Prolonged Fatigue Research Articles

Final Results of A Phase 1 Study Investigating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Quizartinib (AC220) Administered Daily to Patients with Relapsed or Refractory Acute Myeloid Leukemia Irrespective of FLT3-ITD Status

AbstractAbstract 1507FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations in acute myeloid leukemia (AML) are associated with early relapse after standard chemotherapy and poor survival. Quizartinib is an oral FLT3 receptor tyrosine kinase (RTK) inhibitor that inhibits both ITD-mutant and wild-type FLT3 and displays efficacy in preclinical models of AML. In this first-in-human study, quizartinib was evaluated in patients with relapsed or refractory AML who were enrolled irrespective of FLT3-ITD status.Quizartinib was administered orally on an intermittent schedule (ID, 14 days on, 14 days off) at 12–450 mg/day or continuously (CD) at 200 or 300 mg/day. A total of 76 patients (61% male; 90% white; median age 60 years [23–86]) received quizartinib; median number of prior treatments was 3 (0–12), including 16% with a prior hematopoietic stem cell transplant. FLT3-ITD status was 22% positive (+) (n=17), 49% negative (−) (n=37), and 29% indeterminate/not tested (ind) (n=22).Plasma inhibitory activity assays using plasma samples collected at trough timepoints showed a high degree of FLT3 inhibition at low dose levels (18 mg/day and higher), indicative of potent in vivo FLT3 inhibition. Marked inhibition of FLT3 phosphorylation was also demonstrated in peripheral blood following administration of quizartinib.Responses were observed in 23/76 patients (30%), with 10 patients (13%) having a best response of any type of complete remission (CR=morphologic leukemia-free state with absolute neutrophil count >1×109/L and platelet count ≥100×109/L, and normal marrow differential with <5% blasts with no Auer rods; CRp=CR with incomplete platelet recovery; CRi=CR with incomplete hematologic recovery). Responses included 2 CR, 3 CRp, 5 CRi, and 13 (17%) partial remissions (PR, same hematologic values as CR but with a decrease of ’50% in % blasts in the bone marrow aspirate to 5% to 25%; a value of <5% blasts was considered a PR if Auer rods were present). Responses were observed at doses as low as 18 mg/day ID. Nine of 17 FLT3-ITD(+) patients responded (53%; 1 CR, 1 CRp, 2 CRi, 5 PR) compared to 5/37 FLT3-ITD(−) patients (14%; 2 CRp, 3 PR) and 9/22 with FLT3-ITD(ind) status (41%; 1 CR, 3 CRi, 5 PR). Median duration of response was 13.3 weeks (95% confidence interval [CI]: 11.0, 29.0 weeks): 9.7 weeks for FLT3-ITD(+) patients (95% CI: 4.1, 29); 23.7 weeks for FLT3-ITD(−) patients (95% CI: 11, not reached); and 12.4 weeks for FLT3-ITD(ind) patients(95% CI: 8, 53). Median overall survival was 14.0 weeks (95% CI: 10.9, 18.6 weeks): 18.3 weeks for FLT3-ITD(+) patients (95% CI: 10.6, 27.1); 9.7 weeks for FLT3-ITD(−) patients (95% CI: 5.6, 14.0); and 18.7 weeks for FLT3-ITD(ind) patients (95% CI: 14.0, 21.1).Quizartinib was generally well tolerated. The most common drug-related AEs (>10% incidence) were nausea (16%), prolonged ECG QT interval (12%), vomiting (11%), and dysgeusia (11%); most were ≤Grade 2. The maximum tolerated dose was 200 mg/day CD. The dose-limiting toxicity was QTcF interval prolongation, which occurred in 38% of subjects at 300 mg/day CD and in 6% at 200 mg/day CD. QTcF interval prolongation was dose dependent, and there were no associated arrhythmias. Grade 3 AEs related to quizartinib occurring in >1 patient were prolonged ECG QT interval (4 patients [5%]), anemia (3 patients [4%]), and fatigue (2 patients [3%]). Two treatment-related Grade 4 AEs (thrombocytopenia and hypoalbuminemia) were reported in 1 patient each (1%).The encouraging efficacy results in both FLT3-ITD(+) and FLT3 ITD(−) patients and an acceptable safety profile in this high-risk population support continued clinical evaluation of quizartinib with lower doses. A recent 333 patient Phase 2 study in a similar population given quizartinib at 200, 135, or 90 mg/day has been completed, and, considering the clinical activity observed at low doses, quizartinib is also being studied in patients with relapsed or refractory AML at 30 and 60 mg/day. Disclosures:Cortes:Novartis: Consultancy. Kantarjian:Ambit Biosciences: Consultancy. Foran:Ambit Biosciences: Consultancy. Ghirdaladze:Ambit Biosciences: Consultancy. Zodelava:Ambit Biosciences: Consultancy. Borthakur:Ambit Biosciences: Consultancy. Gammon:Ambit Biosciences: Employment. Trone:Ambit Biosciences: Employment. Armstrong:Ambit Biosciences: Employment. James:Ambit Biosciences: Employment. Levis:Ambit Biosciences: Consultancy.

