Influence of donor age on liver transplantation outcomes: A multivariate analysis and comparative study.

BACKGROUND: The growing disparity between the rising demand for liver transplantation (LT) and the limited availability of donor organs has prompted a greater reliance on older liver grafts. Traditionally, utilizing livers from elderly donors has been associated with outcomes inferior to those achieved with grafts from younger donors. By accounting for additional risk factors, we hypothesize that the utilization of older liver grafts has a relatively minor impact on both patient survival and graft viability. AIM: To evaluate the impact of donor age on LT outcomes using multivariate analysis and comparing young and elderly donor groups. METHODS: In the period from April 2013 to December 2018, 656 adult liver transplants were performed at the University Hospital Merkur. Several multivariate Cox proportional hazards models were developed to independently assess the significance of donor age. Donor age was treated as a continuous variable. The approach involved univariate and multivariate analysis, including variable selection and assessment of interactions and transformations. Additionally, to exemplify the similarity of using young and old donor liver grafts, the group of 87 recipients of elderly donor liver grafts (≥ 75 years) was compared to a group of 124 recipients of young liver grafts (≤ 45 years) from the dataset. Survival rates of the two groups were estimated using the Kaplan-Meier method and the log-rank test was used to test the differences between groups. RESULTS: Using multivariate Cox analysis, we found no statistical significance in the role of donor age within the constructed models. Even when retained during the entire model development, the donor age's impact on survival remained insignificant and transformations and interactions yielded no substantial effects on survival. Consistent insignificance and low coefficient values suggest that donor age does not impact patient survival in our dataset. Notably, there was no statistical evidence that the five developed models did not adhere to the proportional hazards assumption. When comparing donor age groups, transplantation using elderly grafts showed similar early graft function, similar graft (P = 0.92), and patient survival rates (P = 0.86), and no significant difference in the incidence of postoperative complications. CONCLUSION: Our center's experience indicates that donor age does not play a significant role in patient survival, with elderly livers performing comparably to younger grafts when accounting for other risk factors.

Direct and indirect impact of the COVID-19 pandemic on the survival of kidney transplant recipients: A national observational study in France.

During the pandemic period, health care systems were substantially reorganized for managing COVID-19 cases. Corresponding consequences on persons with chronic diseases remain insufficiently documented. This observational cohort study investigated the direct and indirect impact of the pandemic period on the survival of kidney transplant recipients (KTR). Using the French National Health Data System, incident persons with end-stage kidney disease between 2015 and 2020, and who received a kidney transplant during this period were included and followed up from their transplantation date to December 31, 2021. The survival of KTR during the prepandemic and pandemic periods was investigated using Cox models with time-dependent covariates. There were 10 637 KTR included in the study, with 324 and 430 deaths observed during the prepandemic and pandemic periods, respectively. The adjusted risk of death during the pandemic period was similar to that observed during the prepandemic period (hazard ratio [HR] [95% confidence interval]: 0.92 [0.77-1.11]), COVID-19-related hospitalization was associated with an increased risk of death (HR: 10.62 [8.46-13.33]), and a third vaccine dose was associated with a lower risk of death (HR: 0.42 [0.30-0.57]). The pandemic period was not associated with an indirect higher risk of death in KTR with no COVID-19-related hospitalization.

Primary tumour category, site of metastasis, and baseline serum S100B and LDH are independent prognostic factors for survival in metastatic melanoma patients treated with anti-PD-1.

Background: Prognostic classification of metastatic melanoma patients treated with anti-PD-1 is of great interest to clinicians. Objective: We aimed to determine the anti-PD-1 treatment related prognostic performance of demographics, clinical and histological prognostic markers and baseline serum S100B and LDH levels in advanced melanoma. Methods: A total of 200 patients with unresectable metastatic melanoma were included in this retrospective study. 34.5% had stage M1c disease and 11.5% had stage M1d disease at the start of therapy. 30% had pT4b primary melanoma. 55.5% had elevated baseline serum S100B levels and 62.5% had elevated baseline serum LDH levels. We analysed the risk of death using univariate and multivariate Cox proportional-hazards models and the median overall (OS) and progression-free (PFS) survival using the Kaplan-Meier estimator. Results: The median follow-up time from the start of anti-PD-1 treatment in patients who were alive at the end of the study (N=81) was 37 months (range: 6.1-95.9). The multivariate Cox regression analysis showed that M1c stage (vs. M1a, p=0.005) or M1d stage at the start of therapy (vs. M1a, p=0.001), pT4b category (vs. pT1a, p=0.036), elevated baseline serum S100B levels (vs. normal S100B, p=0.008) and elevated LDH levels (vs. normal LDH, p=0.049) were independently associated with poor survival. The combination of M1d stage, elevated baseline serum S100B and LDH levels and pT4b category was associated with a very high risk of death (HR 4.72 [1.81; 12.33]). In the subgroup of patients with pT4b primary melanoma, the median OS of patients with normal serum S100B levels was 37.25 months [95% CI 11.04; 63.46]), while the median OS of patients with elevated serum S100B levels was 8.00 months [95% CI 3.49; 12.51]) (p<0.001); the median OS of patients with normal serum LDH levels was 41.82 months [95% CI 11.33; 72.32]), while the median OS of patients with elevated serum LDH levels was 12.29 months [95% CI 4.35; 20.23]) (p=0.002). Conclusion: Our real-world study indicates that the prognostic role of primary melanoma parameters is preserved in anti-PD-1 treated stage IV patients. Furthermore, there seems to be perspective in combining clinical, histological and serum prognostic markers in a prognostic model.

