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Strengthening management and leadership competencies among district and local health managers has emerged as a common approach for health systems strengthening and to achieve Universal Health Coverage (UHC). While the literature is rich with localised examples of initiatives that aim to strengthen the capacity of district or local health managers, particularly in sub-Saharan Africa, considerably less attention is paid to the science of how to scale-up these initiatives. The aim of this paper is thus to examine the process of scaling-up a management strengthening intervention (MSI) and identify new knowledge and key lessons learned that can be used to inform the scale-up process of other complex health interventions, in support of UHC. Qualitative methods were used to identify lessons learned from scaling-up the MSI in Ghana, Malawi and Uganda. We conducted 14 interviews with district health management team members, three scale-up assessments with 20 scale-up stakeholders, and three reflection discussions with 11 research team members. We also kept records of activities throughout MSI and scale-up implementation. Data was recorded, transcribed, and analysed against the Theory of Change to identify both scale-up outcomes and the factors affecting these outcomes. The MSI was ultimately scaled-up across 27 districts. Repeated MSI cycles over time were found to foster greater feelings of autonomy among district health management teams (DHMTs) to address longstanding local problems, a more innovative use of existing resources without relying on additional funding, and improved teamwork. The use of 'resource teams' and the emergence of MSI 'champions', were both instrumental in supporting scale-up efforts. Challenges to the sustainability of the MSI include limited government buy-in and lack of sustained financial investment.
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BACKGROUND: Vaginal microbiota composition is associated with spontaneous preterm birth (sPTB), depending on ethnicity. Host-microbiota interactions are thought to play an important underlying role in this association between ethnicity, vaginal microbiota and sPTB. METHODS: In a prospective cohort of nulliparous pregnant women, we assessed vaginal microbiota composition, vaginal immunoglobulins (Igs), and local inflammatory markers. We performed a nested case-control study with 19 sPTB cases, matched based on ethnicity and midwifery practice to 19 term controls. RESULTS: Of the 294 included participants, 23 pregnancies ended in sPTB. We demonstrated that Lactobacillus iners-dominated microbiota, diverse microbiota, and ethnicity were all independently associated with sPTB. Microbial Ig coating was associated with both microbiota composition and ethnicity, but a direct association with sPTB was lacking. Microbial IgA and IgG coating were lowest in diverse microbiota, especially in women of any ethnic minority. When correcting for microbiota composition, increased microbial Ig coating correlated with increased inflammation. CONCLUSION: In these nulliparous pregnant women, vaginal microbiota composition is strongly associated with sPTB. Our results support that vaginal mucosal Igs might play a pivotal role in microbiota composition, microbiota-related inflammation, and vaginal community disparity within and between ethnicities. This study provides insight in host-microbe interaction, suggesting that vaginal mucosal Igs play an immunomodulatory role similar to that in the intestinal tract. Video Abstract.
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Etnicidad , Lactobacillus , Microbiota , Nacimiento Prematuro , Vagina , Adulto , Femenino , Humanos , Embarazo , Adulto Joven , Estudios de Casos y Controles , Interacciones Microbiota-Huesped , Inmunoglobulina A , Inmunoglobulinas , Lactobacillus/aislamiento & purificación , Nacimiento Prematuro/microbiología , Nacimiento Prematuro/etnología , Estudios Prospectivos , Vagina/microbiologíaAsunto(s)
Terapia Neoadyuvante , Neoplasia Residual , Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/terapia , Neoplasias de la Mama Triple Negativas/patología , Femenino , Terapia Neoadyuvante/métodos , Neoplasia Residual/patología , Quimioterapia Adyuvante/métodos , Inmunoterapia/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
BACKGROUND: In the absence of prognostic biomarkers, most patients with early-stage triple-negative breast cancer (eTNBC) are treated with combination chemotherapy. The identification of biomarkers to select patients for whom treatment de-escalation or escalation could be considered remains an unmet need. We evaluated the prognostic value of histopathologic traits in a unique cohort of young, (neo)adjuvant chemotherapy-naïve patients with early-stage (stage I or II), node-negative TNBC and long-term follow-up, in relation to stromal tumor-infiltrating lymphocytes (sTILs) for which the prognostic value was recently reported. MATERIALS AND METHODS: We studied all 485 patients with node-negative eTNBC from the population-based PARADIGM cohort which selected women aged <40 years diagnosed between 1989 and 2000. None of the patients had received (neo)adjuvant chemotherapy according to standard practice at the time. Associations between histopathologic traits and breast cancer-specific survival (BCSS) were