Impact of intensified therapy on clinical outcome in infants and children with neuroblastoma: the St Jude Children's Research Hospital experience, 1962 to 1988.

1991 ◽  
Vol 9 (9) ◽  
pp. 1599-1608 ◽  
Author(s):  
L C Bowman ◽  
M L Hancock ◽  
V M Santana ◽  
F A Hayes ◽  
L Kun ◽  
...  
Keyword(s):  
Metastatic Disease ◽  
Disease Stage ◽  
Rank Test ◽  
Antineoplastic Drugs ◽  
Limited Disease ◽  
Term Survival ◽  
The Past ◽  
Log Rank Test ◽  
The Impact

To gauge the impact of intensified therapy on the survival of infants (younger than 1 year, n = 129) and children (greater than or equal to 1 year of age, n = 275) with neuroblastoma, we analyzed the results of eight successive clinical trials comparing various combinations of antineoplastic drugs, surgery, and radiotherapy. Changes in treatment did not affect the survival of children with involved noncontiguous lymph nodes or distant metastatic disease until the combination of cisplatin and teniposide (CDDP/VM26) was added to a basic regimen of cyclophosphamide and doxorubicin (CTX/DOX). The resulting 4-year survival was 28% +/- 5% (SE) compared with 7% +/- 2% for previous treatments (P less than .001 by the log-rank test). The 4-year survival of infants with metastatic disease was improved by administering CTX/DOX to all patients, reserving CDDP/VM26 for those whose disease was resistant to the former combination: 82% +/- 6% versus 45% +/- 8% in earlier studies; P less than .001. In the subset of infants whose tumors had disseminated to bone or bone marrow at diagnosis, this therapeutic approach increased the probability of long-term survival from 48% +/- 10% to 85% +/- 9% (P = .01). The small group of children over 1 year of age with localized unresectable tumors also fared significantly better with the switch to CTX/DOX chemotherapy (4-year survival, 93% +/- 7% v 42% +/- 13%; P = .02). Multivariate analysis indicated that young age, limited-disease stage, nonadrenal primary site, and intensified treatment were independent predictors of a more favorable outcome. We conclude that substantial advances in the treatment of neuroblastoma have occurred over the past 25 years at this institution. The current overall 4-year survival probability of 57% +/- 4% compares favorably with estimates for most other common solid tumors of childhood.

scholarly journals The relationship of the prolonged PR interval with the long-term survival in patients with heart failure undergoing cardiac resynchronization therapy

2020 ◽  
Vol 25 (1) ◽  
pp. 33-38
Author(s):  
A. M. Soldatova ◽  
V. A. Kuznetsov ◽  
T. P. Gizatulina ◽  
L. M. Malishevsky ◽  
S. M. Dyachkov
Keyword(s):  
Cardiac Resynchronization ◽  
Rank Test ◽  
Term Survival ◽  
Log Rank Test ◽  
Group I ◽  
Pr Interval ◽  
Qrs Duration ◽  
Group Ii ◽  
The Relationship

Aim. To assess the relationship between the prolonged PR interval (≥200 ms) and the long-term survival of patients undergoing cardiac resynchronization therapy (CRT).Material and methods. A total of 85 patients (mean age — 55,1Ѓ}9,9 years; men — 81,2%) with NYHA class II-IV heart failure (HF) were examined. The mean follow-up was 34,0Ѓ}21,2 months. Patients with PR<200 ms (n=52) made up group I, with PR≥200 ms (n=33) — group II. Then the patients were divided into subgroups depending on the QRS duration: ≥150 ms (n=33 in group I and n=14 in group II, respectively) <150 ms (n=19 in group I and n=19 in group II, respectively).Results. In patients of group II, a history of myocardial infarction (MI) was more often registered (p=0,005), left ventricular ejection fraction (LVEF) was lower (p=0,032). In a multivariate analysis, MI (OR 3,217; CI 95% 1,188-8,712; p=0,022) and LVEF value (OR 0,869; CI 95% 0,780-0,968; p=0,011) had a significant relationship with the PR interval prolongation (≥200 ms). The survival of patients of group I was 59,6%, group II — 18,2% (Log-rank test p<0,001). According to Cox regression model, the initial left ventricle end-systolic volume (OR 1,012; 95% CI 1,006-1,017; p<0,001), inferior wall MI (OR 1,690; 95% CI 1,131-2,527; p=0,011) and PR interval ≥200 ms (OR 2,179; 95% CI 1,213–3,915; p=0,009) were associated with long-term mortality. In patients with PR≥200 ms, survival rate was low, regardless of the QRS duration (21,4% in patients with QRS≥150 ms, 15,8% in patients with QRS<150 ms; Log-rank test p=0,698) In patients with PR<200 ms, the survival rate of patients with QRS≥150 ms was 72,7%, and for patients with QRS<150 ms — 36,8% (Log-rank test p=0,031).Conclusion. In HF patients, PR interval prolongation (≥200 ms) is associated with long-term mortality increase. The highest survival rates were observed in patients with PR<200 ms and QRS≥150 ms. In patients with QRS≥150 ms, the presence of PR≥200 ms should be considered as an additional criterion for CRT.