Colorectal Cancer Survival in German-Danish Border Regions-A Registry-Based Cohort Study.

The aim of this study was (i) to update the reporting of colorectal cancer survival differences over time in the German-Danish border region (Schleswig-Holstein, Southern Denmark, and Zealand) and (ii) to assess the extent to which it can be explained by stage and primary treatment. Incident invasive colorectal cancer cases diagnosed from 2004 to 2016 with a follow-up of vital status through 31 December 2017 were extracted from cancer registries. Analyses were conducted by anatomical subsite and for four consecutive periods. Kaplan-Meier curves and log-rank tests were computed. Cox regression models using data from Schleswig-Holstein from 2004 to 2007 as the reference category were run while controlling for age, sex, stage, and treatment. The cox regression models showed decreasing hazard ratios of death for all three regions over time for both anatomical subsites. The improvement was stronger in the Danish regions, and adjustment for age, sex, stage, and treatment attenuated the results only slightly. In 2014-2016, colon cancer survival was similar across regions, while rectal cancer survival was significantly superior in the Danish regions. Regional survival differences can only partially be explained by differing stage distribution and treatment and may be linked additionally to healthcare system reforms and screening efforts.

Effectiveness and cost-effectiveness analysis of 11 treatment paths, seven first-line and three second-line treatments for Chinese patients with advanced wild-type squamous non-small cell lung cancer: A sequential model.

Background: A total of 11 treatment sequences for advanced wild-type squamous non-small cell lung cancer are recommended by Chinese Society of Clinical Oncology Guidelines, consisting of seven first-line and three second-line treatments. Five of these treatments were newly approved in China between 2021 and 2022. We evaluated the effectiveness and cost-effectiveness of these strategies from the Chinese healthcare system perspective. Methods: Network meta-analysis with non-proportional hazards was used to calculate the relative efficacy between interventions. A sequential model was developed to estimate costs and quality-adjusted life years (QALY) for treatment sequences with first-line platinum- and paclitaxel-based chemotherapy (SC) with or without nedaplatin, tislelizumab, camrelizumab, sintilimab, sugemalimab or pembrolizumab, followed by second-line docetaxel, tislelizumab or nivolumab. SC and docetaxel were used as comparators for first-line and second-line treatments, respectively. QALY and incremental cost-effectiveness ratio (ICER) were used to evaluate effectiveness and cost-effectiveness, respectively. Cost-effective threshold was set as USD 19,091. Subgroup analysis was conducted to determine the best first-line and second-line therapy. Results: Pembrolizumab + SC, followed by docetaxel (PED) was the most effective treatment sequence. QALYs for patients received SC, nedaplatin + SC, tislelizumab + SC, sintilimab + SC, camrelizumab + SC, sugemalimab + SC, pembrolizumab + SC followed by docetaxel were 0.866, 0.906, 1.179, 1.266, 1.179, 1.266, 1.603, 1.721, 1.807; QALYs for SC, nedaplatin + SC followed by tislelizumab were 1.283, 1.301; QALYs for SC, nedaplatin + SC followed by nivolumab were 1.353, 1.389. Camrelizumab + SC, followed by docetaxel (CAD) was the most cost-effective. Compared to SC with or without nedaplatin, tislelizumab, or sintilimab followed by docetaxel, ICERs of CAD were USD 12,276, 13,210, 6,974, 9,421/QALY, respectively. Compared with nedaplatin or SC followed by tislelizumab, the ICERs of CAD were USD 4,183, 2,804/QALY; CAD was dominant compared with nedaplatin or SC followed by nivolumab; The ICER of sugemalimab + SC followed by docetaxel and PED were USD 522,023, 481,639/QALY compared with CAD. Pembrolizumab + SC and camrelizumab + SC were the most effective and cost-effective first-line options, respectively; tislelizumab was the most effective and cost-effective second-line therapy. Tislelizumab used in second-line was more effective than first-line, no significant differences between their cost-effectiveness. Sensitivity and scenario analysis confirmed robustness of the results. Conclusions: PED and CAD are the most effective and cost-effective treatment sequence, respectively; pembrolizumab + SC and camrelizumab + SC are the most effective and cost-effective first-line choice, respectively; tislelizumab is the most effective and cost-effective second-line choice.

Trajetórias e determinantes do alto risco cardiovascular de 30 anos entre participantes de uma coorte brasileira (Estudo CUME) / Trajectories and determinants of 30-year high cardiovascular risk among participants in a Brazilian cohort (CUME Study)

