Universidad de La Frontera

Janjigian Y.Y., Shitara K., Moehler M., Garrido M., Salman P., Shen L., Wyrwicz L., Yamaguchi K., Skoczylas T., Campos Bragagnoli A., Liu T., Schenker M., Yanez P., Tehfe M., Kowalyszyn R., et. al.

SummaryBackground First-line chemotherapy for advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastro-oesophageal junction adenocarcinoma has a median overall survival (OS) of less than 1 year. We aimed to evaluate first-line programmed cell death (PD)-1 inhibitor-based therapies in gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma. We report the first results for nivolumab plus chemotherapy versus chemotherapy alone. Methods In this multicentre, randomised, open-label, phase 3 trial (CheckMate 649), we enrolled adults (≥18 years) with previously untreated, unresectable, non-HER2-positive gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma, regardless of PD-ligand 1 (PD-L1) expression from 175 hospitals and cancer centres in 29 countries. Patients were randomly assigned (1:1:1 while all three groups were open) via interactive web response technology (block sizes of six) to nivolumab (360 mg every 3 weeks or 240 mg every 2 weeks) plus chemotherapy (capecitabine and oxaliplatin every 3 weeks or leucovorin, fluorouracil, and oxaliplatin every 2 weeks), nivolumab plus ipilimumab, or chemotherapy alone. Primary endpoints for nivolumab plus chemotherapy versus chemotherapy alone were OS or progression-free survival (PFS) by blinded independent central review, in patients whose tumours had a PD-L1 combined positive score (CPS) of five or more. Safety was assessed in all patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT02872116. Findings From March 27, 2017, to April 24, 2019, of 2687 patients assessed for eligibility, we concurrently randomly assigned 1581 patients to treatment (nivolumab plus chemotherapy [n=789, 50%] or chemotherapy alone [n=792, 50%]). The median follow-up for OS was 13·1 months (IQR 6·7–19·1) for nivolumab plus chemotherapy and 11·1 months (5·8–16·1) for chemotherapy alone. Nivolumab plus chemotherapy resulted in significant improvements in OS (hazard ratio [HR] 0·71 [98·4% CI 0·59–0·86]; p

Yusuf S., Joseph P., Rangarajan S., Islam S., Mente A., Hystad P., Brauer M., Kutty V.R., Gupta R., Wielgosz A., AlHabib K.F., Dans A., Lopez-Jaramillo P., Avezum A., Lanas F., et. al.

SummaryBackground Global estimates of the effect of common modifiable risk factors on cardiovascular disease and mortality are largely based on data from separate studies, using different methodologies. The Prospective Urban Rural Epidemiology (PURE) study overcomes these limitations by using similar methods to prospectively measure the effect of modifiable risk factors on cardiovascular disease and mortality across 21 countries (spanning five continents) grouped by different economic levels. Methods In this multinational, prospective cohort study, we examined associations for 14 potentially modifiable risk factors with mortality and cardiovascular disease in 155 722 participants without a prior history of cardiovascular disease from 21 high-income, middle-income, or low-income countries (HICs, MICs, or LICs). The primary outcomes for this paper were composites of cardiovascular disease events (defined as cardiovascular death, myocardial infarction, stroke, and heart failure) and mortality. We describe the prevalence, hazard ratios (HRs), and population-attributable fractions (PAFs) for cardiovascular disease and mortality associated with a cluster of behavioural factors (ie, tobacco use, alcohol, diet, physical activity, and sodium intake), metabolic factors (ie, lipids, blood pressure, diabetes, obesity), socioeconomic and psychosocial factors (ie, education, symptoms of depression), grip strength, and household and ambient pollution. Associations between risk factors and the outcomes were established using multivariable Cox frailty models and using PAFs for the entire cohort, and also by countries grouped by income level. Associations are presented as HRs and PAFs with 95% CIs. Findings Between Jan 6, 2005, and Dec 4, 2016, 155 722 participants were enrolled and followed up for measurement of risk factors. 17 249 (11·1%) participants were from HICs, 102 680 (65·9%) were from MICs, and 35 793 (23·0%) from LICs. Approximately 70% of cardiovascular disease cases and deaths in the overall study population were attributed to modifiable risk factors. Metabolic factors were the predominant risk factors for cardiovascular disease (41·2% of the PAF), with hypertension being the largest (22·3% of the PAF). As a cluster, behavioural risk factors contributed most to deaths (26·3% of the PAF), although the single largest risk factor was a low education level (12·5% of the PAF). Ambient air pollution was associated with 13·9% of the PAF for cardiovascular disease, although different statistical methods were used for this analysis. In MICs and LICs, household air pollution, poor diet, low education, and low grip strength had stronger effects on cardiovascular disease or mortality than in HICs. Interpretation Most cardiovascular disease cases and deaths can be attributed to a small number of common, modifiable risk factors. While some factors have extensive global effects (eg, hypertension and education), others (eg, household air pollution and poor diet) vary by a country's economic level. Health policies should focus on risk factors that have the greatest effects on averting cardiovascular disease and death globally, with additional emphasis on risk factors of greatest importance in specific groups of countries. Funding Full funding sources are listed at the end of the paper (see Acknowledgments).

