing oral semaglutide over DPP-4is, including reduced need for additional ADM.
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Background: Calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) are indicated for migraine prevention in the United States. Limited data comparing real-world treatment patterns for CGRP mAbs are available. Objective: To compare the treatment patterns among patients with migraine initiating galcanezumab, fremanezumab, and erenumab. Methods: This retrospective study included adult patients with one or more claims for a self-injectable CGRP mAb (galcanezumab, fremanezumab, or erenumab), with continuous enrollment in medical and pharmacy benefits for 12 months pre-index and 6 and 12 months post-index using MerativeTM MarketScan® Commercial and Medicare databases from May 2017 through March 2021. Propensity-score matching was used to address confounding by observed covariates. Outcomes analyzed included proportion of days covered (PDC), medication-possession ratio (MPR), persistence (≤60-day gap), treatment discontinuation, and switch to a non-index drug. Descriptive X2 and t-test analyses were conducted. Results: At the 12-month follow-up, matched galcanezumab and fremanezumab cohorts each comprised 2674 patients and the galcanezumab and erenumab cohorts 3503 each. The mean (SD) PDC and MPR were both 0.6 (0.3) across all cohorts. Based on PDC ≥0.80 and MPR ≥0.80, a greater proportion of galcanezumab vs fremanezumab (46.2% vs 43.7%, p=0.053; 46.8% vs 44.3%, p=0.053) and galcanezumab vs erenumab (46.2% vs 44%, p=0.156; 46.7% vs 44.5%, p=0.262), respectively, initiators were adherent. Compared to galcanezumab, fremanezumab (248.0 days vs 236.5 days, p=0.001), and erenumab (247.8 days vs 241.7 days, p=0.061) initiators had lower mean persistence. Galcanezumab initiators were less likely to discontinue treatment than fremanezumab (47.8% vs 51.7%, p=0.005) and erenumab (47.7% vs 50.2%, p=0.040) initiators. Across cohorts, most switchers initiated onabotulinum toxin A as subsequent treatment. Similar results were observed for 6-month follow-up cohorts. Conclusion: Patients with migraine who initiated treatment with galcanezumab showed higher persistence and lower treatment discontinuation rates than those initiating either fremanezumab or erenumab.
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OBJECTIVE: The study was to determine the prevalence of baseline risk factors for cardiovascular outcomes and cancer among commercially-insured patients with rheumatoid arthritis (RA) during their first dispensed treatment for either tumor necrosis factor inhibitors (TNFi) or JAK inhibitors (JAKi). METHODS: Patients with RA from August 16, 2019 to March 31, 2022 were identified in the Merative MarketScan Commercial and Medicare databases. The first date that a TNFi or JAKi was dispensed was the index date, and baseline risk factors were assessed among patients continuously eligible for 12 months before the index date. Patients who had the following were stratified into an elevated risk category: age ≥65 years, smoking, or a history of a major adverse cardiovascular event, venous thromboembolism, or cancer. The prevalence of modifiable risk factors was also reported: hypertension, hyperlipidemia, obesity, and diabetes. The crude prevalence and prevalence difference (PD) were reported. RESULTS: A total of 12,673 patients (TNFi [n = 7,748; 61%] and JAKi [n = 4,925; 39%]) met inclusion criteria. The prevalence of elevated risk was the same for all patients using TNFi (n = 2,051; 26%) and JAKi (n = 1,262; 26%). Compared with patients having low risk, patients with an elevated risk also had a higher prevalence of at least one primary modifiable risk factor for both patients using JAKi (79% vs 58%; PD 21%, 95% confidence interval [CI] 18%-24%) and TNFi (81% vs 60%; PD 21%, 95% CI 19%-23%). CONCLUSION: In recent years, JAKi and TNFi were used in similar proportions to treat RA among commercially-insured patients at elevated cardiovascular and cancer risk. Because uncontrolled disease, modifiable comorbidities, and treatment with JAKi are associated with these adverse events, future studies evaluating how practice patterns may be affected by the emergence of safety data will be of value.
