Years Of Failure Research Articles

Real-world analysis of first-line afatinib in patients with EGFR-mutant non-small cell lung cancer and brain metastasis: survival and prognostic factors.

Overall survival (OS) in patients with non-small cell lung cancer (NSCLC) and brain metastases (BMs) is poor. We aimed to identify prognostic factors and ascertain treatment outcomes of first-line afatinib for patients with epidermal growth factor receptor (EGFR)-mutant NSCLC with BM in a real-world setting. This retrospective observational study reviewed electronic records of patients with EGFR-mutant NSCLC who received first-line afatinib treatment between October 2014 and October 2019 in 16 hospitals across South Korea. The Kaplan-Meier method estimated time on treatment (TOT) and OS; multivariate analyses were performed using Cox proportional hazards (PH) models. Among 703 patients who received first-line afatinib, 262 (37.3%) had baseline BM. Of 441 patients without baseline BM, 92 (20.9%) developed central nervous system (CNS) failure. Compared with patients without CNS failure, those with CNS failure during afatinib treatment were younger (P=0.012), had a higher Eastern Cooperative Oncology Group (ECOG) performance status (PS) (P<0.001), increased metastatic site involvement (P<0.001), advanced stage disease (P<0.001), with liver metastasis (P=0.008) and/or bone metastasis (P<0.001) at baseline. Cumulative incidence of CNS failure in years 1, 2 and 3 was 10.1%, 21.5% and 30.0%, respectively. In multivariate analysis, cumulative incidence was significantly higher in patients with ECOG PS ≥2 (P<0.001), uncommon EGFR mutations (P=0.001), and no baseline pleural metastasis (P=0.017). Median TOT was 16.0 months (95% CI: 14.8-17.2) and, in patients with CNS failure, without CNS failure, and with baseline BM was 12.2, 18.9, and 14.1 months, respectively (P<0.001). Median OS was 52.9 months (95% CI: 45.4-60.3) and, in patients with CNS failure, without CNS failure, and with baseline BM was 29.1, 67.3 and 48.5 months, respectively (P<0.001). First-line afatinib in the real-world setting showed clinically meaningful effectiveness in patients with EGFR-mutant NSCLC and BM. CNS failure was a poor prognostic factor for TOT and OS correlating with younger age, poor ECOG PS, higher metastatic number, advanced disease stage, uncommon EGFR mutations, and baseline liver and/or bone metastases.

Severe Eosinophilic Myocarditis in the Portion of Left Ventricular Wall Excised to Insert a Left Ventricular Assist Device for Severe Heart Failure

Described herein are 3 adults in whom histologic study of the left ventricular myocardium excised ("LV core") to insert a left ventricular assist device (LVAD) disclosed severe acute myocarditis and the inflammatory cells included numerous eosinophils (eosinophilic myocarditis). Examination of the clinical records disclosed elevated absolute eosinophil counts at the time of insertion of the LVAD and the counts rapidly (<30 days) returned to normal after the operation. Because of the numerous medications that each patient was taking at the time of LVAD insertion, identification of a specific initiating medication as its cause was not possible. Of the 3 patients, 2 had idiopathic-dilated cardiomyopathy and 1 had ischemic cardiomyopathy and each had had heart failure for years. The eosinophilic myocarditis in these 3 patients appears to have been transient and superimposed on the earlier cardiomyopathy.

