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HIV is one of the fastest evolving organisms known. It evolves about 1 million times faster than its host, humans. Because HIV establishes chronic infections, with continuous evolution, its divergence within a single infected human surpasses the divergence of the entire humanoid history. Yet, it is still the same virus, infecting the same cell types and using the same replication machinery year after year. Hence, one would think that most mutations that HIV accumulates are neutral. But the picture is more complicated than that. HIV evolution is also a clear example of strong positive selection, that is, mutants have a survival advantage. How do these facts come together?

Endovascular aneurysm repair for ruptured abdominal aortic aneurysm has been increasingly advocated due to short term benefits. Most observational studies point towards survival advantage for endovascular aneurysm repair over open repair. However, randomized clinical trials already performed did not support this data. The aim of this review is to compare post-operative outcomes between endovascular aneurysm repair and open surgery for the treatment of ruptured abdominal aortic aneurysms.MEDLINE databases were searched to access outcomes after endovascular aneurysm repair for ruptured abdominal aortic aneurysm and open repair for ruptured abdominal aneurysm repair. All the randomized controlled trials were included. Large and contemporary observational studies were also considered.Thirty day mortality ranged between 18% - 53% for endovascular aneurysm repair for ruptured abdominal aortic aneurysm and between 24% - 53% for open repair. Post-operative complications ranged between 33% - 77% for endovascular aneurysm repair for ruptured abdominal aortic aneurysm and 37% - 80% for open repair. In hospital stay ranged between 8.5 and 14.3 days for endovascular aneurysm repair for ruptured abdominal aortic aneurysm and between 12.2 and 20.5 days for open repair. Intensive care unit days ranged between 1.75 - 4.2 days for endovascular aneurysm repair for ruptured abdominal aortic aneurysm and 2.5 - 6.3 days for open repair.Survival benefit is found for endovascular aneurysm repair for ruptured abdominal aortic aneurysm in most observational studies, but those are not reproduced by randomized controlled trials data. However, endovascular aneurysm repair for ruptured abdominal aortic aneurysm showed less post-operative complications and hospitalization days.Endovascular aneurysm repair for ruptured abdominal aortic aneurysm should be considered as first line of treatment in centers with expertise and proper facilities.Introdução: O tratamento endovascular do aneurisma da aorta abdominal roto tem sido progressivamente preferido pelos potenciais benefícios de curto-prazo. A maioria dos estudos observacionais revela uma vantagem na sobrevida imediata para o tratamento endovascular do aneurisma da aorta abdominal roto, relativamente à cirurgia convencional. Contudo, os ensaios clínicos randomizados até hoje realizados não suportam estes resultados. Esta revisão tem por objetivo comparar os resultados do tratamento endovascular do aneurisma da aorta abdominal roto com cirurgia convencional no tratamento de aneurismas rotos. Materiais e Métodos: Bases de dados MEDLINE foram alvo de pesquisa no sentido de obter informação relativamente a resultados de curto prazo após correção de aneurisma roto por tratamento endovascular do aneurisma da aorta abdominal roto ou cirurgia convencional. Todos os ensaios clínicos randomizados foram incluídos. Estudos observacionais relevantes e contemporâneos foram também considerados. Resultados: Mortalidade aos 30 dias variou entre 18% - 53% para o tratamento endovascular do aneurisma da aorta abdominal roto e entre 24% - 53% para a cirurgia convencional. Complicações pós-operatórias variaram entre 33% - 77% para o tratamento endovascular do aneurisma da aorta abdominal roto e entre 37% - 80% para a cirurgia convencional. Tempo de internamento variou entre 8,5 e 14,3 dias para o tratamento endovascular do aneurisma da aorta abdominal roto e entre 12,2 e 20,5 para a cirurgia convencional. Número de dias em cuidados intensivos variou entre 1,75 - 4,2 para o tratamento endovascular do aneurisma da aorta abdominal roto e entre 2,5 - 6,3 para a cirurgia convencional. Discussão: Vantagem na sobrevida é descrita para o tratamento endovascular do aneurisma da aorta abdominal roto nos estudos observacionais, mas estes dados não foram reproduzidos nos ensaios clínicos randomizados realizados. Contudo, o tratamento endovascular do aneurisma da aorta abdominal roto cursa com menos complicações pós-operatórias e dias de internamento. Conclusão: O tratamento endovascular do aneurisma da aorta abdominal roto deve ser considerado como primeira linha de tratamento em instituições de elevada experiência e com infra-estruturas adequadas.

Summary Ageing of haematopoietic stem cells (HSC) contributes to deficits in the aged haematopoietic system. HSC decline is driven in part by DNA damage accumulation, yet how aging impacts the acute DNA damage response (DDR) of HSCs is poorly understood. We show that old HSCs exhibit diminished ATM activity and attenuated DDR leading to elevated clonal survival in response to a range of genotoxins that was underwritten by diminished apoptotic priming. Distinct HSC subsets exhibited ageing-dependent and subtype-dependent differences in apoptotic priming and survival in response to DNA damage. The defective DDR of old HSCs was non-cell autonomous as ATM signalling, and clonal survival in response to DNA damage could be restored to levels observed in young HSCs post-transplantation into young recipients. These data suggest that defective DDR and diminished apoptotic priming provide a selective advantage to old HSCs that may contribute to mutation accrual and disease predisposition.

Rating the relevance of words for survival in the grasslands of a foreign land often leads to a memory advantage. However, it is as yet unclear whether the survival processing effect generalizes to source memory. Here, we examined whether people have enhanced source memory for the survival context in which an item has been encountered. Participants were asked to make survival-based or moving-based decisions about items prior to a classical source memory test. A multinomial model was used to measure old-new discrimination, source memory, and guessing biases separately. We replicated the finding of a survival advantage in old-new recognition. Extending previous results, we also found a survival-processing advantage in source memory. These results are in line with the richness-of-encoding explanation of the survival processing advantage and with an adaptive perspective on memory.

