The evaluation of a remote support program on quality of life and evolution of disease in COPD patients with frequent exacerbations.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) patients often present considerable individual medical burden in their symptoms, limitations, and well-being that complicate medical treatment. To improve their overall health status, while reducing the number of exacerbations, a multidisciplinary approach including different elements of care is needed. The aim of this study was to evaluate the effects of a remote support program on COPD patients at high risk of experiencing worsening of their disease and other health-related outcomes. METHODS: An observational, multicenter, prospective study aimed at evaluating the impact of a 7-month remote support program on COPD patients in exacerbations control and changes in health status measured with the COPD assessment test (CAT). Factors associated with a clinically relevant decrease in CAT were assessed using a logistic regression analysis. RESULTS: A total of 114 subjects started the program. The majority of the study population were males (81.6 %), retired (70.2 %), without academic qualifications or with a low level of education (68.4 %), and ex-smokers (79.8 %). The mean ± SD age was 69.6 ± 9.1 years and the BMI was 27.8 ± 5.5 Kg/m2. Overall, 41.9 % (95 % CI 31.9-52.0) patients, significantly improved health status (CAT decrease ≥ 2 points). Univariate analysis showed that significant improvement in CAT was associated with baseline CAT scores [high CAT score 19.2 (±7.5) vs. low CAT score 12.4 (±6.4); OR = 1.15, 95 % CI: 1.07-1.24; p < 0.001] and with being non-compliant [62.5 % (15/24) of non-compliant vs 34.7 % (24/69) of compliant patients significantly improved CAT scores; OR = 3.13, 95 % CI: 1.19-8.19; p = 0.021). After controlling for the effect of all variables in a multivariable logistic regression model, the only factor that remained significant was baseline CAT score. The proportion of smokers in the total population remained constant during the study. There was a significant reduction in the number of exacerbations after entering this remote support program with median -1 (IQR: -2, 0), (p < 0.001). The Morisky-Green questionnaire showed an increase of treatment compliance, namely at baseline, 25.8 % (24/93) of patients were noncompliant while in the end 66.7 % (16/24) of them became compliant) (p = 0.053). CONCLUSIONS: A remote support program for high-risk COPD patients results in an improvement of the patients' health status, particularly in those with initially poor health status, and it helps to reduce COPD exacerbations.

Course of COPD assessment test (CAT) and clinical COPD questionnaire (CCQ) scores during recovery from exacerbations of chronic obstructive pulmonary disease.

INTRODUCTION: COPD exacerbations have a negative impact on lung function, decrease quality of life (QoL) and increase the risk of death. The objective of this study was to assess the course of health status after an outpatient or inpatient exacerbation in patients with COPD. METHODS: This is an epidemiological, prospective, multicentre study that was conducted in 79 hospitals and primary care centres in Spain. Four hundred seventy-six COPD patients completed COPD assessment test (CAT) and Clinical COPD Questionnaire (CCQ) questionnaires during the 24 hours after presenting at hospital or primary care centres with symptoms of an exacerbation, and also at weeks 4-6. The scores from the CAT and CCQ were evaluated and compared at baseline and after recovery from the exacerbation. RESULTS: A total of 164 outpatients (33.7%) and 322 inpatients (66.3%) were included in the study. The majority were men (88.2%), the mean age was 69.4 years (SD = 9.5) and the mean FEV1 (%) was 47.7% (17.4%). During the exacerbation, patients presented high scores in the CAT: [mean: 22.0 (SD = 7.0)] and the CCQ: [mean: 4.4 (SD = 1.2)]. After recovery there was a significant reduction in the scores of both questionnaires [CAT: mean: -9.9 (SD = 5.1) and CCQ: mean: -3.1 (SD = 1.1)]. Both questionnaires showed a strong correlation during and after the exacerbation and the best predictor of the magnitude of improvement in the scores was the severity of each score at onset. CONCLUSIONS: Due to their good correlation, CAT and CCQ can be useful tools to measure health status during an exacerbation and to evaluate recovery. However, new studies are necessary in order to identify which factors are influencing the course of the recovery of health status after a COPD exacerbation.