Invited Commentary

The establishment of The Interagency Registry for Mechanically Assisted Circulatory Support (Intermacs) in 2005 was an important step forward for the community of medical providers who are involved in the field of mechanical circulatory support (MCS). For the first time, a large database was established to serve as a repository for all variables affecting patients receiving MCS. The mandate by the regulatory agencies (notably the Joint Commission) to require all programs performing device implantation to benchmark against Intermacs had the added benefit of incentivizing programs in the United States to make substantial internal investments to collect, track, and report their data accurately. On January 1, 2018, oversight and coordination of Intermacs moved to The Society of Thoracic Surgeons (STS) National Database. The incorporation of this database into the larger STS Council on Quality, Research, and Patient Safety will provide additional resources for detailed data collection, analysis, and scientific inquiry similar to the quality work that has emerged from the larger STS databases in cardiac, thoracic, and congenital surgery. In this issue of The Annals of Thoracic Surgery, Kormos and colleagues [1Kormos R.L. Cowger J. Pagani F.D. et al.The Society of Thoracic Surgeons Intermacs Database Annual Report: evolving indications, outcomes, and scientific partnerships.Ann Thorac Surg. 2019; 107: 341-354Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar] have produced the annual report on the data from Intermacs. This report primarily focuses on documenting the outcomes of patients undergoing durable left ventricular assist device with the use of Food and Drug Administration-approved, continuous flow rotary pumps. One of the more interesting data points is the documentation of the shift from axial flow pumps to centrifugal flow pumps. This transition likely represents the natural history of pump implant choices that follow advances in technology with each new generation of devices. This report also continues to highlight the limitations of the current device technology; namely neurologic events, gastrointestinal bleeding, and infections. These remain the areas in need of the greatest improvement for caring for these patients and provide the benchmark by which each individual program should use in evaluating their outcomes. In addition, note that these data have traditionally been published in the Journal of Heart and Lung Transplantation that has a more generalized readership among transplant cardiologists, nursing professionals, pharmacists, and other disciplines. Thus, it is critical that we ensure that the publication of this data be widely accessible to the other members of the heart failure community and not restricted to the STS membership with a paid subscription. Similarly, with new leadership will come the daunting task of ensuring that these safeguarded data are easily accessible to other members in the discipline of MCS for research and analysis. With the STS now behind the database, we expect further scientific inquiries and scrutinized analyzes will continue to improve the outcomes for patients with end-stage heart failure for years to come. The Society of Thoracic Surgeons Intermacs Database Annual Report: Evolving Indications, Outcomes, and Scientific PartnershipsThe Annals of Thoracic SurgeryVol. 107Issue 2PreviewThe Interagency Registry for Mechanically Assisted Circulatory Support (Intermacs), a joint effort among the National Heart, Lung, and Blood Institute, the Food and Drug Administration, the Centers for Medicare and Medicaid Services, and others, was established in 2005 at the University of Alabama at Birmingham. The registry examined clinical outcomes and quality-of-life metrics of patients who received an Food and Drug Administration-approved durable mechanical circulatory support (MCS) device to treat advanced heart failure. Full-Text PDF

Intravenous oxygen: a novel method of oxygen delivery in hypoxemic respiratory failure?

ABSTRACTIntroduction: Hypoxemic respiratory failure is a common problem in critical care. Current management strategies, including mechanical ventilation and extracorporeal membranous oxygenation, can be efficacious but these therapies put patients at risk for toxicities associated with invasive forms of support.Areas covered: In this manuscript, we discuss intravenous oxygen (IVO2), a novel method to improve oxygen delivery that involves intravenous administration of a physiologic solution containing dissolved oxygen at hyperbaric concentrations. After a brief review of the physiology behind supersaturated fluids, we summarize the current evidence surrounding IVO2.Expert commentary: Although not yet at the stage of clinical testing in the United States and Europe, IVO2 has been used safely in Asia. Furthermore, preliminary laboratory data have been encouraging, suggesting that IVO2 may play a role in the management of patients with hypoxemic respiratory failure in years to come. However, significantly more work needs to be done, including definitive evidence that such a therapy is safe, before it can be included in an intensivist’s arsenal for hypoxemic respiratory failure.