Post-cancer fatigue is not associated with immune activation or altered cytokine production

Prolonged fatigue after cancer treatment is common. The pathophysiology of such post-cancer fatigue (PCF) is unknown, although cross-sectional studies suggest increased pro-inflammatory cytokine production. This study investigated the association between cytokine levels and fatigue from the time of treatment to 12 months later. A representative nested case-control series was derived from a prospective cohort of women treated for early-stage breast cancer, including 13 PCF cases and 15 matched control subjects who recovered uneventfully. Serum levels and in vitro production of the cytokines interleukin (IL)-1α, IL-2, interferon (IFN)-γ, IL-4, IL-6, IL-10, IL-12, and tumour necrosis factor (TNF)-β were measured by multiplex immunoassay in longitudinally collected samples. In addition, serum levels of neopterin and the anti-inflammatory regulators, IL-1 receptor antagonist, sIL-6R, and sTNF-rII, were assayed by enzyme-linked immunosorbent assay. Flow cytometric analysis of activated leukocyte subsets was performed. No significant differences in any of these parameters were found between cases and control subjects. Cytokine levels and symptoms showed no clear correlation pattern. The findings in this well-characterised subject group argue against the notion that PCF is mediated by peripheral inflammation.

Carbon fiber reinforced PEEK Optima—A composite material biomechanical properties and wear/debris characteristics of CF-PEEK composites for orthopedic trauma implants

BackgroundThe advantageous properties of carbon fiber reinforced polyetheretherketone (CF-PEEK) composites for use as orthopedic implants include similar modulus to bone and ability to withstand prolonged fatigue strain. MethodsThe CF-PEEK tibial nail, dynamic compression plate, proximal humeral plate and distal radius volar plate were compared biomechanically (by four-point bending, static torsion of the nail, and bending fatigue) and for wear/debris (by amount of the debris generated at the connection between the CF-PEEK plate and titanium alloy screws) to commercially available devices. ResultsFour-point bending stress of the tibial nail and dynamic and distal radius plates yielded characteristics similar to other commercially available devices. The distal volar plate bending structural stiffness of the CF-PEEK distal volar plate was 0.542Nm2 versus 0.376Nm2 for the DePuy's DVR anatomic volar plate. The PHILOS proximal humeral internal locking system stainless steel plate was much stronger (6.48Nm2) than the CF-PEEK proximal humeral plate (1.1Nm2). Tibial nail static torsion testing showed similar properties to other tested nails (Fixion, Zimmer and Synthes). All tested CF-PEEK devices underwent one million fatigue cycles without failure. Wear test showed a lower volume of generated particles in comparison to the common implants in use today. InterpretationThus, these tested implants were similar to commercially used devices and can be recommended for use as implants in orthopedic surgery.

Are subsyndromal symptomatic depression and major depressive disorder distinct disorders?