Impact of Vedolizumab on Extraintestinal Manifestations in Inflammatory Bowel Disease: Results From a Descriptive, Retrospective, Real-world Study.

BACKGROUND: Patients with inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, may develop extraintestinal manifestations (EIMs). The EMOTIVE study aimed to analyze the effect of vedolizumab on EIMs in a real-world cohort of patients with IBD. METHODS: This multicenter, descriptive, retrospective study was conducted in Belgium, Denmark, Israel, the Netherlands, and Switzerland in adults with moderately to severely active IBD and concurrent active EIMs at vedolizumab initiation (index date), with a ≥6-month follow-up after the index date. The primary endpoint was resolution of all EIMs within 6 months of vedolizumab initiation. RESULTS: In 99 eligible patients, the most frequent EIMs were arthralgia (69.7%), peripheral spondyloarthritis (21.2%), and axial spondyloarthritis (10.1%). Within 6 and 12 months of vedolizumab initiation, 19.2% and 25.3% of patients reported resolution of all EIMs, while 36.5% and 49.5% of all EIMs were reported to be improved (combination of resolution and partial response), respectively. Vedolizumab treatment persistence at 12 months was 82.8%. Adverse events were reported in 18.2% of patients, with the most frequent being arthralgia (4.0%). CONCLUSIONS: This real-world study showed resolution of all EIMs in up to one-fourth of patients with IBD and improvement in up to half of EIMs within 12 months of vedolizumab treatment. Overall, vedolizumab was effective on EIMs in patients with IBD and showed a good safety profile.

Real-World Health Care Services Utilization Associated With the Management of Patients With Relapsed and Refractory Multiple Myeloma in Spain: The CharisMMa Study.

BACKGROUND: Most patients with multiple myeloma (MM) relapse or become refractory, resulting in high health care costs. However, real-world data regarding the utilization of health care services among the relapsed/refractory MM (RRMM) population are scarce. METHODS: Observational, cross-sectional, multicenter study of the utilization of health care services by RRMM patients who had relapsed within the previous 6 months in Spain in a real-world setting. Data were collected from the clinical records and during a single structured interview and included sociodemographic and clinical characteristics at last relapse, the treatment and health care services nature, and were presented using descriptive statistics. RESULTS: The 276 patients enrolled (53.3% males), with a mean [SD] age of 67.4 [10.5] years, had experienced their most recent relapse a median (IQR) of 1.61 (0.74, 3.14) months before entering the study. Patients lived a median (IQR) of 9.0 (3.0, 30.0) km away from the hospital and visited the hospital a median (IQR) of 3.0 (2.0, 5.0) times/month to receive treatment for their most recent relapse. They spent a median (IQR) of 15.84 (5.0, 42.0) euros/month on transportation. Since their most recent relapse, most patients had been admitted to a hospital unit (n = 155, 56.2%), had required ≥1 diagnostic tests (n = 227, 82.2%), and had consulted the hematologist (n = 270, 97.8%) a mean (SD) of 5.5 (5.4) times. In half of the visits, patients were accompanied by an actively working caregiver (n = 112, 54.4%). CONCLUSIONS: RRMM treatments are associated with a high utilization of health care services and pose a significant burden for patients and caregivers. TRIAL REGISTRATION NUMBER: NCT03188536.

Assessment of the psychometric properties of the Spanish version of EORTC QLQ-MY20 and evaluation of health-related quality of Life outcomes in patients with relapsed and/or refractory multiple myeloma in the real-world setting in Spain: results from the CharisMMa study.