Organisms that evolved nervous systems that predict, detect, and assess ecological dangers are at a distinct survival advantage compared to those with less sophisticated neural machinery. The strategies generated and honed by adaptive survival circuits in humans, which we call the survival optimization system (SOS), are controlled by both conscious and implicit systems.

Transcatheter aortic valve implantation (TAVI) for severe aortic stenosis (AS) is the first area of interventional cardiology where women are treated as often as men. In this analysis of the gender specific results of randomised controlled trials (RCTs) comparing TAVI with surgical aortic valve replacement (SAVR) we aimed to determine whether gender affects the survival comparison between TAVI and SAVR. We identified all RCTs comparing TAVI versus SAVR for severe AS and reporting 1 and/or 2year survival. Summary odds ratios (ORs) were obtained using a random-effects model. Heterogeneity was assessed using the Q statistic and I 2 . Four RCTs met the criteria, totalling 3758 patients, 1706 women and 2052 men. Amongst females, TAVI recipients had a significantly lower mortality than SAVR recipients, at 1year (OR 0.68; 95%CI 0.50 to 0.94) and at 2years (OR 0.74; 95%CI 0.58 to 0.95). Amongst males there was no difference in mortality between TAVI and SAVR, at 1year (OR 1.09; 95%CI 0.86 to 1.39) or 2years (OR 1.05; 95%CI 0.85 to 1.3). The difference in treatment effect between genders was significant at both 1year (p interaction =0.02) and 2years (p interaction =0.04). In women TAVI has a 26 to 31% lower mortality odds than SAVR. In men, there is no difference in mortality between TAVI and SAVR.

Leukocyte telomere length (LTL) represents a key integrating component of the cumulative effects of environmental, lifestyle, and genetic factors. A question, however, remains on whether LTL can be considered predictive for a longer and healthier life. Within the elderly prospective TRELONG cohort (n = 612), we aimed to investigate LTL as a predictor of longevity and identify the main determinants of LTL among many different factors (physiological and lifestyle characteristics, physical performance and frailty measures, chronic diseases, biochemical measurements and apolipoprotein E genotyping). We found an ever-increasing relationship between LTL quartiles and survival. Hazard ratio analysis showed that for each unit increase in LTL and Short Physical Performance Battery (SPPB) scores, the mortality risk was reduced by 22.41% and 8.78%, respectively. Conversely, male gender, Charlson Comorbidity Index, and age threatened survival, with mortality risk growing by 74.99%, 16.57% and 8.5%, respectively. Determinants of LTL elongation were SPPB scores (OR = 1.1542, p = 0.0066) and years of education (OR = 1.0958, p = 0.0065), while male gender (OR = 0.4388, p = 0.0143) and increased Disease Count Index (OR = 0.6912, p = 0.0066) were determinants of LTL attrition. Longer LTL predicts a significant survival advantage in elderly people. By identifying determinants of LTL elongation, we provided additional knowledge that could offer a potential translation into prevention strategies.

The ability of plants to exert health benefits beyond antioxidant and micronutrient capacity introduces a gap in scientific understanding. The xenohormesis hypothesis aims to fill this gap, proposing that an evolutionary adaptation of enzyme and receptor pathways allow us to react to information that plants provide about the environment, offering a distinct survival advantage. The concept suggests that phytochemicals produced by plants under stress are able to activate longevity pathways in other organisms when consumed. The same pathways activated by calorie restriction, the highly conserved sirtuin enzymes and cellular homeostasis mechanisms provide an exciting perspective for treating chronic conditions related to excessive consumption. Harnessing the biological activity associated with the xenohormesis paradigm could provide a simple and achievable therapeutic alternative, although it needs to be considered within the confounding framework. The objective of this paper is to provide an update on the role of xenohormesis within nutritional medicine and to discuss the impact of modern food supply and consumption practices on evolutionary processes.

An editorial is presented which addresses the relationship between late maternal age at childbirth and the likelihood of living to age 90, and it mentions predictors of longevity for women in America. The risk of childhood-related death for older pregnant women is examined, along with the U.S. Women's Health Initiative, leukocyte telomeres, and additional factors such as educational attainment and higher income among women.

Aim This trial aimed to determine wether postoperative radioactive iodine(RAI) associated with a survival benefit among intermediate-risk Papillary Thyroid Cancer patients or not. Methods this study is a retrospective study of intermediate-risk papillary thyroid cancer patients that were treated with or without post operative RAI from 1st January 2002 till 1st January 2012. Overall survival (OS) and multivariate regression analyses were measured for all patients. Results 100 patients were included in this trial : 70 patients received postoperative RAI and 30 patients did not. The mean follow-up time was 7.1 (4.8 -15.1 years), and a median survival time could not be estimated. Overall survival at 10 years was 96% in the RAI vs 93% in the group without RAI (P < .001). RAI reduced risk of death by a 27% [hazard risk (HR) 0.73, confidence interval (CI) 0.64 - 0.84, P < .001]. Older patient age, male gende, larger tumor size, multifocal tumors, lymph node metastases, aggressive histology, vascular invasion, positive surgical margin, minimal extrathyroidal extension and absence of postoperative RAI were accompanied by compromised OS (all P ≤ .001). Conclusion This representative study addresses the survival advantage of RAI for with intermediate risk PTC patients but conducting of large prospective randomized controlled trial is still warranted.