Depressive conditions that do not meet full symptomatic or duration criteria for a major depressive disorder (MDD) are of considerable interest to both clinicians and researchers. [1-4] The fourth edition of the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) provides descriptions of several types of subthreshold depressive states including dysthymia, minor depression and recurrent brief depression; but many individuals with subthreshold depression and associated impaired functioning do not meet DSM-IV diagnostic criteria for any of these disorders. [3] To cover these cases Judd and colleagues [4] proposed the concept of ‘Subsyndromal Symptomatic Depression’ (SSD) for individuals without depressed affect or anhedonia who have two or more (but less than five) of the other seven symptoms of depression that have been present for most of the time for at least two weeks and that are associated with impaired social functioning. [3,4] The appropriate diagnosis and treatment of individuals with this type of subthreshold depression will require a better understanding of the relationship between SSD and MDD. Are they independent disorders or is SSD a transitional state on the road to MDD? SSD is a relatively common condition. Based on the Epidemiological Catchment Area study in the United States, Judd and colleagues estimated a 12-month prevalence of SSD of 8.4% in the general population; the prevalence in women was double that in men and was particularly high in women who were unmarried and unemployed. [5] A study in Australia reported a 12.9% prevalence in the general population and found that the quality of life for persons with SDD was intermediate, between that for persons without any depressive symptoms and that for persons who met criteria for MDD. [6] A survey of people aged 60 and above in Singapore found that SSD was more common in individuals with a lower socioeconomic status and was often associated with cognitive impairment, anxiety, poor physical health, and poor social functioning. [7] The clinical presentation of SSD is similar to that for other types of depressive disorders. [5] Common symptoms include sleep disturbances (44.7%), prolonged fatigue (42.1%), repetitive thoughts of death (31%), and difficulty concentrating (22.7%). Atypical symptoms such as weight gain, slowed thinking and hypersomnia are somewhat more common in individuals with SSD than in those with minor depression. Risk of suicide is lower among SSD patients than in patients with minor depression or major depressive disorder. [5]

Fatigue behavior of Al0.5CoCrCuFeNi high entropy alloys

Research was performed on an Al0.5CoCrCuFeNi high entropy alloy (HEA) in an attempt to study the fatigue behavior. The present fatigue investigation shows encouraging fatigue resistance characteristics due to the prolonged fatigue lives of various samples at relatively high stresses. The current results indicate that the fatigue behavior of HEAs compares favorably with many conventional alloys, such as steels, titanium alloys, and advanced bulk metallic glasses with a fatigue endurance limit of between 540 and 945MPa and a fatigue endurance limit to ultimate tensile strength ratio of between 0.402 and 0.703. Some unpredictability in the fatigue life of the samples was observed as scattering in the stress vs. lifetime plot. Weibull models were applied to predict the fatigue data and to characterize the variability seen in the HEAs. A Weibull mixture predictive model was used to separate the data into two, strong and weak, groups. This model predicts that at stresses above 858MPa the median time to failure of specimens in the strong group will be greater than 107cycles. It was shown that microstructural defects, such as aluminum oxide inclusions and microcracks, may have a significant effect on the fatigue behavior of HEAs. It is believed that a reduction in the number of these defects may result in a fatigue behavior which exceeds that of conventional alloys.

Fever of unknown origin (FUO) in an elderly adult due to Epstein-Barr virus (EBV) presenting as “typhoidal mononucleosis,” mimicking a lymphoma

We describe fever of unknown origin (FUO) in a 57-year-old woman with hepatosplenomegaly. The diagnostic workup was directed at diagnosing a lymphoma. Her history of travel and exposures to food and water did not make typhoid fever a likely diagnostic possibility. Because she presented with prolonged fevers, fatigue, anorexia, weight loss, and night sweats with hepatosplenomegaly, lymphoma was likely. Initially, Epstein-Barr virus (EBV) was not considered because of her age, the absence of pharyngitis and cervical adenopathy, and the higher likelihood of another diagnosis, ie, lymphoma. Eventually, her FUO was diagnosed as EBV presenting as “typhoidal mononucleosis.” Typhoidal mononucleosis is an extremely rare presentation of EBV as a cause of FUO in an adult. All of her symptoms as well as her clinical and laboratory findings resolved spontaneously.