We evaluated the psychometric properties of the Spanish version of the European Organization for Research and Treatment of Multiple Myeloma (MM) specific quality-of-life (QoL) questionnaire module (QLQ-MY20) in relapsed/refractory MM (RRMM) patients. This was an observational, cross-sectional, multicenter study using EORTC QLQ-C30 and QLQ-MY20 in RRMM patients (ClinicalTrials.gov ID NCT03188536). We assessed the non-response rate, ceiling/floor effects, internal consistency, test-retest reliability, and validity. The study included 276 patients (53.3% males, mean [SD] age of 67.4 [10.5] years). The EORTC QLQ-MY20 showed a low non-response rate, very low ceiling and floor effects, and good internal consistency. The test-retest reliability assessment revealed good temporary stability, the construct validity analysis stated four main factors similar to the ones of the original version, and the criterion validity assessment showed no differences between groups. In conclusion, the Spanish version of EORTC QLQ-MY20 is a reliable and valid tool for assessing QoL in RRMM patients.

A multicenter, open-label, randomized, proof-of-concept phase II clinical trial to assess the efficacy and safety of icatibant in patients infected with SARS-CoV-2 (COVID-19) and admitted to hospital units without invasive mechanical ventilation: study protocol (ICAT-COVID).

BACKGROUND: COVID-19 has quickly become a global pandemic with a substantial number of deaths and is a considerable burden for healthcare systems worldwide. Although most cases are paucisymptomatic and limited to the viral infection-related symptoms, some patients evolve to a second phase, with an impaired inflammatory response (cytokine storm) that may lead to acute respiratory distress syndrome and death. This is thought to be caused by increased bradykinin synthesis. METHODS: ICAT-COVID is a multicenter, randomized, open-label, proof-of-concept phase II clinical trial assessing the clinical efficacy and safety of adding icatibant to the standard of care in patients hospitalized with COVID-19 without invasive mechanical ventilation. Patients hospitalized with a confirmed COVID-19 pneumonia diagnosis (RT-PCR or antigen test ≤ 10 days prior to randomization, and radiographic evidence of pulmonary infiltrates), rated "4" or "5" on the WHO's clinical status scale, are eligible. Patients will be randomized on a 1:1 ratio to either standard of care-plus-icatibant (experimental group) or to standard of care alone (control group). The experimental group will receive 30 mg of icatibant subcutaneously 3 times a day for 3 days (for a total of 9 doses). The expected sample size is 120 patients (60 per group) from 2 sites in Spain. Primary outcomes are the efficacy and safety of Icatibant. The main efficacy outcome is the number of patients reaching grades "2" or "1" on the WHO scale within 10 days of starting treatment. Secondary outcomes include "long-term efficacy": number of patients discharged who do not present COVID-19-related relapse or comorbidity up until 28 days after discharge, and mortality. DISCUSSION: Icatibant, a bradykinin type 2 receptor antagonist with proven effectiveness and safety against hereditary angioedema attacks, may be beneficial for COVID-19 patients by inhibiting bradykinin's action on endothelial cells and by inhibiting the SARS-CoV-2 M protease. Our working hypothesis is that treatment with standard of care-plus-icatibant is effective and safe to treat patients infected with SARS-CoV-2 admitted to hospital for pneumonia without invasive mechanical ventilation. TRIAL REGISTRATION: EudraCT 2020-002166-13. CLINICALTRIALS: gov NCT04978051.

Evaluation of Natural Language Processing for the Identification of Crohn Disease-Related Variables in Spanish Electronic Health Records: A Validation Study for the PREMONITION-CD Project.

BACKGROUND: The exploration of clinically relevant information in the free text of electronic health records (EHRs) holds the potential to positively impact clinical practice as well as knowledge regarding Crohn disease (CD), an inflammatory bowel disease that may affect any segment of the gastrointestinal tract. The EHRead technology, a clinical natural language processing (cNLP) system, was designed to detect and extract clinical information from narratives in the clinical notes contained in EHRs. OBJECTIVE: The aim of this study is to validate the performance of the EHRead technology in identifying information of patients with CD. METHODS: We used the EHRead technology to explore and extract CD-related clinical information from EHRs. To validate this tool, we compared the output of the EHRead technology with a manually curated gold standard to assess the quality of our cNLP system in detecting records containing any reference to CD and its related variables. RESULTS: The validation metrics for the main variable (CD) were a precision of 0.88, a recall of 0.98, and an F1 score of 0.93. Regarding the secondary variables, we obtained a precision of 0.91, a recall of 0.71, and an F1 score of 0.80 for CD flare, while for the variable vedolizumab (treatment), a precision, recall, and F1 score of 0.86, 0.94, and 0.90 were obtained, respectively. CONCLUSIONS: This evaluation demonstrates the ability of the EHRead technology to identify patients with CD and their related variables from the free text of EHRs. To the best of our knowledge, this study is the first to use a cNLP system for the identification of CD in EHRs written in Spanish.