Introdução: As doenças cardiovasculares são o principal problema de saúde pública em todo o mundo. Portanto, a avaliação do risco cardiovascular, com a identificação de seus fatores de risco e de proteção e de suas trajetórias ao longo do tempo são importantes para a proposição, a consolidação e a implementação de medidas de prevenção da ocorrência de doenças cardiovasculares. Objetivo geral: Analisar a trajetória e os determinantes do alto risco cardiovascular de 30 anos em participantes da Coorte de Universidades Mineiras (Estudo CUME). Métodos: Inicialmente, foi realizada uma revisão integrativa da literatura e, em seguida, dois estudos de coorte prospectiva. A) Artigo 1 ­ revisão integrativa da literatura sobre a estimação do alto risco cardiovascular e seus fatores associados, realizada nas bases Medical Literature Analysis and Retrievel System Online, Web of Science, Excerpta Medica Database, Cumulative Index to Nursing and Allied Health Literature e no portal Biblioteca Virtual de Saúde; B) Artigo 2 ­ Coorte aberta prospectiva desenvolvida com 2.854 participantes do Estudo CUME, que é uma pesquisa multicêntrica conduzida com egressos de sete instituições públicas federais de ensino superior do Estado de Minas Gerais desde 2016. A incidência do alto risco cardiovascular de 30 anos foi calculada usando o escore de Framingham e seus determinantes foram estimados usando análise multivariada hierárquica pela técnica de regressão de Cox; C) Artigo 3 ­ Estudo prospectivo fechado desenvolvido com 1.286 participantes da CUME, que responderam ao questionário da linha de base em 2016, aos questionários de seguimento de dois anos (2018) e de quatro anos (2020). O risco cardiovascular foi avaliado com o escore de Framingham de 30 anos. A identificação das trajetórias do risco cardiovascular foi realizada com a técnica de modelagem de crescimento de classe latente com o uso do modelo normal censurado. A análise dos fatores independentemente associados a cada uma das trajetórias foi conduzida com a técnica de regressão logística multinominal. Resultados: Artigo 1 ­ foram selecionados 13 artigos com um ou mais fatores associados ao alto risco cardiovascular, segundo o escore de Framingham de 10 anos. Nenhum artigo investigou os fatores associados ao alto risco cardiovascular de 30 anos. Artigo 2 ­ após média de 2,62 anos de seguimento, a incidência do alto risco cardiovascular de 30 anos foi 8,1 casos/1.000 pessoas-ano no sexo feminino e 20,2 casos/1.000 pessoas-ano no sexo masculino. Sexo masculino (Hazard Ratio ­ HR: 2,34; IC 95%: 1,58 - 3,46), trabalhar (HR: 2,13; IC 95%: 1,13 - 3,99), alto consumo de alimentos processados (HR: 2,44; 95% CI: 1,21 - 4,90) e ser ativo fisicamente (HR: 0,63; IC 95%: 0,41 - 0,98) se associaram independentemente ao alto risco cardiovascular de 30 anos; Artigo 3 - Três trajetórias de risco cardiovascular de 30 anos foram identificadas: Baixo-Baixo (68,3%), Médio-Médio (26,2%) e Alto-Alto (5,5%). Ao longo do tempo, o risco cardiovascular apresentou discreto aumento para a trajetória Baixo-Baixo (2,9%), moderado aumento para a trajetória Médio-Médio (7,6%) e elevado aumento para a trajetória Alto-Alto (13%). O sexo masculino, viver em união estável, ter consumos moderado e alto de alimentos ultraprocessados se associaram positivamente às trajetórias de risco cardiovascular Médio-Médio e Alto-Alto. Ainda, ter formação profissional fora da área da saúde e estar trabalhando se associaram positivamente à trajetória de risco cardiovascular Médio-Médio, enquanto ser ativo fisicamente se associou negativamente à trajetória de risco cardiovascular Alto-Alto. Conclusão: Poucos estudos foram conduzidos para avaliar o alto risco cardiovascular de 30 anos, sendo que em nenhum deles foram estimados fatores associados ao desfecho. Nossos achados científicos indicaram que praticar atividade física reduz a incidência do alto risco cardiovascular de 30 anos. Homens, pessoas que trabalham e com consumo elevado de alimentos processados devem ser monitorados com maior cautela, pois apresentaram maior susceptibilidade de ocorrência do alto risco cardiovascular de 30 anos. Adultos jovens e com melhor situação socioeconômica possuem uma trajetória de baixo risco cardiovascular de 30 anos, entretanto, há uma tendência de piora desta trajetória ao longo do tempo devido aos maus hábitos de vida. Dessa forma, é essencial a implementação de estratégias de prevenção para evitar o adoecimento cardiovascular.