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Developmental stage-specific regulation of transcriptional accessibility helps control V(D)J recombination. Vß segments on unrearranged TCRß alleles are accessible in CD4(-)/CD8(-) (double-negative [DN]) thymocytes, when they recombine, and inaccessible in CD4(+)/CD8(+) (double-positive [DP]) thymocytes, when they do not rearrange. Downregulation of Vß accessibility on unrearranged alleles is linked with Lat-dependent ß-selection signals that inhibit Vß rearrangement, stimulate Ccnd3-driven proliferation, and promote DN-to-DP differentiation. Transcription and recombination of Vßs on VDJß-rearranged alleles in DN cells has not been studied; Vßs upstream of functional VDJß rearrangements have been found to remain accessible, yet not recombine, in DP cells. To elucidate contributions of ß-selection signals in regulating Vß transcription and recombination on VDJß-rearranged alleles, we analyzed wild-type, Ccnd3(-/-), and Lat(-/-) mice containing a preassembled functional Vß1DJCß1 (Vß1(NT)) gene. Vß10 segments located just upstream of this VDJCß1 gene were the predominant germline Vßs that rearranged in Vß1(NT/NT) and Vß1(NT/NT)Ccnd3(-/-) thymocytes, whereas Vß4 and Vß16 segments located further upstream rearranged at similar levels as Vß10 in Vß1(NT/NT)Lat(-/-) DN cells. We previously showed that Vß4 and Vß16, but not Vß10, are transcribed on Vß1(NT) alleles in DP thymocytes; we now demonstrate that Vß4, Vß16, and Vß10 are transcribed at similar levels in Vß1(NT/NT)Lat(-/-) DN cells. These observations indicate that suppression of Vß rearrangements is not dependent on Ccnd3-driven proliferation, and DN residence can influence the repertoire of Vßs that recombine on alleles containing an assembled VDJCß1 gene. Our findings also reveal that ß-selection can differentially silence rearrangement of germline Vß segments located proximal and distal to functional VDJß genes.
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Rearranjo Gênico da Cadeia beta dos Receptores de Antígenos dos Linfócitos T/genética , Genes Codificadores da Cadeia beta de Receptores de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Linfócitos T/citologia , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Separação Celular , Citometria de Fluxo , Rearranjo Gênico da Cadeia beta dos Receptores de Antígenos dos Linfócitos T/imunologia , Genes Codificadores da Cadeia beta de Receptores de Linfócitos T/imunologia , Linfopoese/genética , Camundongos , Camundongos Knockout , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Linfócitos T/imunologiaRESUMO
INTRODUCTION: New extended half-life antibodies for the single-dose prevention of medically attended (MA) respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) have been developed for administration to all infants before or during their first RSV season. For infants born during the season, administration as soon as feasible after birth would provide optimal protection and minimize access disparities. The objective of this study was to assess the time from birth hospitalization discharge to the first outpatient visit (FOV) among US infants in order to determine optimal site of administration for the extended half-life antibody. MATERIAL AND METHODS: This retrospective, observational, time-to-event analysis uses the Merative™ MarketScan® Commercial and Multi-State Medicaid Databases. Time to FOV is reported separately for the COVID-19 and recent pre-COVID-19 eras and for commercially insured and Medicaid infants. RESULTS: Overall, 73.8 % of Medicaid infants had an FOV within 5 days as compared to 84.7 % of commercially insured infants. Estimates were higher during the COVID-19 era. Urban commercially insured infants had much higher FOV completion than their counterparts. Among Medicaid infants, urban Black and rural White infants were least likely to complete their FOV within 5 days of birth hospitalization discharge. DISCUSSION AND CONCLUSION: FOV within 5 days after birth hospitalization discharge for Medicaid infants is substantially lower than that of commercially insured infants. Approximately 1 in 4 Medicaid infants and 1 in 8 infants with commercial insurance did not have an outpatient visit within 5 days of birth hospitalization discharge. For US infants born during the RSV season, administration of extended half-life RSV antibodies in the newborn nursery prior to discharge would ensure optimal uptake and minimize access disparities.