Background Open conversions (OC) due to failed endovascular repair of infrarenal abdominal aortic aneurysms (EVAR) are technically demanding because of preexisting prostheses and advanced aortic disease. This study evaluates the feasibility and outcomes of aorto-uniiliac endografting (AUI) as an alternative treatment option in acute failed EVAR. Methods From March 1995 through February 2012, 26 patients underwent acute conversion of failed EVAR at our tertiary care university center. All data were prospectively entered in our institutional database. Outcomes included 30-day or in-hospital mortality, postoperative complications, and mid-term survival. Results During the investigation period, a total of 692 patients received EVAR at our institution, while five of the 26 patients with acute conversion (19.2%) had an initial EVAR at an outlying institution and were referred for treatment. Therefore, our estimated institutional rate of acute conversions was 3% (21 of 692 EVAR). OC were performed in 14 patients (53.8%), while 12 patients underwent AUI (46.2%). An average time of 20.3 months (median: 18.6; interquartile range Q1–Q3: 0.0–38.6) elapsed between the initial EVAR and the acute conversion. All acute AUI conversion procedures were completed successfully. The 30-day mortality following acute conversions was 42.3% and since the use of AUI, it could be reduced to 33.3%. Kaplan–Meier estimates revealed a survival advantage for AUI at one year (p = 0.046), but the benefit was lost by mid-term follow-up (p = 0.103). Conclusions AUI for the treatment of acute failed EVAR represents a feasible and less invasive alternative to OC, and is associated with better one-year survival rates.

There has been a recent explosion in the number of simultaneous liver and kidney (SLK) transplants performed. This practice is crowding out the population of ESRD patients waiting for a kidney transplant. It has been alleged from retrospective, anecdotal reports, often from voluntary registries, that there is a survival advantage for those with renal dysfunction that receive an SLK compared to Liver Transplant Alone. However, this survival advantage is quite small—about 5% at 1 and 5 years at best. A new algorithm introduced in 2016 by UNOS may make this problem worse by allowing SLK transplant for patients who may not have permanent kidney failure with a glomerular filtration rate (GFR) as high as 30cm3/min. The transplant community needs to have a high degree of vigilance to identify which groups of patients are being disadvantaged when reallocation schemes are created to direct organs from one group to another.

Purpose of Review There is a well-defined knowledge of relative benefits of pancreas transplants to patients with respect to specific diabetic complications; however, the degree of survival advantage of a simultaneous pancreas and kidney versus kidney transplant alone in the type I diabetes mellitus patient population remains controversial.

Otto Warburg’s discovery in the 1920s that tumor cells took up more glucose and produced more lactate than normal cells provided the first clues that cancer cells reprogrammed their metabolism. For many years, however, it was unclear as to whether these metabolic alterations were a consequence of tumor growth or an adaptation that provided a survival advantage to these cells. In more recent years, interest in the metabolic differences in cancer cells has surged, as tumor proliferation and survival have been shown to be dependent upon these metabolic changes. In this educational review, we discuss some of the mechanisms that tumor cells use for reprogramming their metabolism to provide the energy and nutrients that they need for quick or sustained proliferation and discuss the potential for therapeutic targeting of these pathways to improve patient outcomes.

Introduction: Mortality following cardiac arrest (CA) is extremely high, with rates as high as 91.5% after out-of-hospital cardiac arrest (OHCA) and 76.1% after in-hospital cardiac arrest (IHCA). This study assessed the clinical profile and outcomes of a large cohort of patients undergoing primary percutaneous coronary intervention (PCI) for OHCA to determine its effect on clinical outcomes and mortality. Methods: 247,456 patients with OHCA due to acute coronary syndrome (ACS) were abstracted from the Nationwide Inpatient Sample database (2001-2011). Results: Among 247,456 OHCA patients, 11,111 (4.5%) had PCI while 236,345 (95.5%) did not. Patients who underwent PCI were younger than those who did not receive PCI (64 vs. 66 years), p p p p 65 years, female gender, AA or Hispanic race, advanced cancer, and liver dysfunction as independent factors associated with increased mortality, while PCI conferred a survival advantage in OHCA, p 50 years old, and those with Medicare. PCI significantly reduces mortality in OHCA patients and should be considered in all OHCA patients. Further investigation and development of methods to overcome the apparent socioeconomic barriers to PCI is required.