Introduction: Cardiovascular diseases are the main public health problem worldwide. Therefore, the assessment of cardiovascular risk, with the identification of its risk and protection factors and their trajectories over time, are important for proposing, consolidating and implementing measures to prevent the occurrence of cardiovascular diseases. General objective: To analyze the 30-year trajectory and determinants of high cardiovascular risk in participants of the Cohort of Universities of Minas Gerais (CUME Study). Methods: Initially, an integrative literature review was performed, followed by two prospective cohort studies. A) Article 1 ­ integrative review of the literature on the estimation of high cardiovascular risk and its associated factors, carried out in the databases Medical Literature Analysis and Retrievel System Online, Web of Science, Excerpta Medica Database, Cumulative Index to Nursing and Allied Health Literature and the Virtual Health Library portal; B) Article 2 ­ Prospective open cohort developed with 2,854 participants of the CUME Study, which is a multicenter research conducted with graduates from seven federal public institutions of higher education in the State of Minas Gerais since 2016. The incidence of high cardiovascular risk at 30 years was calculated using the Framingham score and its determinants were estimated using hierarchical multivariate analysis by the Cox regression technique; C) Article 3 ­ Prospective closed study developed with 1,286 participants from CUME, who answered the baseline questionnaire in 2016, the two-year follow-up questionnaire in 2018 and the four-year follow-up questionnaire in 2020. The risk Cardiovascular was assessed using the 30-year Framingham score. The identification of cardiovascular risk trajectories was performed using the latent class growth modeling technique using the normal censored model. The analysis of the factors independently associated with each of the trajectories was conducted using the multinomial logistic regression technique. Results: Article 1 ­ 13 articles were selected with one or more factors associated with high cardiovascular risk, according to the Framingham score over 10 years. No article investigated the factors associated with 30-year high cardiovascular risk. Article 2 ­ After an average of 2.62 years of follow-up, the incidence of high cardiovascular risk at 30 years was 8.1 cases/1,000 person-years in females and 20.2 cases/1,000 person-years in males. Male sex (Hazard Ratio ­ HR: 2.34; 95% CI: 1.58 - 3.46), work (HR: 2.13; 95% CI: 1.13 - 3.99), high food intake processed foods (HR: 2.44; 95% CI: 1.21 - 4.90) and being physically active (HR: 0.63; 95% CI: 0.41 - 0.98) were independently associated with high cardiovascular risk 30 years old; Article 3 - Three 30-year cardiovascular risk trajectories were identified: Low-Low (68.3%), Medium-Medium (26.2%) and High-High (5.5%). Over time, cardiovascular risk showed a slight increase for the Low-Low trajectory (2.9%), a moderate increase for the Medium-Medium trajectory (7.6%) and a high increase for the High-High trajectory (13%). Being male, living in a stable relationship, having moderate and high consumption of ultra-processed foods were positively associated with Medium-Medium and High-High cardiovascular risk trajectories. Also, having professional training outside the health area and being working were positively associated with the Medium-Medium cardiovascular risk trajectory, while being physically active was negatively associated with the High-High cardiovascular risk trajectory. Conclusion: Few studies were conducted to assess the 30-year high cardiovascular risk, and none of them estimated factors associated with the outcome. Our scientific findings indicated that practicing physical activity reduces the incidence of 30-year high cardiovascular risk. Men, people who work and with a high consumption of processed foods should be monitored with greater caution, as they were more susceptible to the occurrence of the high cardiovascular risk of 30 years. Young adults with better socioeconomic status have a 30-year trajectory of low cardiovascular risk, however, there is a tendency for this trajectory to worsen over time due to bad lifestyle habits. Thus, it is essential to implement prevention strategies to avoid cardiovascular disease.

Machine learning prediction of atrial fibrillation in cardiovascular patients using cardiac magnetic resonance and electronic health information.

Background: Atrial fibrillation (AF) is a commonly encountered cardiac arrhythmia associated with morbidity and substantial healthcare costs. While patients with cardiovascular disease experience the greatest risk of new-onset AF, no risk model has been developed to predict AF occurrence in this population. We hypothesized that a patient-specific model could be delivered using cardiovascular magnetic resonance (CMR) disease phenotyping, contextual patient health information, and machine learning. Methods: Nine thousand four hundred forty-eight patients referred for CMR imaging were enrolled and followed over a 5-year period. Seven thousand, six hundred thirty-nine had no prior history of AF and were eligible to train and validate machine learning algorithms. Random survival forests (RSFs) were used to predict new-onset AF and compared to Cox proportional-hazard (CPH) models. The best performing features were identified from 115 variables sourced from three data domains: (i) CMR-based disease phenotype, (ii) patient health questionnaire, and (iii) electronic health records. We evaluated discriminative performance of optimized models using C-index and time-dependent AUC (tAUC). Results: A RSF-based model of 20 variables (CIROC-AF-20) delivered an overall C-index of 0.78 for the prediction of new-onset AF with respective tAUCs of 0.80, 0.79, and 0.78 at 1-, 2- and 3-years. This outperformed a novel CPH-based model and historic AF risk scores. At 1-year of follow-up, validation cohort patients classified as high-risk of future AF by CIROC-AF-20 went on to experience a 17.3% incidence of new-onset AF, being 24.7-fold higher risk than low risk patients. Conclusions: Using phenotypic data available at time of CMR imaging we developed and validated the first described risk model for the prediction of new-onset AF in patients with cardiovascular disease. Complementary value was provided by variables from patient-reported measures of health and the electronic health record, illustrating the value of multi-domain phenotypic data for the prediction of AF.

Identifying optimal PD-1/PD-L1 inhibitors in first-line treatment of patients with advanced squamous non-small cell lung cancer in China: Updated systematic review and network meta-analysis.

Objective: After Gemstone-302 was published in Lancet in January 2022, seven PD-(L)1 inhibitors launched or about to be launched in China, but there are no head-to-head RCTs reporting the comparative efficacy for squamous non-small cell lung cancer (sq-NSCLC). Therefore, we aimed to indirectly compare the efficacy of these treatments to provide evidence for clinical decision and Chinese national reimbursement drug listing. Methods: We collected phase III clinical trials targeted on stage IIIB-IV patients for first-line immunotherapy of sq-NSCLC by systematically searching databases. Relative effects of competing treatments were assessed by Bayesian network meta-analysis and non-parametric restricted mean survival time (RMST) model. Hazard ratio (HR), severe adverse events (SAEs, grade 3-5), progression-free survival (PFS) and overall survival (OS) years were the outcomes. Subgroup analysis was done according to PD-(L)1 expression, smoking, gender, Eastern Cooperative Oncology Group performance status, age and disease stage. Sensitivity analysis using the range of parameters distribution as well as different comparison methods was performed to test the robustness of the results. Results: A total of 7 clinical trials with 2,640 patients were included. For OS, the efficiency (HR, 95%CI) ranks from high to low were sugemalimab (0.48, 0.32-0.73), camrelizumab (0.55, 0.40-0.76), sintilimab (0.56, 0.35-0.90), pembrolizumab (0.71, 0.58-0.87) and atezolizumab (0.88, 0.73-1.05). For PFS, the efficiency ranks from high to low were sugemalimab (0.33, 0.24-0.45), camrelizumab (0.37, 0.30-0.46), tislelizumab (0.53, 0.36-0.79), sintilimab (0.54, 0.42-0.69), toripalimab (0.56, 0.38-0.83), pembrolizumab (0.57, 0.47-0.70) and atezolizumab (0.71, 0.59-0.85). Proportional hazard models and non-proportional hazard models showed consistent efficiency ranks. When extrapolated to long-term survival benefit, under non-proportional hazard ratio, sugemalimab achieved the highest PFS benefit (lifeyears, LYs) in 2 years (1.323), with camrelizumab (1.320), sintilimab (1.243), tislelizumab (1.189), pembrolizumab (0.990) and atezolizumab (0.947) ranking in order; Camrelizumab achieved the highest OS benefit (LYs) in 10 years (2.723), with atezolizumab (2.445) and pembrolizumab (2.397) ranking in order. RMST model showed similar results. In terms of safety, PD-(L)1 inhibitors increased the incidence of SAEs when combined with chemotherapy, sugemalimab and camrelizumab was the safest drugs. Conclusion: Sugemalimab is superior both in HR and long-term survival benefit for Chinese patients with advanced sq-NSCLC.