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COVID-19 , Vírus Sincicial Respiratório Humano , Estados Unidos/epidemiologia , Recém-Nascido , Humanos , Lactente , Meia-Vida , Estudos Retrospectivos , Anticorpos AntiviraisRESUMO
Most lymphocytes express cell surface Ag receptor chains from single alleles of distinct Ig or TCR loci. Since the identification of Ag receptor allelic exclusion, the importance of this process and the precise molecular mechanisms by which it is achieved have remained enigmatic. This brief review summarizes current knowledge of the extent to which Ig and TCR loci are subject to allelic exclusion. Recent progress in studying and defining mechanistic steps and molecules that may control the monoallelic initiation and subsequent inhibition of V-to-(D)-J recombination is outlined using the mouse TCRß locus as a model with frequent comparisons to the mouse IgH and Igκ loci. Potential consequences of defects in mechanisms that control Ag receptor allelic exclusion and a reappraisal of the physiologic relevance of this immunologic process also are discussed.
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Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos T/genética , Alelos , Animais , Autoimunidade/genética , Camundongos , Recombinação Genética , Tolerância a Antígenos Próprios/genéticaRESUMO
Feedback inhibition of V(D)J recombination enforces Ag receptor allelic exclusion in mammalian lymphocytes. Yet, in-frame VbetaDJbeta exons can assemble on both alleles in human and mouse alphabeta T lineage cells. To elucidate mechanisms that enforce TCRbeta allelic exclusion in such cells, we analyzed Vbeta expression and rearrangement in mice containing a functional Vbeta14DJbeta1.5Cbeta1 gene (Vbeta14(NT)) and/or Vbeta8.2DJbeta1.1Cbeta1 transgene (Vbeta8(Tg)). The majority of Vbeta14(NT) and Vbeta8(Tg) alphabeta T lineage cells expressed only Vbeta14(+) or Vbeta8(+) TCRbeta-chains, respectively, and lacked Vbeta rearrangements on wild-type TCRbeta loci. However, endogenous Vbeta rearrangements and alphabeta T lineage cells expressing endogenous Vbetas from wild-type alleles alone or with the prerearranged Vbeta in cell surface TCRbeta-chains were observed in Vbeta14(NT) and Vbeta8(Tg) mice. Although nearly all Vbeta8(Tg):Vbeta14(NT) thymocytes and splenic alphabeta T cells expressed Vbeta8(+) TCRbeta-chains, only half of these lymphocytes expressed Vbeta14(+) TCRbeta-chains, even though similar steady-state levels of Vbeta14(NT) mRNA were expressed in Vbeta8(+)Vbeta14(+) and Vbeta8(+)Vbeta14(-) populations. Our data demonstrated that posttranscriptional silencing of functionally assembled endogenous VbetaDJbetaCbeta genes can enforce TCRbeta allelic exclusion and reveal another mechanism that contributes to the development of lymphocytes with monospecific Ag receptors.
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Interferência de RNA , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Linfócitos T/metabolismo , Alelos , Animais , Citometria de Fluxo , Rearranjo Gênico do Linfócito T , Hibridomas/metabolismo , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Camundongos Transgênicos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T/citologiaRESUMO
Ag receptor allelic exclusion is thought to occur through monoallelic initiation and subsequent feedback inhibition of recombinational accessibility. However, our previous analysis of mice containing a V(D)J recombination reporter inserted into Vbeta14 (Vbeta14(Rep)) indicated that Vbeta14 chromatin accessibility is biallelic. To determine whether Vbeta14 recombinational accessibility is subject to feedback inhibition, we analyzed TCRbeta rearrangements in Vbeta14(Rep) mice containing a preassembled in-frame transgenic Vbeta8.2Dbeta1Jbeta1.1 or an endogenous Vbeta14Dbeta1Jbeta1.4 rearrangement on the homologous chromosome. Expression of either preassembled VbetaDJbetaC beta-chain accelerated thymocyte development because of enhanced cellular selection, demonstrating that the rate-limiting step in early alphabeta T cell development is the assembly of an in-frame VbetaDJbeta rearrangement. Expression of these preassembled VbetaDJbeta rearrangements inhibited endogenous Vbeta14-to-DJbeta rearrangements as expected. However, in contrast to results predicted by the accepted model of TCRbeta feedback inhibition, we found that expression of these preassembled TCR beta-chains did not downregulate recombinational accessibility of Vbeta14 chromatin. Our findings suggest that TCRbeta-mediated feedback inhibition of Vbeta14 rearrangements depends on inherent properties of Vbeta14, Dbeta, and Jbeta recombination signal sequences.