Clinical characteristics and prognostic factors for Crohn's disease relapses using natural language processing and machine learning: a pilot study.

BACKGROUND: The impact of relapses on disease burden in Crohn's disease (CD) warrants searching for predictive factors to anticipate relapses. This requires analysis of large datasets, including elusive free-text annotations from electronic health records. This study aims to describe clinical characteristics and treatment with biologics of CD patients and generate a data-driven predictive model for relapse using natural language processing (NLP) and machine learning (ML). METHODS: We performed a multicenter, retrospective study using a previously validated corpus of CD patient data from eight hospitals of the Spanish National Healthcare Network from 1 January 2014 to 31 December 2018 using NLP. Predictive models were created with ML algorithms, namely, logistic regression, decision trees, and random forests. RESULTS: CD phenotype, analyzed in 5938 CD patients, was predominantly inflammatory, and tobacco smoking appeared as a risk factor, confirming previous clinical studies. We also documented treatments, treatment switches, and time to discontinuation in biologics-treated CD patients. We found correlations between CD and patient family history of gastrointestinal neoplasms. Our predictive model ranked 25 000 variables for their potential as risk factors for CD relapse. Of highest relative importance were past relapses and patients' age, as well as leukocyte, hemoglobin, and fibrinogen levels. CONCLUSION: Through NLP, we identified variables such as smoking as a risk factor and described treatment patterns with biologics in CD patients. CD relapse prediction highlighted the importance of patients' age and some biochemistry values, though it proved highly challenging and merits the assessment of risk factors for relapse in a clinical setting.

Matching-Adjusted Indirect Comparisons in the assessment of hemato-oncological drugs.

OBJECTIVE: Matching-Adjusted Indirect Comparison is a methodology that has been developed to assess new treatments vs alternatives when a direct comparison is not available through a randomized controlled trial. These comparisons are of particular interest in the areas of oncology and hematology where uncertainty in decision-making on the inclusion of new drugs is frequently accentuated by both the severity of the disease and the high cost of treatment. The objective of this study was to describe how Matching-Adjusted Indirect Comparison methodology has been used to date in the assessment of hematological cancer drugs by international agencies. METHOD: Between January 2015 and October 2019, an exhaustive search was conducted of the websites of European National Agencies that provided public information on the assessment process. The assessments provided by these agencies were reviewed to obtain a list of hematological cancer drugs for which the presentation of a Matched-Adjusted Indirect Comparison was recorded. For this list of drugs, the role of the comparison in the assessment process was analyzed for each selected agency. RESULTS: Thirteen hematological and oncological treatments were found in which the pharmaceutical marketing authorization holder had presented Matching-Adjusted Indirect Comparisons: most of this information referred to the first half of 2018. Acceptance of this methodology diverges among agencies, ranging from 50% in the case of the British National Institute for Health and Clinical Excellence, to 40% in the case of French National Authority for Health, to not having been taken into account in any of the 3 cases assessed by the German Institute for Quality and Efficiency in Health Care. The main cause of non-acceptance was matching-related problems. CONCLUSIONS: Matching- Adjusted Indirect Comparison methodology is a tool that is being utilized in the decision-making process for assessing new hematological cancer treatments.