Context. The perhaps only CMML-specific Randomized Clinical Trial (RCT) established hydroxyurea (HY) as the main treatment (Tx) for advanced proliferative CMML (Wattel Blood 1996). In Europe, the only hypomethylating agent (HMA) approved in CMML is AZA in non proliferative CMML-2. Phase 2 trials reported the activity of decitabine (DAC) in advanced proliferative CMML (Braun Blood 2011, Santini Leukemia 2018). We performed a RCT of DAC (±HY during the first 3 cycles) vs HY alone in those pts. Methods. The DACOTA trial (EudraCT 2014-000200-10) accrued pts with previously untreated (or < 6 weeks of HY), proliferative (WBC ≥ 13x109/L) CMML with advanced disease defined per Wattel et al as presence of extramedullary disease or ≥2 criteria among: BM blasts ≥5%, abnormal karyotype (except -Y), ANC ≥ 16x109/L, Hb < 10 g/dL, platelets < 100 x109/L or splenomegaly > 5 cm below costal margin. Pts were randomized 1:1 to DAC (20 mg/m2/d IV 5d/28d) or HY (1g/d, adjusted on WBC, 28d cycles) and treated until death, AML transformation or progression. The primary endpoint was EFS, events being death, transformation to AML, progression of myeloproliferation after 3+ cycles or progression of blasts and cytopenias after 6+ cycles. Response was assessed with IWG 2006 criteria modified to account for improvement of myeloproliferation, after central morphology review. Intent-to-treat analyses were done considering missing responses as failures. Results. From Oct 2014 to Sep 2019, 217 pts from 47 centers were screened and 170 randomized (84 DAC and 86 HY), including 12 pts (6 DAC and 6 HY) who never started Tx. Median age was 73 years (IQR 68-78). WHO was CMML-NA/1/2 in 2, 114 and 54 pts, respectively (resp). Median WBC 34.9 x109/L (IQR 22.9-55.7). Cytogenetic risk (Such Haematologica 2011) was fav 69%, int 12%, adv 18% NA 1%. Mutations in TET2, SRSF2, ASXL1 and signaling genes (CBL, JAK2, FLT3, KIT, NRAS, KRAS and CSF3R) were present in 64%, 51%, 62% and 57% resp. 72 pts had received HY for a median 27 days prior to randomization. Aside from older age in the HY arm (median 74 vs 71.5y in the DAC arm), there was no imbalance between Tx arms. DAC and HY pts received a median of 5 (IQR 3-12) and 6 (IQR 3-14) cycles, resp. As of 15th June 2020, 5 and 10 DAC and HY pts were still on Tx. Reasons for Tx cessation in the DAC arm were death (n=19), AML transformation (n=16), progression (n=9) , hematological toxicity (n=13) or other (n=21). Reasons for Tx cessation in the HY arm were death (n=14), AML transformation (n=13), progression (n=18), hematological toxicity (n=6) or other (n=20). 126 and 85 pts received 3 and 6 cycles, resp. In the ITT population, ORR at 3 cycles was 56% (7CR, 25 mCR±HI, 15 SD+HI) and 30% (0 CR, 8 mCR±HI, 18 SD+HI) in the DAC and HY arms, resp (p=0.0011) and ORR at 6 cycles was 32% (6 CR, 9 mCR±HI, 12 SD+HI) and 17% (2 CR, 4 mCR±HI, 9 SD+HI) in the DAC and HY arms, resp (p=0.033). Median response duration was 15.9 vs 18.2 months (mos) in the DAC and HY arm, resp (p=0.81). Infection and hemorrhage occurred at least once in 49% and 31% of pts, resp. 55% of DAC pts and 38% of HY pts required hospitalization at least once (p=0.05). Non-heme ≥ grade 2 AEs occurred in 79% and 63% of DAC and HY arms, resp (p=0.03). Grade ≥3 cardiac AEs occurred in 13 DAC and 4 HY pts, resp. With a median follow-up of 13.9 mos, median EFS was 12.6 vs 10.3 mos in the DAC and HY arms, resp (reference DAC arm, HR= 1.14 CI95 0.8-1.64, p= 0.46). Median AML-free survival (AMLFS) was 13.6 and 15.8 mos in the DAC and HY arms resp (p=0.86). Median OS was 18.4 and 23.1 mos in the DAC and HY arms, resp (p=0.72). Considering death and AML transformation as competing risks there was no significant difference in cumulative incidence of AML (p=0.1) or death without transformation (p=0.06) between arms. 30 pts from the HY arm received an HMA (DAC n= 13, AZA n= 16, both=1) after study exit. Censoring at HMA onset in the HY arm, median OS was 18.4 vs 30.4 in the DAC and HY arm, resp (p=0.15). 13 pts were transplanted (DAC n= 10, HY n= 3). There was no interaction between Tx arm and CMML-0/1 vs -2, platelets ≥ vs 0.05). Conclusion. RCTs are feasible in advanced proliferative CMML, which remains an unmet medical need. In these pts, DAC did not provide an overall or event-free survival advantage over HY. HY remains a valid option in advanced proliferative CMML. However, one third of HY pts subsequently received an HMA and more DAC pts achieved a response and were bridged to HSCT. Figure Disclosures Itzykson: Abbvie: Honoraria; Daiichi Sankyo: Honoraria; Otsuka Pharma: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Sanofi: Honoraria; BMS (Celgene): Honoraria; Janssen: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Stemline: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncoethix (now Merck): Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Santini:BMS, J&J, Novartis: Honoraria; Acceleron, BMS, Menarini, Novartis: Consultancy; Takeda, Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding. Lionel:Abbvie: Consultancy; Takeda: Consultancy; Celgene/BMS: Consultancy, Research Funding; Novartis: Consultancy; Jazz: Consultancy, Research Funding. Thepot:astellas: Honoraria; novartis: Honoraria; sanofi: Honoraria; celgene: Honoraria. Giagounidis:AMGEN: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Luebbert:Janssen: Research Funding. Park:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Other: Travel expenses. Stamatoulas Bastard:Pfizer: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Honoraria; Takeda: Consultancy. Solary:Janssen: Research Funding. Platzbecker:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Geron: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Fenaux:Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Jazz: Honoraria, Research Funding. OffLabel Disclosure: Decitabine for CMML with WBC > 13 x109/L.

Background: We examined paradoxical and barrio advantaging effects on cancer care among socioeconomically vulnerable Hispanic people in California. Methods: We secondarily analyzed a colon cancer cohort of 3,877 non-Hispanic white (NHW) and 735 Hispanic people treated between 1995 and 2005. A third of the cohort was selected from high poverty neighborhoods. Hispanic enclaves and Mexican American (MA) barrios were neighborhoods where 40% or more of the residents were Hispanic or MA. Key analyses were restricted to high poverty neighborhoods. Results: Hispanic people were more likely to receive chemotherapy (RR=1.18), especially men in Hispanic enclaves (RR=1.33) who were also advantaged on survival (RR=1.20). A survival advantage was also suggested among MA men who resided in barrios (RR=1.80). Conclusions: The findings were supportive of Hispanic paradox and MA barrio advantage theories. They further suggested that such advantages are greater for men, perhaps due to their greater spousal and extended familial support. Significance for public health Hispanic Americans are three-times as likely to live in poverty as non-Hispanic white Americans. Despite this, Hispanic enclaves, Mexican American barrios, in particular, seem to be relatively protective. Considering cancer care in California, for example, Hispanic men who live in such Hispanic enclaves/barrios are particularly advantaged in their access to cancer care and survival. Such communities may effectively double the protective effects of familialism that many Hispanic men already enjoy through marriage.