analyzed with Cox proportional hazard models. RESULTS: With a median follow-up of 20.0 years, an independent prognostic value for BCSS was observed for lymphovascular invasion (LVI) [adjusted (adj.) hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.49-3.69], fibrotic focus (adj. HR 1.61, 95% CI 1.09-2.37) and sTILs (per 10% increment adj. HR 0.75, 95% CI 0.69-0.82). In the sTILs <30% subgroup, the presence of LVI resulted in a higher cumulative incidence of breast cancer death (at 20 years, 58%; 95% CI 41% to 72%) compared with when LVI was absent (at 20 years, 32%; 95% CI 26% to 39%). In the ≥75% sTILs subgroup, the presence of LVI might be associated with poor survival (HR 11.45, 95% CI 0.71-182.36, two deaths). We confirm the lack of prognostic value of androgen receptor expression and human epidermal growth factor receptor 2 -low status. CONCLUSIONS: sTILs, LVI and fibrotic focus provide independent prognostic information in young women with node-negative eTNBC. Our results are of importance for the selection of patients for de-escalation and escalation trials.
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Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Pronóstico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Biomarcadores de Tumor , Quimioterapia AdyuvanteRESUMEN
The large majority of patients with HER2-positive metastatic breast cancer (MBC) will eventually develop resistance to anti-HER2 therapy and die of this disease. Despite, relatively high levels of stromal tumor infiltrating lymphocytes (sTILs), PD1-blockade has only shown modest responses. Monalizumab targets the inhibitory immune checkpoint NKG2A, thereby unleashing NK- and CD8 T cells. We hypothesized that monalizumab synergizes with trastuzumab by promoting antibody-dependent cell-mediated cytotoxicity. In the phase II MIMOSA-trial, HER2-positive MBC patients were treated with trastuzumab and 750 mg monalizumab every two weeks. Following a Simon's two-stage design, 11 patients were included in stage I of the trial. Treatment was well tolerated with no dose-limiting toxicities. No objective responses were observed. Therefore, the MIMOSA-trial did not meet its primary endpoint. In summary, despite the strong preclinical rationale, the novel combination of monalizumab and trastuzumab does not induce objective responses in heavily pre-treated HER2-positive MBC patients.
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Neoplasias de la Mama , Mimosa , Femenino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/patología , Linfocitos T CD8-positivos/patología , Receptor ErbB-2 , Trastuzumab/uso terapéuticoRESUMEN
BACKGROUND: Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are inflammatory diseases that often affect the wrist and, when affected, can lead to impaired wrist function and progressive joint destruction if inadequately treated. Standard care consists primarily of disease-modifying anti-rheumatic drugs (DMARDs), often supported by systemic corticosteroids or intra-articular corticosteroid injections (IACSI). IACSI, despite their use worldwide, show poor response in a substantial group of patients. Arthroscopic synovectomy of the wrist is the surgical removal of synovitis with the goal to relieve pain and improve wrist function. The primary objective of this study is to evaluate wrist function following arthroscopic synovectomy compared to IACSI in therapy-resistant patients with rheumatoid or psoriatic arthritis. Secondary objectives include radiologic progress, disease activity, health-related quality of life, work participation and cost-effectiveness during a 1-year follow-up. METHODS: This protocol describes a prospective, randomized controlled trial. RA and PsA patients are eligible with prominent wrist synovitis objectified by a rheumatologist, not responding to at least 3 months of conventional DMARDs and naïve to biological DMARDs. For 90% power, an expected loss to follow-up of 5%, an expected difference in mean Patient-Rated Wrist Evaluation score (PRWE, range 0-100) of 11 and α = 0.05, a total sample size of 80 patients will be sufficient to detect an effect size. Patients are randomized in a 1:1 ratio for arthroscopic synovectomy with deposition of corticosteroids or for IACSI. Removed synovial tissue will be stored for an ancillary study on disease profiling. The primary outcome is wrist function, measured with the PRWE score after 3 months. Secondary outcomes include wrist mobility and grip strength, pain scores, DAS28, EQ-5D-5L, disease progression on ultrasound and radiographs, complications and secondary treatment. Additionally, a cost-effectiveness analysis will be performed, based on healthcare costs (iMCQ questionnaire) and productivity loss (iPCQ questionnaire). Follow-up will be scheduled at 3, 6 and 12 months. Patient burden is minimized by combining study visits with regular follow-ups. DISCUSSION: Persistent wrist arthritis continues to be a problem for patients with rheumatic joint disease leading to disability. This is the first randomized controlled trial to evaluate the effect, safety and feasibility of arthroscopic synovectomy of the wrist in these patients compared to IACSI. TRIAL REGISTRATION: Dutch trial registry (CCMO), NL74744.100.20. Registered on 30 November 2020. CLINICALTRIALS: gov NCT04755127. Registered after the start of inclusion on 15 February 2021.