La albuminuria y la enfermedad polivascular mejoran la capacidad predictiva de los modelos multivariados después de un evento cardiovascular agudo. Cohorte AIRVAG / Albuminuria and polyvascular disease improve multivariate predictive models after an acute cardiovascular event. The AIRVAG cohort

Antecedentes y objetivos: En la enfermedad cardiovascular ateroesclerótica no existe consenso respecto a los instrumentos de estratificación del riesgo en su prevención secundaria. Nuestro objetivo consistía en comparar la capacidad discriminativa de las funciones de riesgo de Framingham, REGICOR, SCORE y REACH y las puntuaciones de riesgo Bohula-TIMI y SMART, así como en evaluar el posible valor añadido de otras variables clínicas en cuanto a la predicción de recurrencias en pacientes con enfermedad cardiovascular. Métodos: Se analizó una cohorte de 269 pacientes con enfermedad cardiovascular establecida (52,8% coronaria, 32% cerebrovascular, 15,2% arteriopatía periférica). Se compararon las funciones de supervivencia de los grupos de riesgo (bajo/intermedio/alto) según los valores de corte de uso habitual de cada función o puntuación y se calcularon las razones de riesgos instantáneos (RRI) correspondientes a cada una mediante regresión de Cox. Se calculó el Δ C de Harrell, el cat-IRN y el cIRN después de añadir nuevos factores predictivos a un modelo base que incluía edad, sexo, colesterol total, tabaquismo activo, hipertensión arterial y diabetes. Resultados: Al cabo de 6 años de seguimiento (mediana de 4,82 años) se habían producido 61 eventos (23%). Los grupos de riesgo alto tuvieron un mayor riesgo de recurrencia: SMART (RRI: 3,17 [1,55-6,5]), Framingham (RRI: 3,08 [1,65-5,75]), REGICOR (RRI: 2,71 [1,39-5,27]), SCORE (RRI: 2,14 [1,01-4,5], REACH (RRI: 5,74 [2,83-11,7]) y B-TIMI (RRI: 3,68 [0,88-15,3]). La enfermedad polivascular (3 territorios, RRI: 5,6 [2,2-14,25]), la albuminuria (RRI: 3,55 [2,06-6,11]) y la insuficiencia cardíaca (RRI: 3,11 [1,34-7,25]) también incrementaron el riesgo. La capacidad discriminativa (índice C de Harrell) fue baja, pero mejoró tras añadir la albuminuria y la enfermedad polivascular. Ambas variables también mejoraron el rendimiento del modelo base (cIRN: 0,326 [0,036; 0,607]) (AU)

Background and aims: There is no consensus regarding risk stratification tools for secondary prevention in atherosclerotic cardiovascular disease. Our aim was to compare the discriminative performance of the Framingham, REGICOR, SCORE, and REACH risk functions and the Bohula-TIMI and SMART risk scores, as well as to assess the potential added value of other clinical variables for the prediction of recurrent events in patients with established vascular disease. Methods: A cohort of 269 patients with established vascular disease (52.8% coronary, 32% cerebrovascular, 15.2% peripheral artery disease) was included. The survival functions of risk groups (low/medium/high) according to commonly used cutoff points for each function/score were compared, and hazard ratios (HR) for each were estimated using Cox regression. We calculated Δ Harrell's C statistic, cat-NRI, and cNRI after adding new predictors to a base model including age, sex, total cholesterol, current smoking status, hypertension, and diabetes. Results: After 6 years of follow-up (median 4.82 years), 61 events occurred (23%). High-risk groups had a higher risk of recurrent event: SMART (HR: 3.17 [1.55-6.5]), Framingham (HR: 3.08 [1.65-5.75]), REGICOR (HR: 2.71 [1.39-5.27]), SCORE (HR: 2.14 [1.01-4.5], REACH (HR: 5.74 [2.83-11.7]), B-TIMI (HR: 3.68 [0.88-15.3]). Polyvascular disease (3 territories HR: 5.6 [2.2-14.25]), albuminuria (HR: 3.55 [2.06-6.11]), and heart failure (HR: 3.11 [1.34-7.25]) also increased risk. Discrimination (Harrell's C) was low but improved after adding albuminuria and polyvascular disease. Both variables also improved the performance of the base model (cNRI: 0.326 [0.036; 0.607]). Conclusions: The Framingham, REGICOR, SCORE, and REACH functions and the B-TIMI and SMART scores showed low yet similar performance in secondary prevention. Albuminuria and polyvascular disease improved the predictive performance of major classical cardiovascular risk factors (AU)

The impact of frailty on mortality in non-surgical head and neck cancer treatment: Shifting the clinical paradigm.