A Case Report: PCR-Assisted Diagnosis of Varicella in an Adult

A 41-year-old woman developed skin lesions on her upper back and arm. Initially, a definitive diagnosis could not be made. Subsequently, PCR detected VZV DNA in skin lesions and saliva. Immediate antiviral treatment led to a quick recovery without complicating prolonged fatigue and weakness typically seen in adults with varicella.

Long-Term Outcomes Following Vocational Rehabilitation Treatments in Patients with Prolonged Fatigue

BackgroundMulti-component vocational rehabilitation (VR) provides positive short-term outcomes in patients with prolonged fatigue.PurposeThe purpose of this study is to evaluate the long-term outcomes of Dutch multi-component VR up to 18 months after treatment.MethodIn a pre–post-study, measurements were taken before treatment (t0), after treatment (t1) and in long-term follow-ups at 6 (t2), 12 (t3) and 18 months (t4) after treatment. Primary outcomes (fatigue, work participation and workability) and secondary outcomes [physical and social functioning, mental health and heart rate variability (HRV)] were assessed over time using linear mixed models analyses. Post hoc long-term outcomes were compared with t0 and t1.ResultsSixty patients with severe fatigue complaints participated. The primary outcomes significantly (p < 0.001) improved at follow-ups compared with t0 and showed no relapse compared with t1. Moreover, fatigue decreased (p < 0.002) whereas workability (p < 0.001) and work participation (p < 0.001) increased further after treatment (t1). The secondary outcomes, physical functioning, mental health, social functioning and HRV, improved significantly (p < 0.001, p < 0.001, p < 0.001 and p = 0.049, respectively) over the long term compared with t0. At 6-month follow-up (t2), mental health (p < 0.003) and social functioning (p = 0.003) further increased after the treatment was stopped.ConclusionMulti-component VR treatments seem to significantly and in a clinically relevant way decrease fatigue symptoms and improve individual functioning and work participation in patients with severe prolonged fatigue over the long term and without showing relapse.

Recovery intention: its association with fatigue in the working population

To investigate the association of the intention to recover from work with fatigue and its moderating effect on the link between occupational characteristics and fatigue. Three hundred and eighty Austrian employees (nurses, teachers and administrative staff) participated in a survey assessing fatigue, the intention to create and engage in recovery activities and effort-reward imbalance as a measure of job characteristics. Data were analysed by regression analysis. Recovery intention was negatively associated with fatigue. This association was especially pronounced under conditions of high effort-reward imbalance, thus suggesting a buffering effect. Effort-reward imbalance, in return, was positively related to prolonged fatigue, indicating that fatigue was partly work related in the present sample. Individuals differ in their intent to engage in recovery activities. Those high in recovery intention are less exhausted, especially under conditions of more demanding and less rewarding work characteristics. Thus, a promotion of recovery intentions could contribute to the prevention of work-related fatigue.

Immunological abnormalities as potential biomarkers in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

BackgroundChronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is characterised by severe prolonged fatigue, and decreases in cognition and other physiological functions, resulting in severe loss of quality of life, difficult clinical management and high costs to the health care system. To date there is no proven pathomechanism to satisfactorily explain this disorder. Studies have identified abnormalities in immune function but these data are inconsistent. We investigated the profile of markers of immune function (including novel markers) in CFS/ME patients.MethodsWe included 95 CFS/ME patients and 50 healthy controls. All participants were assessed on natural killer (NK) and CD8+T cell cytotoxic activities, Th1 and Th2 cytokine profile of CD4+T cells, expression of vasoactive intestinal peptide receptor 2 (VPACR2), levels of NK phenotypes (CD56bright and CD56dim) and regulatory T cells expressing FoxP3 transcription factor.ResultsCompared to healthy individuals, CFS/ME patients displayed significant increases in IL-10, IFN-γ, TNF-α, CD4+CD25+ T cells, FoxP3 and VPACR2 expression. Cytotoxic activity of NK and CD8+T cells and NK phenotypes, in particular the CD56bright NK cells were significantly decreased in CFS/ME patients. Additionally granzyme A and granzyme K expression were reduced while expression levels of perforin were significantly increased in the CFS/ME population relative to the control population. These data suggest significant dysregulation of the immune system in CFS/ME patients.ConclusionsOur study found immunological abnormalities which may serve as biomarkers in CFS/ME patients with potential for an application as a diagnostic tool.