With the increasing incidence and prevalence of ESRD in the elderly, we are now transplanting more elderly patients. Although we know from previous reports that transplantation provides increased survival advantage and/or quality of life when compared to being on dialysis, we also know that transplantation is not the best option for all patients. In this review, we try to identify the upper age limit (if any) for deceased donor renal transplantation, predictive factors that can identify the risks for transplant outcomes, frailty, and immunosenescence.Review of data over the last 5 years have identified certain risk predictors and outcomes that might be helpful in evaluation of the elderly transplant recipient, which we aim to summarize in this review.Identifying predictors to risk stratify elderly patients and promote transplantation is much needed. Modifiable risks should be addressed to ensure more candidates become transplantable. A combination of physical, medical, and immunological markers to better identify recipients is imperative for future research gearing towards precision medicine.

Background: We investigated whether the survival advantage of completing Pulmonary Rehabilitation (PR) in the National COPD PR Audit report (Royal College of Physicians) was related to the effects of PR or to confounding due to differences in case-mix severity. Methods: PR services across England and Wales provided data for consenting patients assessed for PR between Jan - April 2015. Mortality data were extracted from the Office for National Statistics from Jan 2015 to Jan 2017. Time to event analysis, from the end of PR (estimated for non-completers) to Jan 2017, was performed using Cox proportional hazards regression adjusted for baseline gender, age, FEV1, BMI, MRC dyspnoea grade, smoking status, co-morbidities, walking distance, home oxygen use, and hospitalisation in the last year. Multiple imputation was performed for missing data. Results: 7092 patients with COPD were included and 58% completed PR. There were small but statistically significant differences between completers (slightly younger age P The unadjusted mortality rate was higher for non-completers (12.3%) vs. completers (8.3%), mean (95% CI) HR 1.54 [1.33 to 1.78], P Conclusion: In this large, real-life dataset, we report a survival advantage of completing PR compared to non-completion even after adjustment for baseline case-mix severity.

Gastric cancer is a common malignancy worldwide, and treatment of localized disease has shifted from surgery alone to the addition of chemotherapy at various stages in treatment. The role of radiation in the management of gastric cancer has evolved significantly since the seminal publication of INT 0116 demonstrated a survival advantage to adjuvant chemoradiation. In this review, we summarize multiple landmark studies discussing the role of radiation in non-metastatic gastric cancer, both in resectable and unresectable patients. This review will additionally discuss the evidence for pre-operative chemoradiation, as the benefit has already been demonstrated in esophageal and rectal cancer.

Circadian clocks are intrinsic, time-tracking processes that confer a survival advantage on an organism. Under natural conditions, they follow approximately a 24-h day, modulated by environmental time cues, such as light, to maximize an organism’s physiological efficiency. The exact timing of this rhythm is established by cell-autonomous oscillators called cellular clocks, which are controlled by transcription–translation negative feedback loops. Studies of cell-based systems and wholeanimal models have utilized a pharmacological approach in which chemical compounds are used to identify molecular mechanisms capable of establishing and maintaining cellular clocks, such as posttranslational modifications of cellular clock regulators, chromatin remodeling of cellular clock target genes’ promoters, and stability control of cellular clock components. In addition, studies with chemical compounds have contributed to the characterization of light-signaling pathways and their impact on the cellular clock. Here, the use of chemical compounds to study the molecular, cellular, and behavioral aspects of the vertebrate circadian clock system is described.

Background: Solving the nervous system requires understanding how it generates inner sensations of "mind" within it. It was possible to derive a hypothesis of brain functions where the formation of a spectrum inter-postsynaptic (inter-spine) functional LINKs (IPLs) are the key structural changes responsible for encoding at the time of learning and are used for inducing the inner sensation of memory, both taking place at millisecond timescales. Since stages of ontogeny reflect possible stages of evolution, it is possible to examine whether IPLs have features of an evolved mechanism. Objective: To examine whether 1) IPLs have features of an evolved mechanism, 2) significant neuronal death during ontogeny leads to evolutionary adaptations for preventing cell death among the surviving neurons, and 3) loss of these adaptations lead to cellular changes that can cause agingrelated neurodegeneration. Methods: Key milestone changes of the ontogeny of the nervous system were examined to test whether they match with a feasible sequence of steps that lead to the formation of IPLs. Results: Several developmental stages can explain a probable sequence of events that lead to IPL formation among synaptically-connected neurons. When internal sensations generated by the IPLs started providing survival advantage, evolution has started preserving the IPL circuitry. A stage of inter-spine fusion possibly leads to a) significant neuronal death during the early stages of development, and b) trigger an adaptation in the surviving cells to stabilize and prevent the IPLs from undergoing fusion. Since there are no irreversible steps for maintaining the stability of IPLs, agingrelated factors may destroy the adaptation mechanism and destabilize the IPLs predisposing them to cause neurodegeneration. Conclusion: The derived testable IPL mechanism that can explain nervous system functions is capable to have evolved. An adaptation to prevent IPL hemifusion from progressing to fusion is likely the last stage of nervous system evolution. Since the IPL mechanism is utilized during every event of learning, any aging-related factors that can weaken this adaptation can cause IPL fusion and lead to neurodegeneration.