Objetivo: La comparación indirecta ajustada con emparejamiento es una metodología desarrollada para la evaluación de nuevos tratamientos frente a sus alternativas cuando no se dispone de comparación directa mediante un ensayo clínico aleatorizado y controlado. Estas comparaciones son de especial interés en el área de la hematooncología, en la que la incertidumbre en la toma de decisiones sobre la inclusión de nuevos fármacos se ve frecuentemente acentuada tanto por la gravedad de la enfermedad como por el elevado coste del tratamiento. El objetivo de este artículo es describir cómo la metodología de comparación indirecta ajustada con emparejamiento ha sido empleada hasta la fecha en la evaluación de fármacos hematooncológicos por parte de agencias internacionales.Método: Para la obtención de los datos del análisis se ha realizado una búsqueda exhaustiva en las páginas web de las agencias nacionales europeas entre enero de 2015 y octubre de 2019 que mostraran información pública del proceso evaluativo. Se revisaron las evaluaciones de estas agencias para obtener un listado de fármacos oncohematológicos para los que constara la presentación de documentación de una comparación indirecta ajustada con  emparejamiento. Para este listado de fármacos se analizó para cada agencia seleccionada el papel que dicha comparación tuvo en la evaluación.Resultados: Se han encontrado 13 tratamientos para patologías hematooncológicas en las que el laboratorio había presentado comparaciones con metodología de comparación indirecta ajustada con emparejamiento en su documentación, principalmente a partir del primer semestre de 2018. La aceptación de la metodología diverge entre agencias, pasando de un 50% en el caso del Instituto Nacional para la Salud y la Excelencia Clínica británico, a un 40% en el Alto Comisionado de Salud francés, a no haberse tenido en cuenta en ninguno de los tres casos evaluados por el Instituto para la Calidad y Eficiencia en los cuidados de salud alemán. La principal causa de no aceptación fue la existencia de problemas relacionados con el emparejamiento.Conclusiones: La metodología de comparación indirecta ajustada con emparejamiento es una herramienta de comparación indirecta que está siendo considerada por las agencias analizadas en el proceso de toma de decisiones de evaluación de nuevos medicamentos.

Head to head evaluation of second generation ALK inhibitors brigatinib and alectinib as first-line treatment for ALK+ NSCLC using an in silico systems biology-based approach.

Around 3-7% of patients with non-small cell lung cancer (NSCLC), which represent 85% of diagnosed lung cancers, have a rearrangement in the ALK gene that produces an abnormal activity of the ALK protein cell signaling pathway. The developed ALK tyrosine kinase inhibitors (TKIs), such as crizotinib, ceritinib, alectinib, brigatinib and lorlatinb present good performance treating ALK+ NSCLC, although all patients invariably develop resistance due to ALK secondary mutations or bypass mechanisms. In the present study, we compare the potential differences between brigatinib and alectinib's mechanisms of action as first-line treatment for ALK+ NSCLC in a systems biology-based in silico setting. Therapeutic performance mapping system (TPMS) technology was used to characterize the mechanisms of action of brigatinib and alectinib and the impact of potential resistances and drug interferences with concomitant treatments. The analyses indicate that brigatinib and alectinib affect cell growth, apoptosis and immune evasion through ALK inhibition. However, brigatinib seems to achieve a more diverse downstream effect due to a broader cancer-related kinase target spectrum. Brigatinib also shows a robust effect over invasiveness and central nervous system metastasis-related mechanisms, whereas alectinib seems to have a greater impact on the immune evasion mechanism. Based on this in silico head to head study, we conclude that brigatinib shows a predicted efficacy similar to alectinib and could be a good candidate in a first-line setting against ALK+ NSCLC. Future investigation involving clinical studies will be needed to confirm these findings. These in silico systems biology-based models could be applied for exploring other unanswered questions.

Influence of Stress and Depression on the Immune System in Patients Evaluated in an Anti-aging Unit.