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Antirreumáticos , Artritis Psoriásica , Artritis Reumatoide , Sinovitis , Humanos , Muñeca , Sinovectomía/efectos adversos , Estudios Prospectivos , Calidad de Vida , Artritis Psoriásica/diagnóstico , Artritis Psoriásica/tratamiento farmacológico , Artritis Psoriásica/cirugía , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/complicaciones , Sinovitis/tratamiento farmacológico , Antirreumáticos/efectos adversos , Inyecciones Intraarticulares/efectos adversos , Dolor/tratamiento farmacológico , Resultado del Tratamiento , Artroscopía/efectos adversos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Dikes are an effective flood risk reduction measure in deltaic areas. Present risk analyses consist often of decoupled calculations of probabilities of dike failure and calculation of consequences of flooding given dike failure. However, the flood defense design determines not only the probability of failure, but influences the consequences of flooding as well. Especially when the dike has a ductile failure and breach growth behavior, due to a structural robust design, the consequences of flooding reduce. In this article, we present a novel assessment of risks and investments, valuing structural robustness of a construction type, represented by its ductile behavior during high loads. Therefore, the consecutive occurrence of initial dike failure mechanisms, failure path development, breach growth, and consequences is modeled integral and time-dependent. The investments consist of the costs to reinforce or reconstruct the flood defense to behave relatively ductile. This integral assessment enables to compare flood impacts of different construction types and different dimensions of designs. We applied it on a case in a riverine area in the Netherlands. The results show that the total societal costs and the individual risks on victims are very dependent on the construction type. The risk profile of a polder protected by a brittle or a ductile dike differs significantly. The brittle sand dike in the case requires larger dimensions than the more ductile dike with a clay core.
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BACKGROUND: The GLORIA placebo-controlled trial found a favorable balance of benefit and harm for two years of prednisolone (5 mg/day) as add-on treatment for rheumatoid arthritis (RA) patients aged 65+. This study evaluated the cost-effectiveness of low-dose prednisolone in the treatment of RA. METHODS: The economic evaluation had a societal perspective with a time horizon of two years. Cost data were collected with questionnaires and from recorded events, and valued with standard Dutch unit prices of 2017. The primary effectiveness outcome was the disease activity score in 28 joints (DAS28). For cost-utility, quality-adjusted life years (QALYs) were estimated from the EuroQol-5 Dimension (EQ-5D) questionnaire. Bootstrapping assessed the uncertainty around the average differences in costs and health outcomes. RESULTS: In total, 444 of 451 randomized patients were included in the modified intention-to-treat analysis. Patients had median four active comorbidities at baseline. Mean total costs over two years were k10.8 in the prednisolone group, k0.5 (95% CI -4.0; 1.8) lower than in the placebo group. Total direct medical costs were k0.5 (95% CI -4.0; 1.5) lower in the prednisolone group. The mean number of QALYs was similar in both groups (difference 0.02 [-0.03; 0.06] in favor of prednisolone). The DAS28 was 0.38 lower in the prednisolone group than in the placebo group (0.19; 0.56). CONCLUSION: With greater effectiveness (DAS28) at non-significantly lower costs, low-dose, add-on prednisolone is cost-effective for RA compared to placebo over two years. QALYs were equal in both groups, most likely due to the impact of multiple comorbidities.