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Diversidade de Anticorpos , Cromatina/fisiologia , Retroalimentação Fisiológica/fisiologia , Rearranjo Gênico do Linfócito T/imunologia , Região de Junção de Imunoglobulinas , Receptores de Antígenos de Linfócitos T alfa-beta/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Transdução de Sinais/imunologia , Animais , Diversidade de Anticorpos/genética , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Regulação da Expressão Gênica no Desenvolvimento/imunologia , Genes Reporter/imunologia , Mutação em Linhagem Germinativa/imunologia , Região de Junção de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Perda de Heterozigosidade/imunologia , Camundongos , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T alfa-beta/biossíntese , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Transdução de Sinais/genética , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
The genomic organization of TCRbeta loci enables Vbeta-to-DJbeta2 rearrangements on alleles with assembled VbetaDJbetaCbeta1 genes, which could have deleterious physiologic consequences. To determine whether such Vbeta rearrangements occur and, if so, how they might be regulated, we analyzed mice with TCRbeta alleles containing preassembled functional VbetaDJbetaCbeta1 genes. Vbeta10 segments were transcribed, rearranged, and expressed in thymocytes when located immediately upstream of a Vbeta1DJbetaCbeta1 gene, but not on alleles with a Vbeta14DJbetaCbeta1 gene. Germline Vbeta10 transcription was silenced in mature alphabeta T cells. This allele-dependent and developmental stage-specific silencing of Vbeta10 correlated with increased CpG methylation and decreased histone acetylation over the Vbeta10 promoter and coding region. Transcription, rearrangement, and expression of the Vbeta4 and Vbeta16 segments located upstream of Vbeta10 were silenced on alleles containing either VbetaDJbetaCbeta1 gene; sequences within Vbeta4, Vbeta16, and the Vbeta4/Vbeta16-Vbeta10 intergenic region exhibited constitutive high CpG methylation and low histone acetylation. Collectively, our data indicate that the position of Vbeta segments relative to assembled VbetaDJbetaCbeta1 genes influences their rearrangement and suggest that DNA sequences between Vbeta segments may form boundaries between active and inactive Vbeta chromatin domains upstream of VbetaDJbetaCbeta genes.
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Alelos , Rearranjo Gênico da Cadeia beta dos Receptores de Antígenos dos Linfócitos T/imunologia , Inativação Gênica/imunologia , Genes Codificadores da Cadeia beta de Receptores de Linfócitos T/fisiologia , Mutação em Linhagem Germinativa/imunologia , Fragmentos de Peptídeos/genética , Receptores de Antígenos de Linfócitos T alfa-beta/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Animais , Cromatina/química , Cromatina/genética , Proteínas de Homeodomínio/antagonistas & inibidores , Proteínas de Homeodomínio/biossíntese , Proteínas de Homeodomínio/genética , Hibridomas , Região Variável de Imunoglobulina/biossíntese , Região Variável de Imunoglobulina/genética , Região Variável de Imunoglobulina/metabolismo , Terapia de Imunossupressão/métodos , Camundongos , Camundongos Knockout , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/biossíntese , Receptores de Antígenos de Linfócitos T alfa-beta/biossíntese , Transcrição Gênica/imunologiaRESUMO