Elective endovascular repair of an abdominal aortic aneurysm results in lower perioperative mortality than traditional open repair, but after 4 years this survival advantage is not seen; in addition, results of two European trials have shown worse long-term outcomes with endovascular repair than with open repair. Long-term results of a study we conducted more than a decade ago to compare endovascular repair with open repair are unknown.We randomly assigned patients with asymptomatic abdominal aortic aneurysms to either endovascular repair or open repair of the aneurysm. All the patients were candidates for either procedure. Patients were followed for up to 14 years.A total of 881 patients underwent randomization: 444 were assigned to endovascular repair and 437 to open repair. The primary outcome was all-cause mortality. A total of 302 patients (68.0%) in the endovascular-repair group and 306 (70.0%) in the open-repair group died (hazard ratio, 0.96; 95% confidence interval [CI], 0.82 to 1.13). During the first 4 years of follow-up, overall survival appeared to be higher with endovascular repair than with open repair; from year 4 through year 8, overall survival was higher in the open-repair group; and after 8 years, overall survival was once again higher in the endovascular-repair group (hazard ratio for death, 0.94; 95% CI, 0.74 to 1.18). None of these trends were significant. There were 12 aneurysm-related deaths (2.7%) in the endovascular-repair group and 16 (3.7%) in the open-repair group (between-group difference, -1.0 percentage point; 95% CI, -3.3 to 1.4); most deaths occurred during the perioperative period. Aneurysm rupture occurred in 7 patients (1.6%) in the endovascular-repair group, and rupture of a thoracic aneurysm occurred in 1 patient (0.2%) in the open-repair group (between-group difference, 1.3 percentage points; 95% CI, 0.1 to 2.6). Death from chronic obstructive lung disease was just over 50% more common with open repair (5.4% of patients in the endovascular-repair group and 8.2% in the open-repair group died from chronic obstructive lung disease; between-group difference, -2.8 percentage points; 95% CI, -6.2 to 0.5). More patients in the endovascular-repair group underwent secondary procedures.Long-term overall survival was similar among patients who underwent endovascular repair and those who underwent open repair. A difference between groups was noted in the number of patients who underwent secondary therapeutic procedures. Our results were not consistent with the findings of worse performance of endovascular repair with respect to long-term survival that was seen in the two European trials. (Funded by the Department of Veteran Affairs Office of Research and Development; OVER ClinicalTrials.gov number, NCT00094575.).

We introduce a classification of breast tumors into seven classes which are more clearly defined by interpretable mRNA signatures along the PAM50 gene set than the five traditional PAM50 intrinsic subtypes. Each intrinsic subtype is partially concordant with one of our classes, and the two additional classes correspond to division of the classes concordant with the Luminal B and the Normal intrinsic subtypes along expression of the Her2 gene group. Our Normal class shows similarity with the myoepithelial mammary cell phenotype, including TP63 expression (specificity: 80.8% and sensitivity: 82.8%), and exhibits the best overall survival (89.6% at 5 years). Though Luminal A tumors are traditionally considered the least aggressive, our analysis shows that only the Luminal A tumors which are now classified as myoepithelial have this phenotype, while tumors in our luminal class (concordant with Luminal A) may be more aggressive than previously thought. We also find that patients with basal tumors surviving to 48 months exhibit favorable continued survival rates when certain markers for B lymphocytes are present and poor survival rates when they are absent, which is consistent with recent findings.

Survival to extreme ages clusters within families. However, identifying genetic loci conferring longevity and low morbidity in such longevous families is challenging. There is debate concerning the survival percentile that best isolates the genetic component in longevity. Here, we use three-generational mortality data from two large datasets, UPDB (US) and LINKS (Netherlands). We study 20,360 unselected families containing index persons, their parents, siblings, spouses, and children, comprising 314,819 individuals. Our analyses provide strong evidence that longevity is transmitted as a quantitative genetic trait among survivors up to the top 10% of their birth cohort. We subsequently show a survival advantage, mounting to 31%, for individuals with top 10% surviving first and second-degree relatives in both databases and across generations, even in the presence of non-longevous parents. To guide future genetic studies, we suggest to base case selection on top 10% survivors of their birth cohort with equally long-lived family members., While human lifespan is only moderately heritable, “getting old” runs in families. Here, van den Berg et al. study mortality data from three-generation cohorts to define a threshold for longevity and find that individuals have an increasing survival advantage with each additional relative in the top 10% survivors of their birth cohort.

Metastatic gastric cancer is still a disease with a poor prognosis. Recently, different novel agents (e.g., apatinib, nivolumab, TAS-102) have demonstrated a survival advantage compared with placebo for patients with heavily pretreated metastatic gastric cancer. Although the possible availability of active agents may be a desirable option in a very poor therapeutic scenario, clinical data from the recent studies with these drugs raise yet controversial issues. The purpose of this review is to briefly summarize the results of these novel drugs focusing on the limitations that bring some shadows on their positive therapeutic results.

The current literature has shown a clear survival advantage by achieving a radical or as near complete a resection as possible for all grades of gliomas. Challenges arise when gliomas are deep-seated within the brain. With keyhole and neuroendoscopic surgical techniques, deep-seated gliomas can be addressed confidently. Here, we discuss keyhole techniques using five specific tumors as examples of many of the concerns associated with the ability to achieve a radical resection: insular gliomas, mesial temporal gliomas, brain stem gliomas, butterfly gliomas, and thalamic gliomas. An illustrative case is provided for each deep-seated lesion. With the application of the keyhole and neuroendoscopic techniques, a thorough resection of deep-seated gliomas can be obtained with minimal added morbidity from the surgical approach.