BACKGROUND: There is compelling evidence pointing out that stress and depression produce a dramatic impact on human well-being mainly through impairing the regular function of the immune system and producing a low-chronic inflammation status that favors the occurrence of infections, metabolic diseases, and even cancer. The present work aims to evaluate the stress/depression levels of some patients treated in an antiaging unit and detect any potential relationship with their immune system status prior of the implementation of a physical/psychological program designed to prevent health deterioration. METHODS: We evaluated 48 patients (16 men and 32 women with a mean age of 55.11 ± 10.71 years) from middle-upper class from psychological and immunological points of view. In particular, we analyzed neutrophil chemotaxis and phagocytosis; lymphocyte chemotaxis and proliferation, and natural killer (NK) cell activity. RESULTS: Women showed more depressive symptoms than men. Chemotaxis levels of lymphocytes and neutrophils in women showed a significant reduction compared with those in men. We also found a strong negative correlation between depression and NK cell function. This correlation was also significant independently of gender. CONCLUSION: We conclude that NK activity is affected at least by depression state, and we propose that a combined treatment consisting of cognitive behavioral therapy and physical activity programs might improve patient health deterioration.

Impact of comorbidities on anti-TNFα response and relapse in patients with inflammatory bowel disease: the VERNE study.

Objective: To evaluate the impact of comorbidities and extraintestinal manifestations of inflammatory bowel disease on the response of patients with inflammatory bowel disease to antitumour necrosis factor alpha (anti-TNFα) therapy. Design: Data from 310 patients (194 with Crohn's disease and 116 with ulcerative colitis) treated consecutively with the first anti-TNFα in 24 Spanish hospitals were retrospectively analysed. Univariate and multivariate logistic regression analyses were performed to assess the associations between inflammatory bowel disease comorbidities and extraintestinal manifestations with anti-TNFα treatment outcomes. Key clinical features, such as type of inflammatory bowel disease and concomitant treatments, were included as fixed factors in the model. Results: Multivariate logistic regression analyses (OR, 95% CI) showed that chronic obstructive pulmonary disease (2.67, 1.33 to 5.35) and hepato-pancreato-biliary diseases (1.87, 1.48 to 2.36) were significantly associated with primary non-response to anti-TNFα, as was the use of corticosteroids and the type of inflammatory bowel disease (ulcerative colitis vs Crohn's disease). It was also found that myocardial infarction (3.30, 1.48 to 7.35) and skin disease (2.73, 1.42 to 5.25) were significantly associated with loss of response, along with the use of corticosteroids and the type of inflammatory bowel disease (ulcerative colitis vs Crohn's disease). Conclusions: Our results suggest that the presence of some comorbidities in patients with inflammatory bowel disease, such as chronic obstructive pulmonary disease and myocardial infarction, and of certain extraintestinal manifestations of inflammatory bowel disease, such as hepato-pancreato-biliary conditions and skin diseases, appear to be related to failure to anti-TNFα treatment. Therefore, their presence should be considered when choosing a treatment. Trial registration number: NCT02861118.

Prevalence and characterization of breakthrough pain in patients with cancer in Spain: the CARPE-DIO study.

We aimed to evaluate the prevalence, characteristics and impact of breakthrough pain (BTP) in patients with cancer attending the main specialties involved in the diagnosis and management of BTP in Spain using a multicenter, observational, cross-sectional, multidisciplinary study. Investigators had to record all patients seen at the clinic during 1 month, determine whether the patients had cancer pain, and apply the Davies algorithm to ascertain whether the patients were suffering from BTP. Of the 3,765 patients with cancer, 1,117 (30%) had cancer-related pain, and of these patients, 539 had BTP (48%, 95%CI:45-51). The highest prevalence was found in patients from palliative care (61%, 95%CI:54-68), and the lowest was found in those from hematology (25%, 95%CI:20-31). Prevalence varied also according to sex and type of tumor. According to the Alberta Breakthrough Pain Assessment Tool duration, timing, frequency, location, severity, quality, causes, and predictability of the BTP varied greatly among these patients. BTP was moderate (Brief Pain Inventory [BPI]-severity median score = 5.3), and pain interference was moderate (BPI-interference median score = 6.1) with a greater interference with normal work, general activity, and enjoyment of life. Patients with BTP showed a mean ± standard deviation score of 28.5 ± 8.0 and 36.9 ± 9.5 in the physical and mental component, respectively, of the SF-12 questionnaire. In conclusion, prevalence of BTP among patients exhibiting cancer-related pain is high. Clinical presentation is heterogeneous, and therefore, BTP cannot be considered as a single entity. However, uniformly BTP has an important impact on a patient's functionality, which supports the need for early detection and treatment.