scholarly journals Assessing Long-Term Survival Benefits of Immune Checkpoint Inhibitors Using the Net Survival Benefit

2019 ◽  
Vol 111 (11) ◽  
pp. 1186-1191 ◽  
Author(s):  
Julien Péron ◽  
Alexandre Lambert ◽  
Stephane Munier ◽  
Brice Ozenne ◽  
Joris Giai ◽  
...  
Keyword(s):  
Treatment Effect ◽  
Survival Benefit ◽  
Rank Test ◽  
Cure Rate ◽  
Term Survival ◽  
Long Term Survival ◽  
Delayed Treatment ◽  
Net Survival ◽  
Log Rank Test

Abstract Background The treatment effect in survival analysis is commonly quantified as the hazard ratio, and tested statistically using the standard log-rank test. Modern anticancer immunotherapies are successful in a proportion of patients who remain alive even after a long-term follow-up. This new phenomenon induces a nonproportionality of the underlying hazards of death. Methods The properties of the net survival benefit were illustrated using the dataset from a trial evaluating ipilimumab in metastatic melanoma. The net survival benefit was then investigated through simulated datasets under typical scenarios of proportional hazards, delayed treatment effect, and cure rate. The net survival benefit test was computed according to the value of the minimal survival difference considered clinically relevant. As comparators, the standard and the weighted log-rank tests were also performed. Results In the illustrative dataset, the net survival benefit favored ipilimumab [Δ(0) = 15.8%, 95% confidence interval = 4.6% to 27.3%, P = .006]. This favorable effect was maintained when the analysis was focused on long-term survival differences (eg, >12 months, Δ(12) = 12.5% (95% confidence interval = 4.4% to 20.6%, P = .002). Under the scenarios of a delayed treatment effect and cure rate, the power of the net survival benefit test compared favorably to the standard log-rank test power and was comparable to the power of the weighted log-rank test for large values of the threshold of clinical relevance. Conclusion The net long-term survival benefit is a measure of treatment effect that is meaningful whether or not hazards are proportional. The associated statistical test is more powerful than the standard log-rank test when a delayed treatment effect is anticipated.

Interruption of imatinib (IM) in GIST patients with advanced disease after one year of treatment: Updated results of the prospective French Sarcoma Group randomized phase III trial on long term survival

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10016-10016 ◽  
Author(s):  
M. Rios ◽  
A. Lecesne ◽  
B. Bui ◽  
A. Adenis ◽  
F. Bertucci ◽  
...  
Keyword(s):  
Survival Data ◽  
Mutational Analysis ◽  
Phase Iii ◽  
Secondary Response ◽  
Rank Test ◽  
Tumor Control ◽  
Term Survival ◽  
The Impact ◽  
Advanced Gist