e17542 Background: Circulating tumor cells (CTCs) are a potential source of dissemination and relapse in ovarian cancer (OC). Stem cell properties can provide a survival advantage for CTCs. The clinical significance of stem-like CTCs in OC remains to be studied. We aimed to assess the quantities of the stem, epithelial, mesenchymal CTCs and their relationships with the clinical parameters in the OC. Methods: Peripheral blood samples (7.5 ml) were obtained from patients with primary epithelial OC before treatment. CTCs were isolated by flow cytometry (Cytoflex S (Beckman Coulter, USA)) using antibodies to CD45 (BioLegend, USA); CD44 (BioLegend, USA), CD133 (Miltenyi biotec, Germany), ALDH (Stemcell, Canada) to detect the stem markers; EpCAM (BioLegend, USA), cytokeratins 8, 18 (Abcam plc., UK), vimentin (BioLegend, USA) for epithelial and mesenchymal markers. Blood samples from patients with benign ovarian tumors served as a control. Informed voluntary consent was obtained from all the women. Statistical processing included Mann-Whitney U-test, linear regression, Cox proportional hazards model for progression-free survival (PFS) (Statistica 13.0 (TIBCO, USA)). Results: The study included 30 patients, median age 64 (34-76) years. 15 patients had a FIGO stage IV, 12 - stage III, 1 – stage II and 1 – stage I. The content of CTCs populations is presented in the table. The CTCs counts did not differ depending on age, platelet count, and stage 3 or 4. The amount of CD45-CK+Vim- was higher in the presence of ascites (p = 0.035). We found a regression relationship between the serum CA-125 and the number of CD45-CD44+CD133+ (R2= 0.220, p = 0.016); the leukocyte count in blood and CD45-CD44+ALDHhigh (R2= 0.234, p = 0.017); the number of CD45-Vim+ and CD45-CD44+CD133+ALDH+ (R2= 0.305, p = 0.014); CD45-CK-Vim+ and CD45-EpCAM+CK+ (R2= 0.717, p < 0.001). The Cox regression model for PFS included the number of CD45-CD44+CD133+ALDH+ (HR 1.51 95% CI 1.01-2.24 p = 0.043) and the cytoreductive surgery performance (HR 0.09 95% CI 0.01-0.89 p = 0.039) during the first line of treatment. Conclusions: Various populations of circulating tumor cells coexist in ovarian cancer patients. The use of a combination of stem markers in the CTCs detection can increase their prognostic value in OC. This work was supported by the RFBR grant No. 19-315-90011.[Table: see text]

116 Background: Randomized trials have demonstrated a survival advantage to administering docetaxel (D) shortly after initiation of androgen deprivation therapy (ADT) in men with newly diagnosed hormone sensitive metastatic prostate cancer (hsMPC). Clinical trials in breast cancer, research in prostate cancer cell lines, and pharmacokinetic analyses of D clearance in the castrate state, suggest increased efficacy of chemotherapy administered separately from hormone suppression. We proposed that treatment with D before ADT might improve outcomes in newly diagnosed hsMPC. Methods: In an ongoing phase II study (NCT03069937), men with newly diagnosed hsMPC were treated with 4 cycles of D (75mg/m2) every 21 days without ADT followed by 2 cycles of D concurrent with the LHRH antagonist degarelix (Deg) administered every 4 weeks. The Deg alone was continued for a total of 7 injections. Men were trial eligible with high or low volume disease by CHAARTED criteria. Bicalutamide was allowed for < 30 days before trial entry, but LHRH directed therapy was not permitted. The primary endpoint for this trial is percentage of men obtaining PSA < 0.2 ng/ml. Pre-specified secondary endpoints examined here after 4 cycles of docetaxel alone are safety, and efficacy defined by PSA (decrease by > 50%) and radiographic responses. Results: At time of this abstract, 50 patients have been enrolled to trial. Two patients withdrew after 1 cycle of D, and 4 patients have not yet completed 4 cycles. Of the 50 patients evaluable for safety, 6 (12%) had Grade 3 toxicities related to D. No Grade 4/5 toxicities were reported. Of patients who completed 4 cycles of D, 24/44 (55%) had a PSA response and 34/44 (77%) had PSA decline from baseline. All but two patients with declining PSA had stable or improved radiographic imaging. Six of the 44 patients (14%) had PSA progression (>25% increase) with D therapy, 3 of whom also had radiographic progression. Every patient with PSA response after 4 cycles D had PSA decline after 2 cycles. No patient with PSA decline after 2 cycles had PSA progression after 4 cycles. PSA response rate was stratified by baseline variables in table below. Conclusions: In hsMPC patients, 4 cycles D without ADT appears to be a safe and active therapy. Treatment with bicalutamide prior to the start of D predicts poorer PSA response. This result strengthens our hypothesis that sensitivity of hsMPC to taxane therapy may be enhanced if ADT is postponed. Baseline genomics will be analyzed, and we hope to correlate responses to D alone with later primary efficacy outcomes. Clinical trial information: NCT03069937. [Table: see text]

Multiple studies document there are patients for whom hemodialysis can be predicted not to offer a survival advantage. The medical evidence also includes reports of strong, active medical management without dialysis programs in Australia, Canada, and the United Kingdom, yet the nephrology community in the United States has yet to provide to patients with end stage kidney disease an active medical management without dialysis option available throughout the country. This article reviews barriers and facilitators to starting such a program and offers recommendations for the components that have enabled international programs to be successful.

PURPOSE OF REVIEW Radiofrequency ablation (RFA) has been recognized for its potential in palliative treatment for pancreatic cancer as well as malignant biliary strictures. The purpose of this review is to describe the technology, endoscopic technique, and reported outcomes of endoscopic RFA in the management of malignant biliary strictures and unresectable pancreatic cancer. RECENT FINDINGS Intraductal biliary RFA is safe and feasible and appears to confer a survival advantage. Pancreatic endoscopic ultrasound-guided RFA is a promising new technique and may result in either resolution of tumor or reduction in size. SUMMARY Intraductal biliary RFA and pancreatic endoscopic ultrasound-guided RFA are important modalities in malignant biliary obstruction and unresectable pancreatic cancer. Intraductal biliary RFA should be used as an adjunct to biliary stenting. Further trials are needed to determine if RFA leads to a benefit in pancreatic cancer treatment. Two prospective trials are currently underway to determine if intraductal biliary RFA indeed confers a survival advantage in malignant obstruction.