BACKGROUND: Sickle cell disease (SCD) is a lifelong burdensome disorder of heterogenic expression. This study investigated the longer-term economic burden of severe presentation of SCD. As SCD treatment landscapes evolve toward curative intent gene therapies, understanding how SCD-associated costs may change over the patient lifetime will be important for medical decision-making. METHODS: Patients with severe presentation of SCD (presence of acute vaso-occlusive events [VOEs] or history of stroke and/or other disease-related sequelae), were identified within the MarketScan Commercial and Medicare Supplemental and Multi-state Medicaid Databases from 1/1/2010 to 12/31/2018. The first SCD claim served as the index date and patients were followed over a 5-year post-period. Clinical characteristics and healthcare resource utilization and costs were assessed over follow-up for eligible cohorts of commercial and Medicaid patients with severe SCD presentation and age-based subgroups (<18, 18-30, and ≥31). RESULTS: A total of 4,487 patients, primarily insured via Medicaid (79.2%), qualified for the analysis. Patients evidenced persistent VOEs over follow-up; prevalence of most comorbidities increased with age. Mean total healthcare costs over the 5-year follow-up were $275,143 (SD± $406,770) and $362,728 (SD± $620,189) in the commercial and Medicaid samples, respectively. Disease severity, assessed by the number of VOEs and utilization of inpatient and emergency services, peaked in the 18-30 year group in both samples. These groups also evidenced the highest mean healthcare costs over the 5-year follow-up at $344,776 (SD± $434,521) and $671,321 (SD± $938,764) in the commercial and Medicaid samples respectively. CONCLUSION: Results indicate high clinical need and economic burden among patients with severe presentation of SCD. These findings not only highlight the need for improved therapeutic options to limit or prevent disease progression, but also start to provide insight on lifetime costs of SCD that will be needed in the evaluation of emerging curative intent therapies.
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Anemia Falciforme , Estresse Financeiro , Idoso , Estados Unidos , Humanos , Medicare , Medicaid , Anemia Falciforme/terapia , Custos de Cuidados de Saúde , Estudos RetrospectivosRESUMO
BACKGROUND: Extrapyramidal symptoms (EPS) are common side-effects of second-generation antipsychotics (SGA), that can negatively impact patient quality-of-life, and are associated with increased morbidity and mortality. This study examined the incidence and burden of EPS in patients with schizophrenia initiating SGAs. METHODS: Patients with schizophrenia initiating SGAs were identified in the MarketScan Multi-state Medicaid database from 1 January 2012 to 31 December 2018. Incidence of EPS (identified via ICD-9/ICD-10 diagnoses and medications) was assessed during the 12-months following SGA initiation. Cohorts with and without EPS were defined. Multivariate models were used to examine all-cause and schizophrenia-related hospitalizations and total costs in the 12 months following the first EPS claim (EPS) or randomly assigned index date (Non-EPS) while controlling for multiple baseline covariates. Logistic regression was used for hospitalization and two-part models were used for skewed cost data. RESULTS: A total of 11,642 patients with schizophrenia filled a prescription for an SGA; of which, 2,468 (21.2%) experienced EPS in the first year. The age- and gender-matched EPS group and non-EPS group included 2,295 and 5,607 patients, respectively. Multivariate analyses confirmed that EPS patients had 25% higher odds of all-cause (OR = 1.25; 95% CI = 1.11-1.40) and 75% increased odds of schizophrenia-related (OR = 1.75; 95% CI = 1.53-2.00) inpatient admissions compared to non-EPS patients. Multivariate adjustment of post-period costs between groups also found significant differences in both all-cause (EPS: $27,408 vs. non-EPS: $22,489, p < 0.001) and schizophrenia-related (EPS:$12,833 vs. non-EPS:$8,077, p < 0.0001) costs between the EPS and non-EPS cohorts. CONCLUSIONS: Over one-fifth of patients initiating treatment with atypical antipsychotics in this study developed EPS in the 12 months following SGA initiation. Extrapyramidal side-effects associated with atypical antipsychotics increase the risk of hospitalization and contribute to higher healthcare costs. For patients with schizophrenia, treatment options that minimize the risk of EPS may reduce the economic burden associated with the disease.