Anti-Müllerian hormone levels to predict oocyte maturity and embryo quality during controlled ovarian hyperstimulation.

BACKGROUND: The aim of this study was to assess the correlation between controlled ovarian hyperstimulation (COH) outcome parameters and anti-Müllerian hormone (AMH) serum levels during in vitro fertilization (IVF) treatment in women with varying ovarian reserve levels. METHODS: Prospective study of 46 women undergoing GnRH-antagonist short protocol for IVF. Participants included women with low ovarian reserve (N.=11), normoreserve (N.=16), and polycystic ovarian syndrome (PCOS; N.=19). AMH was measured on menstrual cycle day 1-3 (basal AMH), on the day of GnRH-antagonist administration (AMH-GnRH), on the day of hCG administration (AMH-hCG), and in follicular fluid on the day of oocyte retrieval (AMH-FF). RESULTS: Basal AMH was significantly correlated (P<0.001) with antral follicle count and number of follicles >11mm on hCG day (P<0.05). Both basal AMH and AMH-GnRH were significantly correlated (P<0.05) with the number of oocytes retrieved and metaphase II. AMH-hCG was correlated with top quality embryos (P=0.04). No correlations were found between COH outcome parameters and AMH-FF. CONCLUSIONS: Basal AMH serum concentration was the strongest predictor of oocyte yield. AMH concentration at the mid-follicular phase was also a good predictor of oocyte yield and this marker was the only useful ovarian reserve indicator during the follicle growth process to predict IVF outcomes. AMH-hCG levels appear to predict embryo quality. AMH levels during the COH can provide valuable data to help individualize treatment and predict COH results.

Anti-Müllerian hormone dynamics during GNRH-antagonist short protocol for IVF/ICSI in women with varying ovarian reserve levels.

BACKGROUND: Data on variations in anti-Müllerian hormone (AMH) levels according to ovarian reserve are scant. The aim of this study was to investigate changes in AMH levels during controlled ovarian hyperstimulation with a GnRH-antagonist protocol for in vitro fertilization (IVF). METHODS: Prospective, observational study of 46 women. The subjects were divided into three cohorts according to ovarian reserve levels: polycystic ovary syndrome (PCOS; N.=19), low ovarian reserve (LOR; N.=11), and normoreserve (NR; N.=16). Serum AMH concentration was measured at baseline (cycle day 2-3 before follicle stimulating hormone [FSH] administration) and just prior to GnRH-antagonist and human chorionic gonadotropin (hCG) administration. AMH concentration in follicular fluid (FF) was assessed on the day of oocyte retrieval. RESULTS: AMH serum concentration decreased significantly (P<0.001) and progressively in all three groups from baseline (initiation of stimulation) to all subsequent assessments. Serum AMH levels were significantly higher in the PCOS group at all determinations: (AMH1: 8.18±6.26ng/mL, AMH2: 5.3±3.97ng/mL, AMH3: 2.19±1.31ng/mL) versus the NR group (AMH1: 2.94±1.53ng/mL, AMH2: 1.44±0.77ng/mL, AMH3: 0.71±0.57ng/mL) and LOR group (AMH1: 0.63±0.42ng/mL, AMH2: 0.58±0.4ng/mL, AMH3: 0.31±0.2ng/mL). No significant between-group differences were observed for AMH levels in FF (PCOS: 3.56±3.19ng/mL, NR: 4.06±5.44ng/mL, LOR: 1.31±0.47ng/mL) nor for fertilization rate, number of top quality embryos, or clinical pregnancy rates. CONCLUSIONS: Serum AMH levels gradually decrease during GnRH-antagonist protocol for IVF. This decrease starts at the beginning of the follicular phase and continues up to the day of hCG administration. These results underscore the important role that AMH plays in the process of folliculogenesis and dominant follicle selection.