Heart Failure Related Hospitalizations Are Associated with Increased Morbidity and Mortality in Pediatric Oncology Patients

Introduction: Cardiomyopathy is a well-described complication of cancer therapy in pediatric patients. However, the prevalence and outcomes of heart failure related hospitalizations in these patients are unknown. We hypothesize that while heart failure related hospitalizations are uncommon in pediatric oncology patients, they are likely associated with increased morbidity and mortality.Methods: We performed retrospective analysis of the Healthcare Cost and Utilization Project Kids' Inpatient Database, a nationwide database of pediatric hospitalizations in the United States, for oncology patients with and without heart failure for years 2000, 2003, 2006, and 2009.Results: Heart failure was identified in 914 of 259,432 (0.4%) pediatric oncology admissions. Patients with heart failure were more likely to be non-white (52.2 vs 43%, p<0.001), less likely to be in the highest income bracket (23.9 vs 27.5%, p=0.014), more likely to have leukemia (40.7 vs 31.3%, p<0.001), and more likely to undergo bone marrow transplantation on admission (5.0 vs 1.6%, p<0.001). Several morbidities were significantly more common in patients with heart failure including respiratory failure [16.4% vs 1.3%, odds ratio (OR) 14.6, 95% CI 12.2-17.4), sepsis (21.9% vs 7.2%, OR 3.6, 95% CI 3.1-4.3), stroke (1.5% vs 0.6%, OR 2.5, 95% CI 1.5-4.3), and renal failure (11.7% vs 1.2%, OR 10.9, 95% CI 8.9-13.3). Length of stay (LOS) and hospital charges were also significantly greater in oncology patients with heart failure patients compared to those without; median LOS 9 (IQR 4-25) vs 4 days (IQR 2-6); median hospital charges $58,023 (IQR 18,835-169,826) vs $18,161 (IQR 8,860-39,640); p<0.001 for both. Hospital mortality was significantly greater in oncology patients with heart failure compared to those without (13.3% vs 1.3%; OR 11.5, 95% CI 9.5-14.0). On multivariable analysis, heart failure was independently associated with hospital mortality in pediatric oncology patients (OR 2.21, 95% CI 1.63-3.00).Conclusion: Heart failure is an uncommon but serious complication in hospitalized pediatric oncology patients. The presence of heart failure was associated with increased morbidities, resource utilization, and mortality. Further study is needed for the prevention and treatment of heart failure in this population. DisclosuresAplenc:Sigma Tau: Honoraria.

OPTN/SRTR 2013 Annual Data Report: lung.

Lungs are allocated to adult and adolescent transplant candidates (aged ⩾ 12 years) on the basis of age, geography, blood type compatibility, and the lung allocation score (LAS), which reflects risk of waitlist mortality and probability of posttransplant survival. In 2013, the most adult candidates, 2394, of any year were added to the list. Overall median waiting time for candidates listed in 2013 was 4.0 months. The preferred procedure remained bilateral lung transplant, representing approximately 70% of lung transplants in 2013. Measures of short-term and longterm survival have plateaued since the implementation of the LAS in 2005. The number of new child candidates (aged 0-11 years) added to the lung transplant waiting list increased to 39 in 2013. A total of 28 lung transplants were performed in child recipients, 3 for ages younger than 1 year, 9 for ages 1 to 5 years, and 16 for ages 6 to 11 years. The diagnosis of pulmonary hypertension was associated with higher survival rates than cystic fibrosis or other diagnosis (pulmonary fibrosis, bronchiolitis obliterans, bronchopulmonary dysplasia). For child candidates, infection was the leading cause of death in year 1 posttransplant and graft failure in years 2 to 5.