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Antipsicóticos , Esquizofrenia , Antipsicóticos/uso terapêutico , Estresse Financeiro , Humanos , Incidência , Medicaid , Estudos Retrospectivos , Esquizofrenia/tratamento farmacológico , Estados UnidosRESUMO
OBJECTIVES: Extrapyramidal symptoms (EPS) affect 15% to 30% of patients with schizophrenia treated with antipsychotics and have been associated with poor outcomes. This study examined the incidence and economic burden of EPS in patients with schizophrenia initiating atypical antipsychotics (AAPs). STUDY DESIGN: Retrospective analysis of secondary deidentified administrative claims database. METHODS: Patients with schizophrenia initiating AAPs with no prior EPS were identified in the MarketScan Commercial and Medicare Supplemental databases from January 1, 2012, to December 31, 2018. Incidence of EPS (diagnosis or medication use) was assessed in the year following AAP initiation. Annual all-cause and schizophrenia-related health care resource utilization (HCRU) and costs were assessed in cohorts who did or did not develop EPS in the year following first EPS claim (EPS cohort) or randomly assigned index date (non-EPS cohort). Multivariate regression was used to compare all-cause and schizophrenia-related total health care costs and inpatient admissions between cohorts. RESULTS: A total of 3558 patients with schizophrenia newly initiating AAPs were identified; 22.1% developed EPS in the year following AAP initiation (incidence: 26.9 cases per 100 person-years). Multivariate analyses revealed that patients with EPS had 34% higher odds of all-cause (odds ratio [OR], 1.3361; 95% CI, 1.0770-1.6575; P < .01) and 84% increased odds of schizophrenia-related (OR, 1.8436; 95% CI, 1.0434-2.4219; P < .0001) inpatient admission compared with the non-EPS cohort. The EPS cohort also evidenced significantly higher adjusted all-cause ($26,632 vs $21,273; P < .001) and schizophrenia-related ($9018 vs $4475; P < .0001) costs compared with the non-EPS cohort. CONCLUSIONS: The 20% of patients who developed EPS in the year following AAP initiation evidenced significantly increased HCRU and costs over the postindex period. Schizophrenia therapies with reduced EPS risk are needed to improve patient care.
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Antipsicóticos , Esquizofrenia , Idoso , Antipsicóticos/efeitos adversos , Custos de Cuidados de Saúde , Humanos , Medicare , Estudos Retrospectivos , Esquizofrenia/tratamento farmacológico , Estados Unidos/epidemiologiaRESUMO
BACKGROUND AND AIMS: Acute myeloid leukemia (AML) prognosis is poor, with sustained remission occurring in <35% of young adults and <15% of older adults. This descriptive study examined the potential benefit of prolonged remission on the economic burden of AML. METHODS: Using the IBM MarketScan Commercial and Medicare Supplemental databases, we identified newly diagnosed patients with AML without hematopoietic stem cell transplantation from January 1, 2012 to December 31, 2018; AML diagnosis was the index date. Patients had 6 months of pre-index eligibility and were followed until the end of continuous eligibility, study data, or death. Active treatment and supportive care cohorts were defined; duration-of-remission subgroups (0 to <3, 3 to <6, 6 to <12, and ≥12 months) were established among active treatment patients with remission. Healthcare service utilization and costs were reported over follow-up and mutually exclusive treatment, remission, and post-relapse periods. RESULTS: This study included 1,558 active treatment and 1,127 supportive care patients who were followed for a median of 232 and 62 days, respectively. Over follow-up, active treatment and supportive care patients incurred mean ± standard deviation all-cause healthcare costs of $55,723 ± $61,994 and $68,596 ± $100,375 per-patient-per-month (PPPM), respectively. Decreasing PPPM costs were observed with increased remission duration (0 to <3 months: $71,823 ± $62,635; 3 to <6 months: $54,262 ± $44,734; 6 to <12 months: $35,287 ± $23,699; and ≥12 months: $15,615 ± $10,560). Although median follow-up varied by up to 5-fold, total costs were largely similar across duration-of-remission subgroups (0 to <3 months: $438,569 ± $332,675; 3 to <6 months: $590,411 ± $598,245; 6 to <12 months: $482,902 ± $369,115; and ≥12 months: $448,867 ± $316,133). CONCLUSIONS: The economic burden of AML is substantial, even among untreated patients. Further, among patients with remission, longer durations in remission are associated with reduced PPPM healthcare costs, suggesting that remission-prolonging treatments could help mitigate healthcare costs.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Idoso , Estresse Financeiro , Custos de Cuidados de Saúde , Humanos , Leucemia Mieloide Aguda/terapia , Medicare , Estudos Retrospectivos , Estados Unidos , Adulto JovemRESUMO