10016 Background: IM the first-line treatment for advanced GIST, must be given continuously until disease progression (PD) or intolerance (Blay et al, ASCO 2004). The impact on long term overall survival (OS) of IM discontinuation in responding patients (pts) and its re-introduction at progression is unknown. Methods: This prospective multicenter BFR14 study was initiated in June 2002. After 1 year of IM 400mg/day, 58 pts free from progression were randomly offered to continue or interrupt IM until PD. Pts allocated to the interruption (I) arm could restart IM (same dose) in case of PD. Primary endpoint was progression-free survival (PFS); secondary endpoints were OS, secondary response after IM re-introduction, identification of molecular determinants of response. Survival data were compared using the log-rank test. Results: Pt characteristics were well balanced between the two arms. Current median follow- up after randomization is 37 months (range 0–42): 29/32 pts (91%) in arm I vs. 16/26 pts (62%) in continuous (C) arm experienced PD. IM interruption was significantly associated with reduced PFS (p<10-4) with a median of 6 months (95% CI, 3.5–9.5) for arm I. Among the 26 pts of I arm who restarted IM after first progression, 24 (92%) achieved tumor control (OR or SD), one progressed, one died from an unrelated cause. The 2-yr OS rates were 87% and 92% for arms I and C, respectively (P = 0.78). Conclusions: Despite a significant increase of PD in the experimental arm, IM re-introduction is safe and allows a tumor control in the majority of pts. No unfavourable impact of IM interruption on OS was reported. Treatment interruption could be a therapeutic option in advanced GIST pts exhibiting intolerance to IM. Updated results including mutational analysis will be presented at the meeting. No significant financial relationships to disclose.

Randomized trial of hyperthermic intraperitoneal chemotherapy (HIPEC) in women with primary advanced peritoneal, ovarian, and tubal cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5520-5520 ◽  
Author(s):  
Myong Cheol Lim ◽  
Suk-Joon Chang ◽  
Heong Jong Yoo ◽  
Byung-Ho Nam ◽  
Robert Bristow ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cytoreductive Surgery ◽  
Residual Tumor ◽  
Study Endpoint ◽  
Rank Test ◽  
Control Group ◽  
Term Survival ◽  
Log Rank Test ◽  
And Control ◽  
The Impact

5520 Background: Cytoreductive surgery followed by taxane and platinum-based chemotherapy is standard treatment for advanced ovarian cancer. We compared results of randomly allocated HIPEC in primary advanced epithelial ovarian cancer who have optimal cytoreductive surgery in this prospective randomized multicenter trial. The study endpoint is to evaluate progression free survival (PFS) and overall survival (OS). Methods: 184 patients staged III and IV were randomly allocated to trial arm (HIPEC, cisplatin 75 mg/m2, 90 min) or control arm (no HIPEC), intraoperatively based on residual tumor (size <1cm) from July 2010 to January 2016. The groups were well balanced according to the age, body mass index, performance status, stage, histology, serum CA125 level, and use of neoadjuvant chemotherapy (NAC) at study entry. Results: 184 pts (HIPEC, 92; control, 92) were included in this preplanned analysis. No mortality after surgery ± HIPEC was identified in both groups. Postoperative outcomes including extent of surgery, estimated blood loss, residual tumor, and hospitalization day were not different between both group, except operation time (487 vs. 404 min, p<0.001) due to HIPEC procedure. The most common adverse event was anemia: 67.4% in HIPEC and 50% in control group (p=0.025). The other toxicity common in HIPEC group is the elevation of creatinine (15.2% vs. 4.3%, p=0.026). There were no differences between both groups for transfusion (35.9 vs. 29.3, p=0.432), neutropenia (19.6 vs. 10.9%, p=0.151), and thrombocytopenia (9.8 vs. 3.3%, p=0.136). Two-year PFS was 43.2% and 43.5% and 5-year PFS was 20.9% and 16.0% in HIPEC and control group, respectively (p=0.569). Five-year OS was 51.0% and 49.4% in HIPEC and control group, respectively (p=0.574). In women who received NAC, the median PFS for HIPEC and control group were 20 and 19 months, respectively (log-rank test, p = 0.137) and the median OS for HIPEC and control group were 54 and 51 months, respectively (log-rank test, p = 0.407). In the subgroup with NAC, 2-year PFS was 37.2% in HIPEC group and 29.5% in control group and 5-year OS was 47.9% in HIPEC group and 27.7% in control group. After 20 months in PFS and 30 months in OS, two survival curves in women who received NAC showed the trend of gradual distinction, favoring HIPEC group. Conclusions: No mortality was identified and postoperative morbidities were not statistically different between two groups except anemia and creatinine elevation in HIPEC group. The survival analysis did not show the statistical superiority of the HIPEC arm. More follow-up is required to confirm the impact of HIPEC on long-term survival outcome in ovarian cancer, especially in NAC group. Clinical trial information: NCT01091636.