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Artritis Reumatoide , Prednisolona , Humanos , Prednisolona/uso terapéutico , Análisis Costo-Beneficio , Artritis Reumatoide/tratamiento farmacológico , Años de Vida Ajustados por Calidad de Vida , EtnicidadAsunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Biomarcadores de Tumor/genéticaRESUMEN
BACKGROUND: Invasive lobular breast cancer (ILC) is the second most common type of breast cancer after invasive breast cancer of no special type (NST), representing up to 15% of all breast cancers. DESIGN: Latest data on ILC are presented, focusing on diagnosis, molecular make-up according to the European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT) guidelines, treatment in the early and metastatic setting and ILC-focused clinical trials. RESULTS: At the imaging level, magnetic resonance imaging-based and novel positron emission tomography/computed tomography-based techniques can overcome the limitations of currently used imaging techniques for diagnosing ILC. At the pathology level, E-cadherin immunohistochemistry could help improving inter-pathologist agreement. The majority of patients with ILC do not seem to benefit as much from (neo-)adjuvant chemotherapy as patients with NST, although chemotherapy might be required in a subset of high-risk patients. No differences in treatment efficacy are seen for anti-human epidermal growth factor receptor 2 (HER2) therapies in the adjuvant setting and cyclin-dependent kinases 4 and 6 inhibitors in the metastatic setting. The clinical utility of the commercially available prognostic gene expression-based tests is unclear for patients with ILC. Several ESCAT alterations differ in frequency between ILC and NST. Germline BRCA1 and PALB2 alterations are less frequent in patients with ILC, while germline CDH1 (gene coding for E-cadherin) alterations are more frequent in patients with ILC. Somatic HER2 mutations are more frequent in ILC, especially in metastases (15% ILC versus 5% NST). A high tumour mutational burden, relevant for immune checkpoint inhibition, is more frequent in ILC metastases (16%) than in NST metastases (5%). Tumours with somatic inactivating CDH1 mutations may be vulnerable for treatment with ROS1 inhibitors, a concept currently investigated in early and metastatic ILC. CONCLUSION: ILC is a unique malignancy based on its pathological and biological features leading to differences in diagnosis as well as in treatment response, resistance and targets as compared to NST.
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Neoplasias de la Mama , Carcinoma Ductal de Mama , Carcinoma Lobular , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Neoplasias de la Mama/terapia , Cadherinas/uso terapéutico , Carcinoma Ductal de Mama/genética , Carcinoma Lobular/diagnóstico , Carcinoma Lobular/genética , Carcinoma Lobular/terapia , Femenino , Humanos , Pronóstico , Proteínas Proto-OncogénicasRESUMEN
In estrogen-receptor-positive, HER2-negative (ER+HER2-) breast cancer, higher levels of tumor infiltrating lymphocytes (TILs) are often associated with a poor prognosis and this phenomenon is still poorly understood. Fibroblasts represent one of the most frequent cells in breast cancer and harbor immunomodulatory capabilities. Here, we evaluate the molecular and clinical impact of the spatial patterns of TILs and fibroblast in ER+HER2- breast cancer. We used a deep neural network to locate and identify tumor, TILs, and fibroblasts on hematoxylin and eosin-stained slides from 179 ER+HER2- breast tumors (ICGC cohort) together with a new density estimation analysis to measure the spatial patterns. We clustered tumors based on their spatial patterns and gene set enrichment analysis was performed to study their molecular characteristics. We independently assessed the spatial patterns in a second cohort of ER+HER2- breast cancer (N = 630, METABRIC) and studied their prognostic value. The spatial integration of fibroblasts, TILs, and tumor cells leads to a new reproducible spatial classification of ER+HER2- breast cancer and is linked to inflammation, fibroblast meddling, or immunosuppression. ER+HER2- patients with high TIL did not have a significant improved overall survival (HR = 0.76, P = 0.212), except when they had received chemotherapy (HR = 0.447). A poorer survival was observed for patients with high fibroblasts that did not show a high level of TILs (HR = 1.661, P = 0.0303). Especially spatial mixing of fibroblasts and TILs was associated with a good prognosis (HR = 0.464, P = 0.013). Our findings demonstrate a reproducible pipeline for the spatial profiling of TILs and fibroblasts in ER+HER2- breast cancer and suggest that this spatial interplay holds a decisive role in their cancer-immune interactions.