Janjigian Y.Y., Kawazoe A., Yañez P., Li N., Lonardi S., Kolesnik O., Barajas O., Bai Y., Shen L., Tang Y., Wyrwicz L.S., Xu J., Shitara K., Qin S., Van Cutsem E., et. al.

Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) amplification or overexpression occurs in approximately 20% of advanced gastric or gastro-oesophageal junction adenocarcinomas1–3. More than a decade ago, combination therapy with the anti-HER2 antibody trastuzumab and chemotherapy became the standard first-line treatment for patients with these types of tumours4. Although adding the anti-programmed death 1 (PD-1) antibody pembrolizumab to chemotherapy does not significantly improve efficacy in advanced HER2-negative gastric cancer5, there are preclinical6–19 and clinical20,21 rationales for adding pembrolizumab in HER2-positive disease. Here we describe results of the protocol-specified first interim analysis of the randomized, double-blind, placebo-controlled phase III KEYNOTE-811 study of pembrolizumab plus trastuzumab and chemotherapy for unresectable or metastatic, HER2-positive gastric or gastro-oesophageal junction adenocarcinoma22 ( https://clinicaltrials.gov , NCT03615326). We show that adding pembrolizumab to trastuzumab and chemotherapy markedly reduces tumour size, induces complete responses in some participants, and significantly improves objective response rate. Interim analysis of a phase III clinical trial of HER2-positive gastric adenocarinoma shows pembrolizumab plus trastuzumab and chemotherapy improves response rates compared with trastuzumab and chemotherapy alone.

Dagenais G.R., Leong D.P., Rangarajan S., Lanas F., Lopez-Jaramillo P., Gupta R., Diaz R., Avezum A., Oliveira G.B., Wielgosz A., Parambath S.R., Mony P., Alhabib K.F., Temizhan A., Ismail N., et. al.

To our knowledge, no previous study has prospectively documented the incidence of common diseases and related mortality in high-income countries (HICs), middle-income countries (MICs), and low-income countries (LICs) with standardised approaches. Such information is key to developing global and context-specific health strategies. In our analysis of the Prospective Urban Rural Epidemiology (PURE) study, we aimed to evaluate differences in the incidence of common diseases, related hospital admissions, and related mortality in a large contemporary cohort of adults from 21 HICs, MICs, and LICs across five continents by use of standardised approaches.The PURE study is a prospective, population-based cohort study of individuals aged 35-70 years who have been enrolled from 21 countries across five continents. The key outcomes were the incidence of fatal and non-fatal cardiovascular diseases, cancers, injuries, respiratory diseases, and hospital admissions, and we calculated the age-standardised and sex-standardised incidence of these events per 1000 person-years.This analysis assesses the incidence of events in 162 534 participants who were enrolled in the first two phases of the PURE core study, between Jan 6, 2005, and Dec 4, 2016, and who were assessed for a median of 9·5 years (IQR 8·5-10·9). During follow-up, 11 307 (7·0%) participants died, 9329 (5·7%) participants had cardiovascular disease, 5151 (3·2%) participants had a cancer, 4386 (2·7%) participants had injuries requiring hospital admission, 2911 (1·8%) participants had pneumonia, and 1830 (1·1%) participants had chronic obstructive pulmonary disease (COPD). Cardiovascular disease occurred more often in LICs (7·1 cases per 1000 person-years) and in MICs (6·8 cases per 1000 person-years) than in HICs (4·3 cases per 1000 person-years). However, incident cancers, injuries, COPD, and pneumonia were most common in HICs and least common in LICs. Overall mortality rates in LICs (13·3 deaths per 1000 person-years) were double those in MICs (6·9 deaths per 1000 person-years) and four times higher than in HICs (3·4 deaths per 1000 person-years). This pattern of the highest mortality in LICs and the lowest in HICs was observed for all causes of death except cancer, where mortality was similar across country income levels. Cardiovascular disease was the most common cause of deaths overall (40%) but accounted for only 23% of deaths in HICs (vs 41% in MICs and 43% in LICs), despite more cardiovascular disease risk factors (as judged by INTERHEART risk scores) in HICs and the fewest such risk factors in LICs. The ratio of deaths from cardiovascular disease to those from cancer was 0·4 in HICs, 1·3 in MICs, and 3·0 in LICs, and four upper-MICs (Argentina, Chile, Turkey, and Poland) showed ratios similar to the HICs. Rates of first hospital admission and cardiovascular disease medication use were lowest in LICs and highest in HICs.Among adults aged 35-70 years, cardiovascular disease is the major cause of mortality globally. However, in HICs and some upper-MICs, deaths from cancer are now more common than those from cardiovascular disease, indicating a transition in the predominant causes of deaths in middle-age. As cardiovascular disease decreases in many countries, mortality from cancer will probably become the leading cause of death. The high mortality in poorer countries is not related to risk factors, but it might be related to poorer access to health care.Full funding sources are listed at the end of the paper (see Acknowledgments).