LimsPortal and BonsaiLIMS: development of a lab information management system for translational medicine

BackgroundLaboratory Information Management Systems (LIMS) are an increasingly important part of modern laboratory infrastructure. As typically very sophisticated software products, LIMS often require considerable resources to select, deploy and maintain. Larger organisations may have access to specialist IT support to assist with requirements elicitation and software customisation, however smaller groups will often have limited IT support to perform the kind of iterative development that can resolve the difficulties that biologists often have when specifying requirements. Translational medicine aims to accelerate the process of treatment discovery by bringing together multiple disciplines to discover new approaches to treating disease, or novel applications of existing treatments. The diverse set of disciplines and complexity of processing procedures involved, especially with the use of high throughput technologies, bring difficulties in customizing a generic LIMS to provide a single system for managing sample related data within a translational medicine research setting, especially where limited IT support is available.ResultsWe have designed and developed a LIMS, BonsaiLIMS, around a very simple data model that can be easily implemented using a variety of technologies, and can be easily extended as specific requirements dictate. A reference implementation using Oracle 11 g database and the Python framework, Django is presented.ConclusionsBy focusing on a minimal feature set and a modular design we have been able to deploy the BonsaiLIMS system very quickly. The benefits to our institute have been the avoidance of the prolonged implementation timescales, budget overruns, scope creep, off-specifications and user fatigue issues that typify many enterprise software implementations. The transition away from using local, uncontrolled records in spreadsheet and paper formats to a centrally held, secured and backed-up database brings the immediate benefits of improved data visibility, audit and overall data quality. The open-source availability of this software allows others to rapidly implement a LIMS which in itself might sufficiently address user requirements. In situations where this software does not meet requirements, it can serve to elicit more accurate specifications from end-users for a more heavyweight LIMS by acting as a demonstrable prototype.

Absence of XMRV Retrovirus and Other Murine Leukemia Virus-Related Viruses in Patients with Chronic Fatigue Syndrome

Chronic fatigue syndrome (CFS) is a multisystem disorder characterized by prolonged and severe fatigue that is not relieved by rest. Attempts to treat CFS have been largely ineffective primarily because the etiology of the disorder is unknown. Recently, CFS has been associated with xenotropic murine leukemia virus-related virus (XMRV) as well as other murine leukemia virus (MLV)-related viruses, though not all studies have found these associations. We collected blood samples from 100 CFS patients and 200 self-reported healthy volunteers from the same geographical area. We analyzed these in a blind manner using molecular, serological, and viral replication assays. We also analyzed samples from patients in the original study that reported XMRV in CFS patients. We did not find XMRV or related MLVs either as viral sequences or infectious viruses, nor did we find antibodies to these viruses in any of the patient samples, including those from the original study. We show that at least some of the discrepancy with previous studies is due to the presence of trace amounts of mouse DNA in the Taq polymerase enzymes used in these previous studies. Our findings do not support an association between CFS and MLV-related viruses, including XMRV, and the off-label use of antiretrovirals for the treatment of CFS does not seem justified at present.