Objective: This study examined the rate and economic burden of pediatric mental illness from 2012 to 2018. Study design: Observational, retrospective analysis of administrative healthcare data. Methods: This retrospective study of the MarketScan Commercial Research Database included calendar year-based samples (2012-2018) of children aged 4-17 with continuous medical, pharmacy, and mental health/substance abuse coverage for the year of interest and prior year. Incidence and prevalence rates of overall and specific mental illness diagnoses were calculated based on the appearance of diagnosis codes on claims: alcohol/substance abuse, depression, anxiety, eating disorders, bipolar, schizophrenia, developmental disorders, attention deficit/hyperactivity, and conduct disorders. Annual direct medical costs were compared between children with any mental illness and a matched non-mental illness control population. Results: Between 2.4 and 4.1 million children qualified for each calendar year sample. From 2012 to 2018, there was a 34.6% increase in the prevalence of mental illness. Attention deficit/hyperactivity, conduct disorders, anxiety, and depression were the most common conditions, while eating disorders, anxiety, and depression presented the greatest increases at 96%, 95%, and 73% respectively. Children with a mental illness incurred significantly greater medical costs compared to matched controls in all years assessed (2018 comparison: $6,055±$27,198 vs. $1,629±$7,274; p < 0.001). Conclusions: Childhood mental illness diagnoses have increased substantially in the United States from 2012 to 2018. In addition to patient impacts, mental health diagnoses also place a notable burden on the healthcare system via increased medical costs. As mental illness is known to be underdiagnosed, the true rate of mental illnesses among children is likely even greater.
RESUMO
BACKGROUND: Intravenous (IV) taxane therapy for metastatic breast cancer (mBC) has been associated with toxicities and demanding dosing schedules, which can limit treatment effectiveness. OBJECTIVES: To assess treatment patterns, toxicities, and costs in women with mBC initiating IV paclitaxel or IV nab-paclitaxel. METHODS: Adult women diagnosed with BC from January 1, 2014, to September 30, 2018, were identified in the MarketScan Commercial and MarketScan Medicare Supplemental databases. Women had a metastatic disease diagnosis and newly initiated treatment with IV paclitaxel/nab-paclitaxel (first administration date was considered the index date), and continuous enrollment for at least 12 months prior to and at least 3 months following the index date. Treatment discontinuation, dose reductions, toxicities, and health care utilization and costs per patient per month (PPPM) were assessed over the full follow-up and the index line of IV paclitaxel/nab-paclitaxel therapy (Index LOT). RESULTS: The sample included 8890 women aged 54.6 (±10.9) years, followed for 18.9 (±13.5) months. Most (82.0%) initiated IV paclitaxel/nab-paclitaxel monotherapy; 83.1% had early discontinuation (<18 weeks of treatment) of the Index LOT. Among the 6943 women eligible for the dose-change analysis, 42.4% evidenced an IV paclitaxel/nab-paclitaxel dose reduction ≥10% during the Index LOT. The most common toxicities during the Index LOT were gastrointestinal upset (30.5%), myelotoxicity (27.0%), infection (26.2%), general symptoms (25.9%), and chemotherapy-induced peripheral neuropathy (22.7%). Over follow-up, 39.7% of women had an inpatient admission and 43.0% had an emergency department visit. The mean of all-cause total costs was $11,991 PPPM, while BC-related total costs were $5320 PPPM. CONCLUSIONS: Many mBC patients initiating IV paclitaxel/nab-paclitaxel experienced dose reductions, toxicities, and/or early discontinuation of the Index LOT, which may limit treatment effectiveness. More tolerable treatments with reduced dosing complexity could improve mBC treatment and help contain costs.