scholarly journals Preoperative Peak Oxygen Consumption: A Predictor of Survival in Resected Lung Cancer

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 836
Author(s):  
Joerg Lindenmann ◽  
Nicole Fink-Neuboeck ◽  
Melanie Fediuk ◽  
Alfred Maier ◽  
Gabor Kovacs ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Oxygen Consumption ◽  
Cancer Patients ◽  
Peak Oxygen Consumption ◽  
Rank Test ◽  
Term Survival ◽  
The Impact ◽  
Related Survival

The peak oxygen consumption (VO2 peak) serves as a prognostic factor in cardio-respiratory diseases and plays an important role in cancer patients. The long-term prognostic relevance of VO2 peak in lung cancer patients has not been investigated extensively. The aim of this study was to evaluate the impact of the preoperative VO2 peak on the postoperative long-term survival in patients with operated lung cancer. Retrospective analysis of 342 patients with curatively resected non-small-cell lung cancer using a multivariate Cox proportional hazard model. Results: Preoperative VO2 peak ranged from 10.2 to 51.8 mL/kg/min (mean: 18.3 ± 4.6), VO2 peak % of predicted ranged from 32 to 172% (mean: 65.2 ± 18.0%). Overall 10-year survival was 23%. A Log-rank test comparing predicted VO2 peak ≥ 60% with predicted VO2 peak < 60% showed overall survival of 30% and 17%, respectively (p < 0.001) and non-tumour-related survival of 71% and 51% (p = 0.001) at 10 years. In multivariable Cox analysis, overall 10-year survival correlated with a high predicted VO2 peak% (p = 0.001) and low N-stage corresponding to N0 and N1 (p < 0.001). Non-tumour-related death correlated with low VO2 peak% of predicted (p = 0.001), and age (p < 0.001). Low preoperative VO2 peak was associated with both decreased postoperative overall survival and decreased non-tumour-related survival during the 10-year follow-up.

Patterns of mortality after prolonged follow-up of a randomized trial using granulocyte colony-stimulating factor (G-CSF) to maintain chemotherapy dose intensity in non-Hodgkin lymphoma (NHL)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7590-7590
Author(s):  
A. R. Clamp ◽  
S. Bhattacharya ◽  
D. W. Ryder ◽  
R. Pettengell ◽  
J. A. Radford
Keyword(s):  
Randomized Trial ◽  
Dose Intensity ◽  
Rank Test ◽  
Second Malignancies ◽  
Term Survival ◽  
Log Rank Test ◽  
Chemotherapy Dose ◽  
Chemotherapy Dose Intensity

7590 Background: Recombinant G-CSF is commonly used to maintain chemotherapy dose intensity and reduce the incidence of infective complications in the management of NHL. The possible impact of this effect on mortality patterns after prolonged follow-up is worthy of investigation. We investigated the long-term survival and incidence of second malignancies in the first randomized trial utilising recombinant G-CSF in NHL (Pettengell R et al Blood 1992, 80: 1430–1436). Methods: Data on overall survival (OS), progression-free survival (PFS), freedom from progression (FFP) and the incidence of second malignancies were extracted from medical records and cancer registry databases for 80 patients with aggressive subtypes of NHL, who had previously been randomised to receive either VAPEC-B chemotherapy alone (39 patients) or VAPEC-B with G-CSF (41 patients). 10 year survival figures were extracted and Kaplan-Meier survival curves were drawn for the above parameters and compared between treatment groups using the log-rank test. Results: Median follow-up was 11.8 years for surviving patients (range 7.8–13.1 yrs). Patients receiving G-CSF achieved a 12% higher median dose intensity of chemotherapy. No significant differences were found in PFS or OS but 10 year FFP appeared to be better in the G-CSF arm (60.8%) compared with the control arm (45.6%) (log-rank test p=0.12). Eleven deaths from non-NHL causes occurred in the G-CSF arm compared with three in the control arm (log- rank test p=0.06). Five second malignancies were detected on long-term follow-up in the G-CSF arm compared with two in the control arm. Conclusions: The demonstration of different mortality patterns in the two arms may be related to the greater dose intensity of chemotherapy received in the G-CSF arm. Although, our study has insufficient statistical power to draw definite conclusions, this finding warrants further investigation. No significant financial relationships to disclose.