Vocational rehabilitation of patients with prolonged fatigue

Vocational rehabilitation of patients with prolonged fatigue

Modulation of contractile apparatus Ca2+ sensitivity and disruption of excitation–contraction coupling by S‐nitrosoglutathione in rat muscle fibres

S-Nitrosoglutathione (GSNO) is generated in muscle and may S-glutathionylate and/or S-nitrosylate various proteins involved in excitation–contraction (EC) coupling, such as Na+-K+-ATPases, voltage-sensors (VSs) and Ca2+ release channels (ryanodine receptors,RyRs), possibly changing their properties. Using mechanically skinned fibres from rat extensor digitorum longus muscle, we sought to identify which EC coupling processes are most susceptible to GSNO-modulated changes and whether these changes could be important in muscle function and fatigue. For comparison, we examined the effect of other oxidation, nitrosylation, or glutathionylation treatments (S-nitroso-N-acetyl-penicillamine (SNAP), hydrogen peroxide,2,2-dithiodipyridine and reduced glutathione) on twitch and tetanic force, action potential (AP) repriming, sarcoplasmic reticulum (SR) Ca2+ loading and leakage, and contractile apparatus properties. None of the treatments detectably altered AP repriming, indicating that t-system excitability was relatively insensitive to such oxidative modification. Importantly, the overall effect on twitch and tetanic force of a given treatment was determined primarily by its action on Ca2+ sensitivity of the contractile apparatus. For example, S-nitrosylation with the NO• donor,SNAP, caused matching decreases in the contractile Ca2+ sensitivity and twitch response, and GSNO applied ∼10 min after preparation had very similar effects. The only exception was when GSNO was applied immediately after preparation, which resulted in irreversible decreases in twitch and tetanic responses even though it concomitantly increased Ca2+ sensitivity by∼0.1 pCaunits, the latter evidently due to S-glutathionylation of the contractile apparatus. This decrease in AP-mediated force responses was due to impaired VS–RyR coupling and was accompanied by increased Ca2+ leakage through RyRs. Such oxidation-related impairment of coupling could be responsible for prolonged low frequency fatigue in certain circumstances.

Phase I safety and pharmacokinetic study of SU-014813 in combination with docetaxel in patients with advanced solid tumours

BackgroundIn pre-clinical models enhanced anti-tumour activity was observed when SU-014813, an oral multi-targeted tyrosine kinase inhibitor was combined with docetaxel. This synergy might be explained by improvement of the penetration of cytotoxic agents into tumours as a result of both VEGFR and PDGFR inhibition. We assessed the maximal tolerated dose (MTD), evaluated the pharmacokinetics and preliminary anti-tumour efficacy of oral SU-014813 administered continuously in combination with docetaxel to patients with advanced solid tumours. MethodsIn this phase I study successive patient cohorts received docetaxel 60 or 75mg/m2 every 3weeks in combination with chronic daily dosing of SU-014813. Dose limiting toxicity was assessed both in the first and second treatment cycle. ResultsTwenty-five patients were entered on study of which 24 started treatment. Dose limiting toxicities were prolonged neutropenia, neutropenic fever, fatigue and diarrhoea. Other toxicities included fatigue, alopecia, nausea, vomiting, anorexia, rash, hypertension and hair discolouration. The recommended phase II dose was determined to be docetaxel 75mg/m2 in combination with SU-014813 50mg/day. There was no clinically relevant pharmacokinetic drug–drug interaction. Two patients (8%) achieved a partial response (PR) and 7 patients (29%) had stabilisation of their disease (SD) >6months, for a clinical benefit rate of 37.5%. The activity observed in patients with melanoma and sunitinib refractory gastrointestinal stromal tumours (GIST) was particularly noteworthy. ConclusionsOral SU-014813 50mg/day with docetaxel 75mg/m2 is a clinically feasible regimen with a manageable safety profile and anti-tumour activity. Further development is warranted in patients with melanoma and GIST.