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OBJECTIVES: The prevalence of psoriatic arthritis (PsA) is the same in men and women; however, the latter experience a higher burden of disease and are affected more frequently by polyarthritis. Here, we performed an early PsA cohort analysis to assess sex-related differences in demographics, disease characteristics, and evolution over 1 year including applied treatment strategies. METHODS: Our study is embedded in the Dutch south-west Early Psoriatic Arthritis cohoRt. We described patient characteristics and treatment decisions. For the comparison across sexes and baseline and 1 year follow-up, appropriate tests depending on the distribution were used. RESULTS: Two hundred seventy-three men and 294 women with no significant differences in age and ethnicity were included. Women reported significantly longer duration of symptoms before diagnosis and significantly higher tender joint count, a higher disease activity, higher levels of pain, and lower functional capacity. Although minimal disease activity (MDA) rates increased over time for both sexes, MDA remained significantly more prevalent among men at 1 year (58.1% vs 35.7%, p < 0.00). Initially, treatment strategies were similar in both sexes with methotrexate being the most frequently used drug during the first year. Women received methotrexate for a shorter period [196 (93-364) vs 306 (157-365), p < 0.00] and therefore received a lower cumulative dose compared to men. Retention time was shorter for all DMARDs, and women had a delayed start on b-DMARDs. CONCLUSION: After 1 year of standard-of-care treatment, women did not surpass their baseline disadvantages. Despite the overall improvement, they still presented higher disease activity, higher levels of pain, and lower functional capacity score than men. The nature of these findings may advocate a need for sex specific adjustment of treatment strategies and evaluation in early PsA patients.
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Antirreumáticos , Artritis Psoriásica , Antirreumáticos/uso terapéutico , Artritis Psoriásica/diagnóstico , Artritis Psoriásica/tratamiento farmacológico , Artritis Psoriásica/epidemiología , Estudios de Cohortes , Femenino , Humanos , Masculino , Metotrexato/uso terapéutico , Resultado del TratamientoRESUMEN
PURPOSE: To analyze the macular microvascular (MMV) architecture, radial peripapillary capillary (RPC) network and choriocapillaris using optical coherence tomography angiography (OCT-A) in patients with systemic sclerosis (SSc) without systemic comorbidities. METHODS: The vessel densities (VDs) of the MMV, foveal avascular zone (FAZ) parameters, choriocapillaris flow areas (CCFAs), RPC VDs, and optic nerve head (ONH) parameters were measured by OCT-A. Retinal thickness and subfoveal choroidal thickness (SFCT) were measured by spectral-domain optical coherence tomography (SD-OCT). The SD-OCT and OCT-A measurements of 53 eyes of 30 SSc patients were compared with 61 eyes of 33 healthy controls. RESULTS: In the MMV analysis, a decrease in the VDs of the superficial capillary plexus and an increase in the FAZ area, FAZ perimeter and non-flow area were detected in the SSc group compared to the controls (P=0.007, P=0.001, P=0.029, P=0.018, and P=0.039, respectively). While there was a decrease in SFCT, no change was found in CCFA (P=0.001 and P=0.902, respectively). The RPC analysis revealed a decrease in the VDs of all vessels for the entire area and the intradisc area, as well as the VDs of the small vessels for the intradisc area (P=0.021, P=0.001, and P=0.003, respectively). In the ONH analysis, there was an increase in the C/D area ratios and cup volumes, and a decrease in the rim areas and nasal quadrant retinal nerve fiber layer thickness (P=0.004, P=0.004, P=0.013, and P=0.032, respectively). CONCLUSION: Decreases in RPC and MMV VDs and changes in ONH parameters were found in OCT-A measurements in patients with SSc.