Recent studies have focused on associations of the APOL1 risk variants with outcomes beyond kidney disease, including cardiovascular disease and mortality. Ma and colleagues now expand on this growing but contradicting body of work. Their analysis of a prevalent cohort of African American hemodialysis patients shows that the risk variants are associated with a survival benefit among nondiabetics. Whether this simply reflects a healthier status at hemodialysis initiation among those carrying 2 risk variants or whether these variants truly confer a survival advantage is unclear.

We report on a 6-year, field-based experiment in north-western Ecuador, evaluating the relative importance of relatedness, conspecific density and microhabitat on the growth and survival of seedlings of an ecologically and economically important palm, Oenocarpus bataua. We planted O. bataua seedlings in high-density seed deposition sites (leks) of the long-wattled umbrellabird (Cephalopterus penduliger) and randomly selected control sites. We analysed seedling performance in relation to conspecific relatedness, conspecific density and microhabitat. Among the parameters we measured, light availability was the most important determinant for survival and growth. Higher relatedness of neighbouring experimental seedlings and higher conspecific seedling densities were both associated with reduced growth, but did not influence survival, even in umbrellabird leks. These findings are consistent with a survival advantage of umbrellabird dispersal into lek sites (i.e. directed dispersal) that counterbalances negative density-dependent processes expected to occur at these high-density deposition sites. This study highlights the importance of a multi-tiered approach to understanding palm demography and underlines the importance of seed disperser behaviour in determining seedling fate.

The treatment landscape for metastatic melanoma has increased dramatically in the past five years, with the pivotal discovery of activating BRAF mutations in half of all melanomas spurring the development for effective treatments that target mitogen-activated protein kinase (RAS/RAF/MEK/ERK) pathway. Vemurafenib, a selective mutant BRAF Val600 inhibitor, results in striking tumour responses and a survival advantage over conventional chemotherapy. We present here the case of a 38-year-old woman with metastatic BRAFV600E mutant melanoma and a severe tablet phobia, who was found to have been crushing and/or chewing her vemurafenib tablets. In this case, she attained a partial response and significant clinical benefit, albeit temporarily.

Transcatheter aortic valve implantation is one of the most significant technological advances in cardiovascular medicine. It offers a safe alternative in high risk cardiac patients with proven durability, economical viability and survival advantage. Current trials may expand its application in intermediate or low risk groups.

On 7 January 1948, a meeting was held at the Royal Society of Medicine in London. Its purpose was to settle a controversy. Robert McWhirter, an Edinburgh-based radiotherapist, had been invited to defend the scandalous position advocated by Geoffrey Keynes ten years previously: that radical mastectomy offered no survival advantage when compared to simple mastectomy plus local radiotherapy. The negative publicity surrounding the meeting proved overwhelming for Keynes and he abandoned his research. Indeed, the events of the meeting may have been quietly buried were it not for McWhirter who, over the following decade, pursued Keynes’ research. He refined his technique, sparing patients the disfiguring and painful radical mastectomy without compromising overall survival. Later, he garnered support from other researchers, which led to a series of papers confirming his original findings. Towards the end of his career, he also made contributions to service organisation and hormone therapy, eventually holding the Presidency of the Faculty of Radiologists. By keeping the controversy alive, McWhirter was instrumental in overturning 60 years of surgical dogma. He remains a pivotal figure in the history of breast cancer.

The Warburg effect describes the increased utilization of glycolysis rather than oxidative phosphorylation by tumour cells for their energy requirements under physiological oxygen conditions. This effect has been the basis for much speculation on the survival advantage of tumour cells, tumourigenesis and the microenvironment of tumours. More recently, studies have begun to reveal how the Warburg effect could influence drug efficacy and how our understanding of tumour energetics could be exploited to improve drug development. In particular, evidence is emerging demonstrating how better modelling of the tumour metabolic microenvironment could lead to a better prediction of drug efficacy and the identification of new combination strategies. This review will provide details of the current understanding of the complex interplay between glucose metabolism and pharmacology and discuss opportunities for utilizing the Warburg effect in future drug development.

BACKGROUND: Volunteering has been linked to reduced mortality in older adults, but the mechanisms explaining this effect remain unclear. This study investigated whether volunteering is associated with increased survival in participants of the English Longitudinal Study of Ageing and whether differences in survival are modified by functional disabilities. METHODS: A multivariate Cox Proportional Hazards model was used to estimate the association of volunteering with survival over a period of 10.9 years in 10 324 participants, while controlling for selected confounders. To investigate effect modification by disability, the analyses were repeated in participants with and without self-reported functional disabilities. RESULTS: Volunteering was associated with a reduced probability of death from all causes in univariate analyses (HR=0.65, CI 0.58 to 0.73, p

Polymorphism of clotting factor V, comprising Arg506Gln substitution in the factor V molecule, commonly known as Factor V Leiden, represents the most common heritable risk factor for thrombotic events in Indo-Europeans and some Semitic nations. Although it is suggested that this mutation is associated with a survival advantage that has facilitated the spread of this polymorphism in the human population, in this paper we argue against such a Darwinian evolutionary mechanism responsible for the high prevalence of FV Leiden in some countries. Instead, we propose that cultural, climatic, and geographic factors played a role. Taking into account the current distribution of FV Leiden polymorphism and the results of recent assessments of pre-historic human DNA, we suggest that actually the origin of FV Leiden mutation did not occur in the Near East, as is widely believed, but rather in a small isolated population of so-called Basal Eurasians, probably in northern Africa. This founder group probably migrated to the Near East during the Younger Dryas, a geological period associated with climate cooling. Here, they mixed with local people; still Factor V Leiden mutation remained very prevalent in this population. The invention of agriculture, which took place approximately 2,000 years later, gave the descendants of Basal Eurasians an enormous advantage over hunter-gatherers, and probably enabled a successful spread of FV Leiden polymorphism to Europe, Central Asia, and towards the Indian subcontinent.