Timing Concepts Affecting the Odds of Success or Failure of M&amp;As

M&As are a strategic instrument to grow for corporations. However, acquiring corporations have to face a large number of challenges to really succeed in merging two organisations. Half of all transactions have been failing resulting in disastrous write-offs and losses for corporations. Research has been trying to find a panacea against M&A failure for years investigating motives, synergies, performance and the M&A process. In more detail, research has focused on different timing concepts: market timing and integration speed. Other timing concepts seem to have been neglected so far, although several cases show early evidence for their existence. The purpose of this paper is to identify further concepts of timing besides integration speed and market timing. In order to identify such concepts the author has chosen a qualitative meta-analysis. The author has collected 30 cases of past mergers within various industries. To avoid any bias, the collection consists of 15 successful and 15 failed mergers. These cases have been investigated for any codes highlighting timing concepts. This study reveals six timing concepts with crucial impact on the M&A outcome: time for acquisition, M&A duration in its entirety, M&A sequence, synergy chronology, frequency of acquisitions and time to step back. The extent of their impact varies as does the ability to control them. Most important are the M&A sequence and synergy chronology as they do have the highest impact and are most likely to be controlled by acquiring corporations. It is suggested to focus on these timing concepts in future research. Time for acquisitions cannot be chosen freely in some cases. The M&A duration in its entirety does not influence the outcome of a transaction. The frequency of acquisitions only refers to huge corporations and the time to step back should only be considered as an emergency exit granting the minimal loss.

Comparison of allogeneic stem cell transplantations in chronic myeloid leukemia before and after the era of tyrosine kinase inhibitors.

7038 Background: In this retrospective study we aimed to evaluate the rates and the clinical outcomes of allo-HSCT in CML following the advent of TKIs. Methods: We compared the transplantations (Txs) performed prior to 2002 (old era), the first year of TKIs, with the Txs during and after 2002 (new era). Results: Between 1989 and 2012 inour Tx unit a total of 189 allo-HSCTs were performed in 185 CML patients (second Tx for 4 patients). The ratio of Tx for CML among the whole Tx group decreased from 40 % to 12 % after 2002. The ratio also dropped to less than 5 % after 2008 and increased again to 15% in 2012. Time from diagnosis to Tx was longer in the old era than in the new era (9.2 months vs 15.4 months, p&lt;.0001). The ratio of patients with advanced disease (accelerated or blastic phase) was higher in the new era. Although the progression free survival (PFS) was shorter in the new era than in the old era (median 13.8 months vs 37.1 months, p=0.09), overall survival, Tx outcomes and survival curves did not change. Conclusions: AlloHSCT rates sharply decreased after the TKIs, but a slight increase in recent years have been observed compatible with the TKI’s failure in years. Despite the fact that patients who underwent allo HSCT in the new era had more challenging disease biologically, overall survival was not affected possibly due to post-Tx interventions such as use of TKI alone or with donor lymphocyte infusion. [Table: see text]

Probleme bei Implantation und Revision von Schrittmacher-/Defibrillatorsonden

Pacemaker and ICD leads have complex compound designs and are therefore the weakest link in cardiac rhythm device therapy. Technical problems are mostly insulation defects. Their number increases during follow-up and makes up more than 50 percent of the yearly failure rate of up to 20% after ten years of service life. Design flaws of specific lead models need special management. The implanting physician is first confronted with anatomic barriers to lead introduction, but his technique also impacts the hardware's failure rate, and his training and procedure volume are predictive of the dislodgment risk, the need for revision and, eventually, infection. Every potential hardware contamination urges complete removal of the system. Early explantation improves prognosis. First choice is transvenous lead extraction which achieves high success rates even with left heart leads but also has specific risks of complications.

Associations of Renal Function at 1-Year After Kidney Transplantation With Subsequent Return to Dialysis, Mortality, and Healthcare Costs

Improved early kidney transplant outcomes limit the contemporary utility of standard clinical endpoints. Quantifying the relationship of renal function at 1 year after transplant with subsequent clinical outcomes and healthcare costs may facilitate cost-benefit evaluations among transplant recipients. Data for Medicare-insured kidney-only transplant recipients (1995-2003) were drawn from the United States Renal Data System. Associations of estimated glomerular filtration rate (eGFR) level at the first transplant anniversary with subsequent death-censored graft failure and patient death in posttransplant years 1 to 3 and 4 to 7 were examined by parametric survival analysis. Associations of eGFR with total health care costs defined by Medicare payments were assessed with multivariate linear regression. Among 38,015 participants, first anniversary eGFR level demonstrated graded associations with subsequent outcomes. Compared with patients with 12-month eGFR more than or equal to 60 mL/min/1.73 m, the adjusted relative risk of death-censored graft failure in years 1 to 3 was 31% greater for eGFR 45 to 59 mL/min/1.73 m (P<0.0001) and 622% greater for eGFR 15 to 30 mL/min/1.73 m (P<0.0001). Associations of first anniversary eGFR level with graft failure and mortality remained significant in years 4 to 7. The proportions of recipients expected to return to dialysis or die attributable to eGFR less than 60 mL/min/1.73 m over 10 years were 23.1% and 9.4%, respectively, and were significantly higher than proportions attributable to delayed graft function or acute rejection. Reduced eGFR was associated with graded and significant increases in health care spending during years 2 and 3 after transplant (P<0.0001). eGFR is strongly associated with clinical and economic outcomes after kidney transplantation.