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Esclerodermia Sistémica , Tomografía de Coherencia Óptica , Coroides/diagnóstico por imagen , Angiografía con Fluoresceína , Humanos , Microvasos/diagnóstico por imagen , Vasos Retinianos/diagnóstico por imagen , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/diagnóstico por imagenRESUMEN
OBJECTIVE: To assess the association between preterm birth and cervical length after arrested preterm labor in high-risk pregnant women. METHODS: In this post-hoc analysis of a randomized clinical trial, transvaginal cervical length was measured in women whose contractions had ceased 48 h after admission for threatened preterm labor. At admission, women were defined as having a high risk of preterm birth based on a cervical length of < 15 mm or a cervical length of 15-30 mm with a positive fetal fibronectin test. Logistic regression analysis was used to investigate the association of cervical length measured at least 48 h after admission and of the change in cervical length between admission and at least 48 h later, with preterm birth before 34 weeks' gestation and delivery within 7 days after admission. RESULTS: A total of 164 women were included in the analysis. Women whose cervical length increased between admission for threatened preterm labor and 48 h later (32%; n = 53) were found to have a lower risk of preterm birth before 34 weeks compared with women whose cervical length did not change (adjusted odds ratio (aOR), 0.24 (95% CI, 0.09-0.69)). The risk in women with a decrease in cervical length between the two timepoints was not different from that in women with no change in cervical length (aOR, 1.45 (95% CI, 0.62-3.41)). Moreover, greater absolute cervical length after 48 h was associated with a lower risk of preterm birth before 34 weeks (aOR, 0.90 (95% CI, 0.84-0.96)) and delivery within 7 days after admission (aOR, 0.91 (95% CI, 0.82-1.02)). Sensitivity analysis in women randomized to receive no intervention showed comparable results. CONCLUSION: Our study suggests that the risk of preterm birth before 34 weeks is lower in women whose cervical length increases between admission for threatened preterm labor and at least 48 h later when contractions had ceased compared with women in whom cervical length does not change or decreases. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
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Medición de Longitud Cervical/estadística & datos numéricos , Complicaciones del Trabajo de Parto/patología , Trabajo de Parto Prematuro/patología , Admisión del Paciente/estadística & datos numéricos , Nacimiento Prematuro/etiología , Adulto , Cuello del Útero/diagnóstico por imagen , Cuello del Útero/patología , Femenino , Humanos , Complicaciones del Trabajo de Parto/diagnóstico por imagen , Trabajo de Parto Prematuro/diagnóstico por imagen , Embarazo , Ensayos Clínicos Controlados Aleatorios como Asunto , Medición de Riesgo , Factores de TiempoRESUMEN
BACKGROUND: High tumor mutation burden (TMB-H) has been proposed as a predictive biomarker for response to immune checkpoint blockade (ICB), largely due to the potential for tumor mutations to generate immunogenic neoantigens. Despite recent pan-cancer approval of ICB treatment for any TMB-H tumor, as assessed by the targeted FoundationOne CDx assay in nine tumor types, the utility of this biomarker has not been fully demonstrated across all cancers. PATIENTS AND METHODS: Data from over 10 000 patient tumors included in The Cancer Genome Atlas were used to compare approaches to determine TMB and identify the correlation between predicted neoantigen load and CD8 T cells. Association of TMB with ICB treatment outcomes was analyzed by both objective response rates (ORRs, N = 1551) and overall survival (OS, N = 1936). RESULTS: In cancer types where CD8 T-cell levels positively correlated with neoantigen load, such as melanoma, lung, and bladder cancers, TMB-H tumors exhibited a 39.8% ORR to ICB [95% confidence interval (CI) 34.9-44.8], which was significantly higher than that observed in low TMB (TMB-L) tumors [odds ratio (OR) = 4.1, 95% CI 2.9-5.8, P < 2 × 10-16]. In cancer types that showed no relationship between CD8 T-cell levels and neoantigen load, such as breast cancer, prostate cancer, and glioma, TMB-H tumors failed to achieve a 20% ORR (ORR = 15.3%, 95% CI 9.2-23.4, P = 0.95), and exhibited a significantly lower ORR relative to TMB-L tumors (OR = 0.46, 95% CI 0.24-0.88, P = 0.02). Bulk ORRs were not significantly different between the two categories of tumors (P = 0.10) for patient cohorts assessed. Equivalent results were obtained by analyzing OS and by treating TMB as a continuous variable. CONCLUSIONS: Our analysis failed to support application of TMB-H as a biomarker for treatment with ICB in all solid cancer types. Further tumor type-specific studies are warranted.