OBJECTIVE: Compare survival of head and neck cancer (HNC) patients treated with surgical or non-surgical management according to frailty, quantify frailty with the Risk Analysis Index (RAI), a validated 14-item instrument. MATERIALS AND METHODS: Prospective cohort study of newly diagnosed HNC patients (≥18 years) who had frailty assessment from April 13, 2016 to September 30, 2016. Primary outcome was overall survival at 1- and 3-years. Cox proportional hazard models were utilized to examine mortality with predictor variables. Adjusted and unadjusted (Kaplan-Meier) survival curves stratified by either RAI scores or treatment modality were plotted. Kruskal-Wallis and likelihood ratio chi-square tests were used for comparing clinicodemographic variables. RESULTS: Of 165 patients, 54 (32.7%) were managed non-surgically, 49 (29.7%) were treated with definitive surgery only, and 62 (37.6%) were treated with multimodality (surgery + adjuvant) therapy. Among the full cohort and subgroup analysis of the frail/very frail (RAI ≥ 37), non-surgical patients had worse or similar 3-year survival than those treated with surgery +/- adjuvant therapy. Multivariable Cox proportional hazard models demonstrate that frail patients treated non-surgically experienced worse survival than their counterparts treated with surgery (HR = 2.50, p = 0.015, 95% CI: 1.19, 5.23) or multimodality therapy (HR = 3.91, p < 0.001, 95% CI: 1.94-7.89). CONCLUSION: Across all levels of frailty, long term survival of HNC patients treated without surgery is either worse than or like those treated with surgery. These findings (1) challenge current practices of steering patients "too frail for surgery" towards non-surgical, "non-invasive" therapy, and (2) suggest equipoise warranting randomized trials to clarify treatment of frail patients.

Albuminuria and polyvascular disease improve multivariate predictive models after an acute cardiovascular event. The AIRVAG cohort.

BACKGROUND AND AIMS: There is no consensus regarding risk stratification tools for secondary prevention in atherosclerotic cardiovascular disease. Our aim was to compare the discriminative performance of the Framingham, REGICOR, SCORE, and REACH risk functions and the Bohula-TIMI and SMART risk scores, as well as to assess the potential added value of other clinical variables for the prediction of recurrent events in patients with established vascular disease. METHODS: A cohort of 269 patients with established vascular disease (52.8% coronary, 32% cerebrovascular, 15.2% PAD) was included. The survival functions of risk groups (low/medium/high) according to commonly used cutoff points for each function/score were compared, and hazard ratios for each were estimated using Cox regression. We calculated Δ Harrell's C statistic, cat-NRI, and cNRI after adding new predictors to a base model including age, sex, total cholesterol, current smoking status, hypertension, and diabetes. RESULTS: After six years of follow-up (median 4.82 years), 61 events occurred (23%). High-risk groups had a higher risk of recurrent event: SMART (HR: 3.17 [1.55-6.5]), Framingham (HR: 3.08 [1.65-5.75]), REGICOR (HR: 2.71 [1.39-5.27]), SCORE (HR: 2.14 [1.01-4.5], REACH (HR: 5.74 [2.83-11.7]), B-TIMI (HR: 3.68 [0.88-15.3]). Polyvascular disease (three territories HR: 5.6 [2.2-14.25]), albuminuria (HR: 3.55 [2.06-6.11]), and heart failure (HR: 3.11 [1.34-7.25]) also increased risk. Discrimination (Harrell's C) was low but improved after adding albuminuria and polyvascular disease. Both variables also improved the performance of the base model (cNRI.326 [.036; .607]). CONCLUSIONS: The Framingham, REGICOR, SCORE, and REACH functions and the B-TIMI and SMART scores showed low yet similar performance in secondary prevention. Albuminuria and polyvascular disease improved the predictive performance of major classical cardiovascular risk factors.

Periodontitis as a Risk Factor for Rheumatoid Arthritis: a Matched-Cohort Study.

OBJECTIVE: The intent was to analyse the association of periodontitis with the development of rheumatoid arthritis (RA) using a representative population-based cohort and longitudinal matched-cohort design. METHODS: Participants were 40 years of age or older and had not been diagnosed with RA between 2002 and 2006. Among the participants, those who were newly diagnosed with periodontitis between 2004 and 2006 (excluding cases that had already been diagnosed with periodontitis between 2002 and 2003) were allotted to the periodontitis group. Among the participants, those who had never been diagnosed with periodontitis between 2002 and 2006 formed the control group, matched by sex, age, and household income at a 1:1 ratio. From 2007 to 2018, the 2 groups (n = 691,506) were followed to monitor the development of RA. The t-test and χ2 test compared the general characteristics and health-related variables of both groups. The Kaplan-Meier method with a log-rank test was conducted to compare the incidence of RA in both groups. The hazard ratio (HR) and adjusted hazard ratio (aHR) were calculated using a Cox proportional hazard regression analysis to evaluate the risk of subsequent RA. RESULTS: Univariate analysis revealed that the periodontitis group was more likely to develop RA than the control group (hazard ratio 1.10), and multivariate analysis also revealed a higher incidence risk of RA (adjusted hazard ratio 1.09) in the periodontitis group. CONCLUSIONS: Our findings demonstrate that periodontitis is associated with an increased risk of developing RA.