Approaches To Anti-HLA Antibody Profiles In Patients Waiting For Renal Re-Transplantation

This review focuses on the mechanisms of anti-HLA antibody development in patients waiting for a renal re-transplantation. Pre- existence or post transplant de novo production of these antibodies have been found to contribute to renal allograft failure in years. In addition to the detrimental effect of donor specific and non-donor specific anti-HLA antibodies on graft survival, many researchers emphasized the effect of non-HLA antibodies (e.g.; anti-MICA antibodies), auto-antibodies (e.g.; anti-vimentin antibodies), allo-nephrectomy and combined liver-kidney transplantations on rejection processes. Beyond all these, a newly developed computer algorithm, 'HLAMatchmaker' has changed the concept of transplantation possibility in highly sensitized patients.

Isotopic and genetic evidence for culturally inherited site fidelity to feeding grounds in southern right whales (Eubalaena australis)

Ocean warming will undoubtedly affect the migratory patterns of many marine species, but specific changes can be predicted only where behavioural mechanisms guiding migration are understood. Southern right whales show maternally inherited site fidelity to near-shore winter nursery grounds, but exactly where they feed in summer (collectively and individually) remains mysterious. They consume huge quantities of copepods and krill, and their reproductive rates respond to fluctuations in krill abundance linked to El Niño Southern Oscillation (ENSO). Here we show that genetic and isotopic signatures, analysed together, indicate maternally directed site fidelity to diverse summer feeding grounds for female right whales calving at Península Valdés, Argentina. Isotopic values from 131 skin samples span a broad range (-23.1 to -17.2‰ δ¹³C, 6.0 to 13.8‰ δ¹⁵N) and are more similar than expected among individuals sharing the same mitochondrial haplotype. This pattern indicates that calves learn summer feeding locations from their mothers, and that the timescale of culturally inherited site fidelity to feeding grounds is at least several generations. Such conservatism would be expected to limit the exploration of new feeding opportunities, and may explain why this population shows increased rates of reproductive failure in years following elevated sea-surface temperature anomalies off South Georgia, the richest known feeding ground for baleen whales in the South Atlantic.

Stress Corrosion Cracking of Tough Pitch Copper in a Bolting Application

Stress corrosion cracking was observed in C11000 and C10200 copper electrical feedthrough pins used in a bolting application. The component provided the balancing tensile stress required for compression of a gasket seal of a refrigeration compressor. The component, as designed, had functioned without failure for years of production and thousands of units. The fractures were mixed brittle intergranular with ductile microvoid dimples. An extensive analysis of actual failed samples as well as a process of elimination methodology indicated that the fractures were due to SCC by an unidentified chemical species within the sealed compressor chamber. A unique combination of applied stress, residual stress, a stress riser, and fine-grain size isolated the failure mechanism to a single production lot of material.

Optimal cost design with sensitivity analysis using decomposition techniques. Application to composite breakwaters

Minimizing the expected total cost of a structure, including maintenance and construction is a difficult problem because of the presence in the objective function of the yearly failure rates, which have to be calculated by an optimization problem per each failure mode. In this paper, a new method for the design of structures that minimizes the total expected costs of the structure during its lifetime based on Benders’ decomposition is presented. In addition, some tools for sensitivity analysis are introduced, which make it possible to determine how the cost and yearly failure rates of the optimal solution are affected by small changes in the input data values. The proposed method is illustrated by its application to the design of a composite breakwater under breaking and non-breaking wave conditions.