The chronic obstructive pulmonary disease assessment test improves the predictive value of previous exacerbations for poor outcomes in COPD.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) exacerbations have a negative impact on the quality of life of patients and the evolution of the disease. We have investigated the prognostic value of several health-related quality of life questionnaires to predict the appearance of a composite event (new ambulatory or emergency exacerbation, hospitalization, or death) over a 1-year follow-up. METHODS: This was a multicenter, prospective, observational study. Patients completed four questionnaires after recovering from an exacerbation (COPD Assessment Test [CAT], a Clinical COPD Questionnaire [CCQ], COPD Severity Score [COPDSS], and Airways Questionnaire [AQ20]). Patients were followed-up until the appearance of the composite event or for 1 year, whichever came first. RESULTS: A total of 497 patients were included in the study. The majority of them were men (89.7%), with a mean age of 68.7 (SD 9.2) years, and a forced expiratory volume in 1 second of 47.1% (SD 17.5%). A total of 303 (61%) patients experienced a composite event. Patients with an event had worse mean scores of all questionnaires at baseline compared to patients without event: CAT=12.5 vs 11.3 (P=0.028); CCQ=2.2 vs 1.9 (P=0.013); COPDSS=12.3 vs 10.9 (P=0.001); AQ20=8.3 vs 7.5 (P=0.048). In the multivariate analysis, only previous history of exacerbations and CAT score ≥13.5 were significant risk factors for the composite event. A CAT score ≥13.5 increased the predictive value of previous exacerbations with an area under the receiver operating characteristic curve of 0.864 (95% CI: 0.829-0.899; P=0.001). CONCLUSION: The predictive value of previous exacerbations significantly increased only in one of the four trialled questionnaires, namely in the CAT questionnaire. However, previous history of exacerbations was the strongest predictor of the composite event.

Characterization of the rat Na+/nucleoside cotransporter 2 and transport of nucleoside-derived drugs using electrophysiological methods.

The Na(+)-dependent nucleoside transporter 2 (CNT2) mediates active transport of purine nucleosides and uridine as well as therapeutic nucleoside analogs. We used the two-electrode voltage-clamp technique to investigate rat CNT2 (rCNT2) transport mechanism and study the interaction of nucleoside-derived drugs with the transporter expressed in Xenopus laevis oocytes. The kinetic parameters for sodium, natural nucleosides, and nucleoside derivatives were obtained as a function of membrane potential. For natural substrates, apparent affinity (K(0.5)) was in the low micromolar range (12-34) and was voltage independent for hyperpolarizing membrane potentials, whereas maximal current (I(max)) was voltage dependent. Uridine and 2'-deoxyuridine analogs modified at the 5-position were substrates of rCNT2. Lack of the 2'-hydroxyl group decreased affinity but increased I(max). Increase in the size and decrease in the electronegativity of the residue at the 5-position affected the interaction with the transporter by decreasing both affinity and I(max). Fludarabine and formycin B were also transported with higher I(max) than uridine and moderate affinity (102 +/- 10 and 66 +/- 6 microM, respectively). Analysis of the pre-steady-state currents revealed a half-maximal activation voltage of about -39 mV and a valence of about -0.8. K(0.5) for Na(+) was 2.3 mM at -50 mV and decreased at hyperpolarizing membrane potentials. The Hill coefficient was 1 at all voltages. Direct measurements of radiolabeled nucleoside fluxes with the charge associated showed a ratio of two positive inward charges per nucleoside, suggesting a stoichiometry of two Na(+) per nucleoside. This discrepancy in the number of Na(+) molecules that bind rCNT2 may indicate a low degree of cooperativity between the Na(+) binding sites.