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Neoplasias da Mama , Adulto , Idoso , Albuminas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/tratamento farmacológico , Efeitos Psicossociais da Doença , Feminino , Humanos , Medicare , Paclitaxel/uso terapêutico , Estados UnidosRESUMO
BACKGROUND: Intravenous (IV) taxanes for metastatic breast cancer (mBC) are associated with toxicities, such as chemotherapy-induced peripheral neuropathy (CIPN), which can detrimentally impact outcomes. OBJECTIVE: To assess the impact of CIPN on clinical and economic outcomes in women with mBC, initiating IV paclitaxel/ nab-paclitaxel. METHODS: Adult women in the MarketScan Commercial and Medicare Supplemental Database with a mBC diagnosis, initiating IV paclitaxel or IV nab-paclitaxel (index date = first administration) from November 1, 2013, to September 30, 2018, who had no prior neuropathy diagnoses, and continuous enrollment 12 months prior to and ≥ 3 months following index were selected. Propensity score-matched CIPN and non-CIPN cohorts were defined, based on postindex CIPN diagnosis. Clinical characteristics and all-cause and breast cancer (BC)-related health care utilization and costs per patient per month (PPPM) were compared between matched CIPN and non-CIPN cohorts during follow-up. RESULTS: Among the 5870 women with mBC initiating IV paclitaxel/nab-paclitaxel, 42.7% developed CIPN. The matched cohorts each included 1950 women. Patients with CIPN were more likely to have a dose reduction (46.1% vs 38.2%, P < .001) or develop depression, diabetes, insomnia, liver dysfunction, or arthritis compared with the non-CIPN cohort, P < .05. Patients with CIPN were more likely to have an inpatient admission (39.2% vs 34.9%, P < .01) or emergency department visit (46.7% vs 35.6%, P < .001), as well as all-cause and BC-related costs that were $1102 and $725 PPPM higher, respectively, than women without CIPN (P < .01). CONCLUSIONS: CIPN was common in women, following IV paclitaxel/nab-paclitaxel treatment and was associated with dose reductions, the development of comorbidities, and elevated health care costs. Therapies for mBC that offer increased tolerability are needed to help improve patient outcomes and control costs.
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Antineoplásicos , Neoplasias da Mama , Doenças do Sistema Nervoso Periférico , Adulto , Idoso , Albuminas/uso terapêutico , Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Medicare , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Estados UnidosRESUMO
Despite advances in antiretroviral therapy (ART), human immunodeficiency virus (HIV) remains a significant issue in the United States. Early diagnosis, continuous treatment access/adherence, and long-term care engagement help patients benefit fully from ART; however, a shortfall in care engagement remains, potentially leading to poorer health outcomes. This analysis benchmarks rates of health care quality and process measures to identify areas for improvement. This retrospective, claims-based, real-world cohort study assessed the percentage of prevalent (existing) and incident (newly diagnosed) patients with HIV with commercial or public health insurance meeting 4 National Quality Forum (NQF)-endorsed, 1 Pharmacy Quality Alliance (PQA), and 3 Centers for Disease Control and Prevention (CDC) measures over a 4-year period. Most prevalent patients consistently met the NQF-endorsed prescribed ART and gaps in visits measures. Longer-term visit frequency measure rates were well below the 90% Joint United Nations Programme on HIV/AIDS target. Proportion of prevalent patients meeting each NQF-endorsed measure was maintained/increased with increasing age in 2015-2016. Substantially fewer incident patients than prevalent patients met NQF-endorsed measures across all measurement periods, particularly for visit frequency (32%-51%). PQA ART adherence was low (36%-73%). CDC receipt of care rates were high (83%-92%), whereas retention in care rates were low (67%-72%) among prevalent patients. For incident patients, linkage to care rates were consistently low (21%-44%). This study benchmarks current US HIV care engagement and highlights the need for improvement in early care engagement, ART adherence and long-term retention of care among patients with HIV.