Metformin usage and the risk of colorectal cancer: a national cohort study.

PURPOSE: This study aimed to investigate the association between metformin usage and the risk of colorectal cancer (CRC) using data from the Korean National Health Insurance Service-National Health Screening Cohort database. METHODS: Data from the NHIS-HEALS cohort between 2002 and 2015 were longitudinally analyzed. Subjects were divided into three groups: metformin non-users with diabetes mellitus (DM), metformin users with DM, and no DM group. CRC was defined using the ICD-10 code (C18.0-C20.0) at the time of admission. Cox proportional hazard regression models were adopted after stepwise adjustment for confounders to investigate the association between metformin usage and colorectal cancer risk. RESULTS: During the follow-up period, of the total 323,430 participants, 2341 (1.33%) of the 175,495 males and 1204 (0.81%) of the 147,935 females were newly diagnosed with CRC. The estimated cumulative incidence of CRC was significantly different among the three groups based on Kaplan-Meier's survival curve (p values < 0.05 in both sexes). Compared with metformin non-users, hazard ratios (95% CIs) of metformin users and the no DM group were 0.66 (0.51-0.85) and 0.72 (0.61-0.85) in males and 0.59 (0.37-0.92) and 0.93 (0.66-1.29) in females, respectively, after being fully adjusted. CONCLUSIONS: Metformin users with diabetes appear to have a significantly lower risk of CRC compared with metformin non-users.

Assessing the Survival Benefit of Surgery and Various Types of Radiation Therapy for Treatment of Hepatocellular Carcinoma: Evidence from the Surveillance, Epidemiology, and End Results Registries.

OBJECTIVE: To evaluate the survival benefit of surgery and radiation for hepatocellular carcinoma (HCC) after adjusting for patient-specific and tumor-specific factors. METHODS: This study analyzed HCC patients who enrolled in the Surveillance, Epidemiology, and End Results (SEER) registry between January 2004 and December 2013. Of the 5552 HCC patients, 4597 received surgery and 955 received radiation. Patients who received radiation were further divided into 3 subgroups: 541 who received beam radiation (BR), 197 who received radioactive implants (RI), and 217 who received radioisotopes (RIT). Propensity score weighting analysis derived from generalized boosted models (GBMs) was performed to ensure well-balanced characteristics in all comparison groups. RESULTS: Overall survival rates and HCC-specific survival rates were higher in those receiving surgery compared with those receiving radiotherapy. This was confirmed by Cox proportional hazard regression both before and after inverse probability of treatment weighting (IPTW). Before IPTW, the RIT group had a better outcome than the BR group in terms of overall and HCC-specific survival rates, but there was no significant difference between the RI and BR groups. After IPTW, Cox proportional hazard regression demonstrated that both the RIT and RI groups had higher survival rates than the BR group. CONCLUSION: In HCC patients, surgery was associated with higher survival rates compared with radiotherapy while adjusting for other factors. Among those who received radiotherapy, RIT and RI granted survival benefits.

Outcomes of a nine-month regimen for rifampicin-resistant tuberculosis up to 24 months after treatment completion in nine African countries.

BACKGROUND: Treatment outcomes of the shorter regimen for rifampicin-resistant tuberculosis are not completely established. We report on these outcomes two years after treatment completion among patients enrolled in an observational cohort study in nine African countries. METHODS: 1,006 patients treated with the nine-month regimen were followed every six months with sputum cultures up to 24 months after treatment completion. The risk of any unfavourable outcome, of failure and relapse, and of death during and after treatment was analysed according to patient's characteristics and initial drug susceptibility by Cox proportional hazard models. FINDINGS: Respectively 67.8% and 57.2% patients had >=1 culture result six months and 12 months after treatment completion. Fourteen relapses were diagnosed. The probability of relapse-free success was 79.3% (95% confidence interval [CI] 76.6-82.0%) overall, 80.9% (95% CI 78.0-84.0%) among HIV-negative and 72.5% (95% CI 66.5-78.9%) among HIV-infected patients. Initial fluoroquinolone (adjusted hazard ratio [aHR] 6.7 [95% CI 3.4-13.1]) and isoniazid resistance (aHR 9.4 [95% CI 1.3-68.0]) were significantly associated with increased risk of failure/relapse and of any unfavourable outcome. INTERPRETATION: The close to 80% relapse-free success indicates the good outcome of the regimen in low-and middle-income settings. Results confirm the lesser effectiveness of the regimen in patients with initial resistance to fluoroquinolones and support the use of high-dose isoniazid, but do not support exclusion of patients for resistance to drugs other than fluoroquinolones. FUNDING: Expertise-France and Agence Française de Développement.

Serum Uric Acid is Associated with Renal Prognosis of Lupus Nephritis in Women but not in Men.

Lupus nephritis (LN) is a major complication of systemic lupus erythematosus. Early intervention in lupus nephritis improves prognosis. There is an association between hyperuricemia and lupus nephritis; nevertheless, the sex-specific role of uric acid in lupus nephritis remains unclear. We retrospectively analyzed 578 patients diagnosed with LN by renal biopsy. We determine the relationship of serum uric acid to progression of LN using Kaplan-Meier survival analyses and Cox proportional hazards models. The primary end point was LN progression defined as the initiation of dialysis or kidney transplantation. Men had higher mean serum uric acid levels than did women. Every 1 mg/dL increase in baseline uric acid level increased the risk of LN progression by 15.1%. The serum uric acid level was an independent risk factor for LN progression in women (hazard ratio [HR], 1.158; confidence interval [CI], 1.018-1.317; p = 0.028) but not in men (HR, 1.499; CI, 0.964-2.331; p = 0.072). Sensitivity analysis involving serum uric acid terciles generated consistent and robust results. Serum uric acid level was an independent risk factor for LN progression in women but not in men.