The St. Jude Toronto stentless bioprosthesis: Up to 20 years follow-up in younger patients

2015 ◽  
Vol 18 (4) ◽  
pp. 129 ◽  
Author(s):  
Torsten Christ ◽  
Benjamin Claus ◽  
Robin Borck ◽  
Wolfgang Konertz ◽  
Herko Grubitzsch
Keyword(s):  
Valve Replacement ◽  
Artery Bypass ◽  
Rank Test ◽  
Term Survival ◽  
Younger Patients ◽  
Long Term Survival ◽  
Stentless Bioprosthesis ◽  
Log Rank Test

<p><strong>Background:</strong>A retrospective long-term evaluation of the St. Jude Toronto stentless bioprosthesis in patients aged 60 years or younger.</p><p><strong>Methods:</strong>From 1994 to 1997, 50 patients underwent aortic valve replacement with the prosthesis. Patients mean age at surgery was 54.5±6.3 years. Follow-up data were acquired by patient file research and telephone interviews. Morbidity and mortality were evaluated with time-to-event analyses using the Kaplan-Meier-method. The log-rank test was used to determine influencing factors for long-term survival and reoperation.</p><p><strong>Results:</strong>Mean follow-up was 13.5±6.3 years with a total follow-up of 661.8 patient-years and a maximum of 20.0 years. Follow-up was 97.8% complete. Associated procedures were performed in 12 patients (24%), including coronary artery bypass grafting, mitral valve replacement and replacement of the ascending aorta. Freedom from reoperation at 10 and 15 years was 76.0±6.7% and 44.1±8.9%, respectively. Reoperations (n=26) started 4.4 years after implantation and were necessary due to: valve degeneration with regurgitation in 79.2% and stenosis in 12.5%, endocarditis in 4.2% and sinus valsalva aneurysm in 4.2% of the cases. The log-rank test revealed that only body-mass-index&gt;25 lowered freedom-from-reoperation, while renal dysfunction, diabetes mellitus and arterial hypertension were not. Overall long-term survival at 10 and 20 years was 82.3±5.7% and 49.9±8.9%, respectively.</p><p><strong>Conclusion:</strong>In younger patients the Toronto-bioprosthesis provided reliable long-term survival despite limited durability.</p>

Long-term Results after Carpentier-Edwards Pericardial Aortic Valve Implantation, with Attention to the Impact of Age

2011 ◽  
Vol 14 (3) ◽  
pp. 160 ◽  
Author(s):  
Karl F. Welke ◽  
YingXing Wu ◽  
Gary L. Grunkemeier ◽  
Aftab Ahmad ◽  
Albert Starr
Keyword(s):  
Aortic Valve ◽  
Older Patients ◽  
Long Term Results ◽  
Rank Test ◽  
Term Survival ◽  
Younger Patients ◽  
Kaplan Meier ◽  
Valve Implantation ◽  
The Impact

<p><b>Background:</b> The purpose of this study was to determine long-term patient survival and valve durability for Carpentier-Edwards pericardial valves (Edwards Lifesciences) implanted in the aortic position, with specific attention to the impact of patient age.</p><p><b>Methods:</b> We performed a retrospective cohort study of 2168 patients who underwent implantation of a Carpentier-Edwards pericardial aortic valve between 1991 and 2008. The mean follow-up time was 4.5 years. Primary outcomes of interest were mortality and valve explantation. Survival curves and event-free curves were obtained with the Kaplan-Meier method and compared with the log-rank test.</p><p><b>Results:</b> Survival was 92% at 1 year, 73% at 5 years, 38% at 10 years, and 18% at 15 years. Although the mortality rate of younger patients was worse than in the general population, older patients had significantly better survival than their contemporaries. Age was the independent variable most significantly associated with explantation. There was an early hazard phase for patients between 21 and 49 years of age, such that the freedom from explantation was 89% at 3 years. By 10 years, the freedom from explantation was 58% for patients 21 to 49 years of age, compared with 68% for patients 50 to 64 years, 93% for patients 65 to 74 years, and 99% for patients 75 years of age and older.</p><p><b>Conclusion:</b> We found good long-term survival and durability. Older patients had excellent freedom from explantation, whereas younger patients fared worse. As our population ages, this information becomes increasingly important. Assessing the durability of this pericardial aortic valve may aid in predicting the durability of the transcatheter aortic valves that share the same leaflets.</p>