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Inhibidores de Puntos de Control Inmunológico , Neoplasias , Biomarcadores de Tumor , Humanos , Masculino , Mutación , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Resultado del TratamientoRESUMEN
Objective: This paper describes the baseline demographics, clinical characteristics, and patient-reported outcomes (PROs) according to clinical phenotype of patients with early psoriatic arthritis (PsA) for the purpose of creating a decision support system for daily clinical practice.Method: Patients with newly diagnosed PsA were included in the Dutch south west Early Psoriatic ARthritis (DEPAR) study. No classification criteria were applied, to ensure collection of real-world data on demographics, medication, clinical characteristics, and PROs. An IT infrastructure facilitated data collection.Results: We described 527 patients, categorized according to the clinical phenotype stated by the rheumatologist at the time of diagnosis, namely monoarthritis (15%), oligoarthritis (40%), polyarthritis (23%), enthesitis (10%), axial disease (2%), and dactylitis (10%). Overall psoriasis severity was mild and 83 patients (16%) had no psoriasis. Short-term sick leave (> 1 day per 4 weeks) was 17% and long-term sick leave (> 4 weeks) was 4%. The group with phenotype enthesitis reported the longest duration of complaints, had the highest fatigue scores, and contained the highest percentage of patients with a Hospital Anxiety and Depression Scale (HADS) anxiety score ≥ 8 and depression score ≥ 8.Conclusion: PsA patients presenting at outpatient clinics in the Netherlands had a mild degree of psoriasis, with impairment of quality of life and work productivity. Most patients presented with phenotype oligoarthritis. Those presenting with phenotype enthesitis more often reported scores suggestive of an anxiety or depression disorder and fatigue. It is important for attending rheumatologists to be aware of these differences when assessing patients with PsA.
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Artritis Psoriásica/diagnóstico , Calidad de Vida , Adulto , Anciano , Artritis Psoriásica/tratamiento farmacológico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Países Bajos , Medición de Resultados Informados por el Paciente , Fenotipo , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: The anticancer effects of Phyllanthus amarus extract on various cancer cells have been investigated, however, the effects of its major constituents on HCT116 human colorectal cancer cells have not been reported. OBJECTIVE: In the present study, we investigated the cytotoxic effect of 80% ethanol extract of P. amarus and its marker constituents (phyllanthin, hypophyllanthin, gallic acid, niranthin, greraniin, phyltetralin, isolintetralin, corilagin and ellagic acid) on HCT116 and their underlying mechanisms of action. METHODS: Their antiproliferative and apoptotic effects on HCT 116 were performed using MTT assay and flow cytometric analysis, respectively, while caspases 3/7, 8 and 9 activities were examined using the colorimetric method. The expression of cleaved poly ADP ribose polymerase enzyme (PARP) and cytochrome c proteins was investigated by the immune-blot technique. RESULTS AND DISCUSSION: HPLC and LC-MS/MS analyses demonstrated that the extract contained mainly lignans and polyphenols. The plant samples markedly suppressed the growth and expansion of HCT116 cells in a concentration- and time-dependent manner with no toxicity against normal human fibroblast CCD18 Co. P. amarus extract, phyllanthin and gallic acid induced mode of cell death primarily through apoptosis as confirmed by the exteriorization of phosphatidylserine. Caspases 3/7, 8, and 9 activities increased in a concentration-dependent manner following 24h treatment. The expressions of cleaved PARP (Asp 214) and cytochrome c were markedly upregulated. CONCLUSION: P. amarus extract, phyllanthin and gallic acid exhibited an apoptotic effect on HCT116 cells through the caspases-dependent pathway.