Demography of Lemur catta at Berenty Reserve, Madagascar: Effects of Troop Size, Habitat and Rainfall

We censused Lemur catta within a 1 km2 study area at Berenty Reserve, Madagascar, during the September–October birth season for 19 years between 1963 and 2000, a total of 290 troop counts (266 with age and sex). The non-infant population was 155 in 1972–5, fell to 105 in 1985, and rose to a maximum of 282 in 1997, while troops increased from 12 in 1972–1985 up to 25 in 1998–2000. Local density varies between habitat types from 1 per ha to ca. 6 per ha. Troops fission at ca. 15–25 individuals, or 6–10 females. Adult sex ratio has no apparent correlation with fissions, birth rate or survival. Birth rate falls steeply with number of adult females, from 80–100% in 2-female troops to about 50% in 8–10 female troops. The penalty for large troop size is greater in the dense, rich areas, but nonetheless troops there are also larger. One-year-survival does not vary with troop size, and is lower in the sparse, dry zone. Troop size is too large for optimal birth rate, but fissioning to much lower size might make troops too small for optimal adult survival, given the intense intertroop competition. This reflects Sibley's (1983) conjecture that troop sizes may not reach stable optima. Rainfall per lemur-year (beginning Oct 1) varied from 265 to 894 mm. Drought followed by rain can eliminate >90% of a cohort, especially in the dryest zone. Possibly this results from fruit failure in years following drought. It is unknown whether food supplementation of some Berenty troops is dangerous for the forest, or helpful for an isolated and vulnerable ring-tailed lemur population.

A research on the importance function used in the calculation of the fracture probability through the optimum method

On the basis of the research into original distribution function as the importance function after shifting an appropriate distance, this paper takes the variation of similar ratio of the original function to the importance function as the objective function, the optimum shifting distance obtained by use of an optimization method. The optimum importance function resulting from the optimization method can ensure that the number of Monte Carlo simulations is decreased and at the same time the good estimates of the yearly failure probabilities are obtained.

A Review of Recent Research and Current Issues in Accelerated Testing

Summary Accelerated tests are used to obtain timely information on the life distribution or performance over time of products. Test units are used more frequently than usual or are subjected to higher than usual levels of stress or stresses like temperature and voltage. Then the results are used to make predictions about product life or performance over time at the more moderate use or design conditions. Changes in technology, the calls for rapid product development, and the need to continuously improve product reliability have put new demands on the applications for these tests. In this paper we briefly review the basic statistical and other ideas behind accelerated testing and give an overview of some current and planned statistical research to improve accelerated test planning and methods. Today's manufacturers are facing strong pressure to develop newer, higher technology products in record time, while improving productivity, product field reliability, and overall quality. This has motivated the development of methods like concurrent engineering and encouraged wider use of designed experiments for product and process improvement efforts. The requirements for higher reliability have increased the need for more up-front testing of materials, components and systems. This is in line with the generally accepted modern quality philosophy for producing high reliability products: achieve high reliability by improving the design and manufacturing processes; move away from reliance on inspection to achieve high reliability. Estimating the time-to-failure distribution or long-term performance of components of high reliability products is particularly difficult. Most modern products are designed to operate without failure for years, tens of years, or more. Thus few units will fail or degrade importantly in a test of practical length at normal use conditions. For this reason, Accelerated Tests (ATS) are used widely in manufacturing industries, particularly to obtain timely information on the reliability of product components and materials. Generally, information from tests at high levels of stress (e.g., use rate, temperature, voltage, or pressure) is extrapolated, through a physically reasonable statistical model, to obtain estimates of life or long-term performance at lower, normal levels of stress. In some cases stress is increased or otherwise changed during the course of a test (step-stress and progressive-stress ATS). AT results are used in the reliability-design process to assess or demonstrate component and subsystem reliability, certify components, detect failure