Hua F., Bruijnzeel L.A., Meli P., Martin P.A., Zhang J., Nakagawa S., Miao X., Wang W., McEvoy C., Peña-Arancibia J.L., Brancalion P.H., Smith P., Edwards D.P., Balmford A.

Forest restoration is being scaled up globally to deliver critical ecosystem services and biodiversity benefits; however, there is a lack of rigorous comparison of cobenefit delivery across different restoration approaches. Through global synthesis, we used 25,950 matched data pairs from 264 studies in 53 countries to assess how delivery of climate, soil, water, and wood production services, in addition to biodiversity, compares across a range of tree plantations and native forests. Benefits of aboveground carbon storage, water provisioning, and especially soil erosion control and biodiversity are better delivered by native forests, with compositionally simpler, younger plantations in drier regions performing particularly poorly. However, plantations exhibit an advantage in wood production. These results underscore important trade-offs among environmental and production goals that policy-makers must navigate in meeting forest restoration commitments.

Tortella G.R., Rubilar O., Durán N., Diez M.C., Martínez M., Parada J., Seabra A.B.

Silver nanoparticles (AgNPs) have attracted remarkable attention due to their powerful antimicrobial action as well as their particular physicochemical properties. This has led to their application in a wide variety of products with promising results. However, their interaction with the environment and toxicity in live terrestrial or aquatic organisms is still a matter of intense debate. More detailed knowledge is still required about the toxicity of AgNPs, their possible uptake mechanisms and their adverse effects in live organisms. Several studies have reported the interactions and potential negative effects of AgNPs in different organisms. In this review, we report and discuss the current state of the art and perspectives for the impact of AgNPs on different organisms present in the environment. Recent progress in interpreting uptake, translocation and accumulation mechanisms in different organisms and/or living animals are discussed, as well as the toxicity of AgNPs and possible tolerance mechanisms in live organisms to cope with their deleterious effects. Finally, we discuss the challenges of accurate physicochemical characterization of AgNPs and their ecotoxicity in environmentally realistic conditions such as soil and water media.

Iwanaga J., Singh V., Ohtsuka A., Hwang Y., Kim H., Moryś J., Ravi K.S., Ribatti D., Trainor P.A., Sañudo J.R., Apaydin N., Şengül G., Albertine K.H., Walocha J.A., Loukas M., et. al.

Research within the anatomical sciences often relies on human cadaveric tissues. Without the good will of these donors who allow us to use their bodies to push forward our anatomical knowledge, most human anatomical research would come to a standstill. However, many research papers omit an acknowledgement to the donor cadavers or, as no current standardized versions exist, use language that is extremely varied. To remedy this problem, 20 editors-in-chiefs from 17 anatomical journals joined together to put together official recommendations that can be used by authors when acknowledging the donor cadavers used in their studies. The goal of these recommendations is to standardize the writing approach by which donors are acknowledged in anatomical studies that use human cadaveric tissues. Such sections in anatomical papers will not only rightfully thank those who made the donation but might also encourage, motivate, and inspire future individuals to make such gifts for the betterment of the anatomical sciences and patient care.

Reyes-Riveros R., Altamirano A., De La Barrera F., Rozas-Vásquez D., Vieli L., Meli P.

Public urban green spaces provide people with many benefits. Understanding the relationship between public urban green spaces’ characteristics and human well-being components may assist in future planning and design of these spaces. This study performed a systematic bibliographic review to analyse the relationships between green spaces' specific characteristics and human well-being components. The green spaces characteristics found in 153 articles were divided in four groups: structure, biodiversity, naturalness , and others; while dimensions of human well-being were divided into four groups: health, security, good social relations, and freedom of choice and action. The number of green spaces and their percentage of vegetation cover and size (structure category) improved human well-being, in all aspects, especially in health. Structure and biodiversity are the characteristics most highly rated in the literature. These green spaces’ biodiversity and naturalness contribute to human well-being through improvements in health (particularly mental health) and good social relations. The most frequently methods used to assess the relationship of public urban green spaces and human well-being are mainly oriented towards studying perception of the green space’s users. This result highlights an opportunity to assess the congruence between methods evaluating perception and objective measurement. Our findings may provide tools for decision-makers to integrate green spaces into planning, identifying specific characteristics of public urban green spaces that promote human well-being and to face climate change.