Perioperative and Long-term Outcomes of Laparoscopic, Open Abdominal, and Vaginal Surgery for Endometrial Cancer in Patients Aged 80 Years or Older

2014 ◽  
Vol 24 (5) ◽  
pp. 894-900 ◽  
Author(s):  
Giorgio Bogani ◽  
Antonella Cromi ◽  
Stefano Uccella ◽  
Maurizio Serati ◽  
Jvan Casarin ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Postoperative Complications ◽  
Intraoperative Complications ◽  
Vaginal Surgery ◽  
Perioperative Outcomes ◽  
Surgical Approaches ◽  
Rank Test ◽  
Term Survival ◽  
Log Rank Test

ObjectiveThis study was undertaken to evaluate the safety, feasibility, and the long-term effectiveness of laparoscopy in endometrial cancer patients aged 80 years or older.MethodsData of consecutive patients aged 80 years and older undergoing laparoscopic, open abdominal, and vaginal approaches were compared. Postoperative complications were graded per the Accordion Severity Classification. Survival outcomes within the first 5 years were analyzed using the Kaplan-Meier method.ResultsAmong 726 patients, 63 (9%) were aged 80 years and older. Laparoscopic, open abdominal, and vaginal surgery were performed in 22 (35%), 25 (40%), and 16 (25%) cases, respectively. All laparoscopic procedures were completed laparoscopically, whereas a conversion from vaginal to open procedure occurred (0% vs 6%; P = 0.42). Patients undergoing laparoscopy experienced similar operative time (P > 0.05), lower blood loss (P < 0.05), and shorter hospital stay (P < 0.05) than patients undergoing open and vaginal surgery. No intraoperative complications were recorded. Laparoscopy is related to a lower rate of postoperative complications (P = 0.09) and Accordion grade greater than or equal to 2 complications (P = 0.05) in comparison to open abdominal and vaginal surgery. The route of surgical approaches did not influence the 5-year disease-free (P = 0.97, log-rank test) and overall (P = 0.94, log-rank test) survivals.ConclusionsLaparoscopy seems to represent a safe and effective treatment of endometrial cancer in women aged 80 years or older. Our data suggest that in elderly women, laparoscopic surgery improves perioperative outcomes compared with open and vaginal approaches without compromising long-term survival.

scholarly journals Sex Specific Effects of PET-MPs On Drosophila Lifespan

2021 ◽  
Author(s):  
Jie Shen ◽  
Boying Liang ◽  
Dake Zhang ◽  
Sitong Ding ◽  
Yan Li ◽  
...  
Keyword(s):  
Ecological Environment ◽  
Rank Test ◽  
Anova Analysis ◽  
Specific Effects ◽  
Log Rank Test ◽  
Emerging Pollutant ◽  
Hormesis Effect ◽  
Males And Females ◽  
The Impact

Abstract In recent years, as an emerging pollutant, microplastic pollution is gradually becoming a research hotspot. Microplastics are ubiquitous in the entire ecological environment. Organisms can be exposed to microplastics via inhalation or ingestion. In view of the widespread of microplastics pollution, the impact of microplastics on biology should be further investigation. In previous experiments, we have conducted research on the physiology of Drosophila exposed to PET Microplastics (PET-MPs). However, under long-term exposure, will PET-MPs affect the lifespan of Drosophila? Our experimental results indicate that for ANOVA analysis, there are significant differences between males and females (F (1, 895) =68.19, p<0.001), between PET-MPs concentration (F (3, 895) = 8.11, p<0.001). There are also significant interactions between sex and Microplastic concentration (F (3, 895) = 4.00, p<0.01). For Cox and log rank test, 1g/L of PET-MPs prolongs the lifespan of male flies. The reason of this phenomenon may be the hormesis effect.

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