Individual and joint effects of metformin and statins on mortality among patients with high-risk prostate cancer.

BACKGROUND: Pre-clinical studies suggest that metformin and statins may delay prostate cancer (PCa) metastases; however, data in humans are limited. To the best of our knowledge, this is the first human study aimed to quantify the individual and joint effects of statin and metformin use among patients with high-risk PCa. METHODS: This population-based retrospective cohort study identified patients from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Exposure to metformin and statins was ascertained from Medicare Prescription Drug Event files. The association with all-cause and PCa mortality were evaluated using Cox proportional hazard model with competing causes of death, where propensity scores were used to adjusted imbalances in covariates across groups. RESULTS: Based on 12 700 patients with high-risk PCa, statin alone or in combination with metformin was significantly associated with reduced all-cause mortality (Hazard Ratio [HR]: 0.89; 95% Confidence Interval [CI]: 0.83, 0.96; and HR: 0.75; 95% CI, 0.67-0.83, respectively) and PCa mortality (HR, 0.80; 95% CI: 0.69, 0.92) and 0.64; 95% CI, d 0.51-0.81, respectively. The effects were more pronounced in post-diagnostic users: combination use of metformin/statins was associated with a 32% reduction in all-cause mortality (95% CI, 0.57-0.80), and 54% reduction in PCa mortality (95% CI, 0.30-0.69). No significant association of metformin alone was observed with either all-cause mortality or PCa mortality. CONCLUSIONS: Statin use alone or in combination with metformin was associated with lower all-cause and PCa mortality among high-risk patients, particularly in post-diagnostic settings; further studies are warranted.

Black/white differences in mortality among veteran and non-veteran males.

U.S. military veterans are a large and racially heterogeneous population. There are reasons to expect that racial disparities in mortality among veterans are smaller than those for non-veterans. For example, blacks are favorably selected into the military, receive relatively equitable treatment within the military, and after service accrue higher socioeconomic status and receive health and other benefits after service. Using the 1997-2009 National Health Interview Survey (N = 99,063) with Linked Mortality Files through the end of 2011 (13,691 deaths), we fit Cox proportional hazard models to estimate whether racial disparities in the risk of death are smaller for veterans than for non-veterans. We find that black/white disparities in mortality are smaller for veterans than for non-veterans, and that this is explained by the elevated socioeconomic resources of black veterans relative to black non-veterans. Leveraging birth cohort differences in military periods, we document that the smaller disparities are concentrated among All-Volunteer era veterans.

Partially linear mixed-effects joint models for skewed and missing longitudinal competing risks outcomes.

Longitudinal competing risks data frequently arise in clinical studies. Skewness and missingness are commonly observed for these data in practice. However, most joint models do not account for these data features. In this article, we propose partially linear mixed-effects joint models to analyze skew longitudinal competing risks data with missingness. In particular, to account for skewness, we replace the commonly assumed symmetric distributions by asymmetric distribution for model errors. To deal with missingness, we employ an informative missing data model. The joint models that couple the partially linear mixed-effects model for the longitudinal process, the cause-specific proportional hazard model for competing risks process and missing data process are developed. To estimate the parameters in the joint models, we propose a fully Bayesian approach based on the joint likelihood. To illustrate the proposed model and method, we implement them to an AIDS clinical study. Some interesting findings are reported. We also conduct simulation studies to validate the proposed method.

Increased Risk Of Type 2 Diabetes And Abnormal FPG Due To Shift Work Differs According To Gender: A Retrospective Cohort Study Among Thai Workers In Bangkok, Thailand.

PURPOSE: The gender differential evidence of the association between shift work and type 2 diabetes risk remains scarce. This longitudinal study determines whether the association between shift-work exposure and type 2 diabetes risk and abnormal fasting plasma glucose (FPG) differs according to gender; the study aims to find the association between shift work and changes in physiological, behavioral, and psychosocial stress. PATIENTS AND METHODS: This retrospective cohort study was conducted among 5947 workers (4647 female and 1300 male) aged ≤60 years old in Bangkok, Thailand. Participants required a normal FPG level (<100 mg/dL) at baseline and at least two health check-up results from 2009 to 2016. Shift-work exposure history was assessed using a self-administered questionnaire; FPG levels were measured annually. Cox proportional hazard models were used to assess the aforementioned association. RESULTS: During the follow-up period, 1470 new abnormal FPG and 154 new type 2 diabetes cases developed. Stratified analysis of male workers' data revealed an association was significant in the unadjusted model, which tended to be stronger after adjustment for demographic data and the baseline values of anthropometric and biochemical parameters. This was the case both for type 2 diabetes [Hazard Ratio (HR) (95% Confidence Interval (CI))=2.98 (1.58-5.62)] and abnormal FPG [HR (95% CI)=1.86 (1.43-2.41)]; this association was less obvious among women. CONCLUSION: Shift work is a risk factor for type 2 diabetes and abnormal FPG; this risk is gender differential, being more pronounced in men. Preventive measures aiming at ameliorating shift work induced type 2 diabetes risk should pay more attention to men.