Seron P., Oliveros M., Gutierrez-Arias R., Fuentes-Aspe R., Torres-Castro R.C., Merino-Osorio C., Nahuelhual P., Inostroza J., Jalil Y., Solano R., Marzuca-Nassr G.N., Aguilera-Eguía R., Lavados-Romo P., Soto-Rodríguez F.J., Sabelle C., et. al.

Abstract Objective The purpose of this article was to summarize the available evidence from systematic reviews on telerehabilitation in physical therapy. Methods We searched Medline/PubMed, EMBASE, and Cochrane Library databases. In addition, the records in PROSPERO and Epistemonikos and PEDro were consulted. Systematic reviews of different conditions, populations, and contexts—where the intervention to be evaluated is telerehabilitation by physical therapy—were included. The outcomes were clinical effectiveness depending on specific condition, functionality, quality of life, satisfaction, adherence, and safety. Data extraction and risk of bias assessment were carried out by a reviewer with non-independent verification by a second reviewer. The findings are reported qualitatively in the tables and figures. Results Fifty-three systematic reviews were included, of which 17 were assessed as having low risk of bias. Fifteen reviews were on cardiorespiratory rehabilitation, 14 on musculoskeletal conditions, and 13 on neurorehabilitation. The other 11 reviews addressed other types of conditions and rehabilitation. Thirteen reviews evaluated with low risk of bias showed results in favor of telerehabilitation versus in-person rehabilitation or no rehabilitation, while 17 reported no differences between the groups. Thirty-five reviews with unclear or high risk of bias showed mixed results. Conclusions Despite the contradictory results, telerehabilitation in physical therapy could be comparable with in-person rehabilitation or better than no rehabilitation for conditions such as osteoarthritis, low-back pain, hip and knee replacement, and multiple sclerosis and also in the context of cardiac and pulmonary rehabilitation. It is imperative to conduct better quality clinical trials and systematic reviews. Impact Providing the best available evidence on the effectiveness of telerehabilitation to professionals, mainly physical therapists, will impact the decision-making process and therefore yield better clinical outcomes for patients, both in these times of the COVID-19 pandemic and in the future. The identification of research gaps will also contribute to the generation of relevant and novel research questions.

Shitara K., Ajani J.A., Moehler M., Garrido M., Gallardo C., Shen L., Yamaguchi K., Wyrwicz L., Skoczylas T., Bragagnoli A.C., Liu T., Tehfe M., Elimova E., Bruges R., Zander T., et. al.

Standard first-line chemotherapy results in disease progression and death within one year in most patients with human epidermal growth factor receptor 2 (HER2)-negative gastro-oesophageal adenocarcinoma1–4. Nivolumab plus chemotherapy demonstrated superior overall survival versus chemotherapy at 12-month follow-up in gastric, gastro-oesophageal junction or oesophageal adenocarcinoma in the randomized, global CheckMate 649 phase 3 trial5 (programmed death ligand-1 (PD-L1) combined positive score ≥5 and all randomized patients). On the basis of these results, nivolumab plus chemotherapy is now approved as a first-line treatment for these patients in many countries6. Nivolumab and the cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor ipilimumab have distinct but complementary mechanisms of action that contribute to the restoration of anti-tumour T-cell function and induction of de novo anti-tumour T-cell responses, respectively7–11. Treatment combining 1 mg kg−1 nivolumab with 3 mg kg−1 ipilimumab demonstrated clinically meaningful anti-tumour activity with a manageable safety profile in heavily pre-treated patients with advanced gastro-oesophageal cancer12. Here we report both long-term follow-up results comparing nivolumab plus chemotherapy versus chemotherapy alone and the first results comparing nivolumab plus ipilimumab versus chemotherapy alone from CheckMate 649. After the 24.0-month minimum follow-up, nivolumab plus chemotherapy continued to demonstrate improvement in overall survival versus chemotherapy alone in patients with PD-L1 combined positive score ≥5 (hazard ratio 0.70; 95% confidence interval 0.61, 0.81) and all randomized patients (hazard ratio 0.79; 95% confidence interval 0.71, 0.88). Overall survival in patients with PD-L1 combined positive score ≥ 5 for nivolumab plus ipilimumab versus chemotherapy alone did not meet the prespecified boundary for significance. No new safety signals were identified. Our results support the continued use of nivolumab plus chemotherapy as standard first-line treatment for advanced gastro-oesophageal adenocarcinoma. Results in the CheckMate 649 phase 3 trial for first-line combined nivolumab and chemotherapy treatment continue to show clinically meaningful efficacy in gastric, gastro-oesophageal junction or oesophageal adenocarcinoma after 24 months, with no new safety signals.