The Effect of Shift Rotation on Employee Cortisol Profile, Sleep Quality, Fatigue, and Attention Level

Disrupted circadian rhythm, especially working night duty together with irregular sleep patterns, sleep deprivation, and fatigue, creates an occupational health risk associated with diminished vigilance and work performance. This study reviewed the effect of shift rotations on employee cortisol profile, sleep quality, fatigue, and attention level. Researchers conducted a systematic review of relevant articles published between 1996 and 2008 that were listed on the following databases: SCOPUS, OVID, Blackwell Science, EBSCO Host, PsycINFO, Cochrane Controlled Trials Register, and CEPS. A total of 28 articles were included in the review. Previous research into the effects of shift work on cortisol profiles, sleep quality, fatigue, and attention used data assessed at evidence Levels II to IV. Our systematic review confirmed a conflict between sleep-wake cycle and light-dark cycle in night work. Consequences of circadian rhythm disturbance include disruption of sleep, decreased vigilance, general feeling of malaise, and decreased mental efficiency. Shift workers who sleep during the day (day sleepers) experience cortisol secretion increases, which diminish the healing power of sleep and enjoy 1 to 4 hours less sleep on average than night sleepers. Sleep debt accumulation results in chronic fatigue. Prolonged fatigue and inadequate recovery result in decreased work performance and more incidents. Rotation from day shift to night shift and its effect on shift workers was a special focus of the articles retained for review. Disturbed circadian rhythm in humans has been associated with a variety of mental and physical disorders and may negatively impact on work safety, performance, and productivity.

Fracture toughness and fatigue crack growth characteristics of nanotwinned copper

Recent studies have shown that nanotwinned copper (NT Cu) exhibits a combination of high strength and moderate ductility. However, most engineering and structural applications would also require materials to have superior fracture toughness and prolonged subcritical fatigue crack growth life. The current study investigates the effect of twin density on the crack initiation toughness and stable fatigue crack propagation characteristics of NT Cu. Specifically, we examine the effects of tailored density of nanotwins, incorporated into a fixed grain size of ultrafine-grained (UFG) copper with an average grain size of 450 nm, on the onset and progression of subcritical fracture under quasi-static and cyclic loading at room temperature. We show here that processing-induced, initially coherent nanoscale twins in UFG copper lead to a noticeable improvement in damage tolerance under conditions of plane stress. This work strongly suggests that an increase in twin density, at a fixed grain size, is beneficial not only for desirable combinations of strength and ductility but also for enhancing damage tolerance characteristics such as fracture toughness, threshold stress intensity factor range for fatigue fracture and subcritical fatigue crack growth life. Possible mechanistic origins of these trends are discussed, along with issues and challenges in the study of damage tolerance in NT Cu.

Work–family conflict and prolonged fatigue among Japanese married male physicians

Fatigue experienced by physicians may not only endanger their own health but may also affect the safety of patients. Such fatigue may be associated with the work environment and personal factors such as work-family conflict (WFC). This study aimed to determine the association between WFC and prolonged fatigue among Japanese married male physicians. Physicians who graduated from a Japanese medical school answered a mailed anonymous self-report questionnaire. For assessment of WFC and prolonged fatigue, the Japanese versions of the WFC scale and the Checklist of Individual Strength questionnaire (CIS) were used. Prolonged fatigue was defined as the upper quartile of total CIS scores. The WFC scale comprises six dimensions. Total scores were divided into tertiles: low, intermediate, and high levels of WFC. A multiple logistic regression analysis was performed to examine the association between WFC and prolonged fatigue. A total of 540 male physicians answered the questionnaire, and the data of 444 married male physicians were analyzed. The data were then adjusted for age and work condition factors. Prolonged fatigue was significantly associated with high strain-based work interference with family (WIF; corrected odds ratio, 5.56; 95% confidence interval, 2.55-12.1), intermediate strain-based WIF (2.53, 1.25-5.10), high time-based family interference with work (FIW; 1.92, 1.08-3.40), and there was a weak association with high strain-based FIW (1.93, 0.98-3.83). Employers should take measures to improve working conditions in hospitals, and give physicians the opportunity to learn how to cope with WFC. These measures could ultimately help prevent prolonged fatigue.

Electrocardiographic abnormalities and diagnostic criteria in athletic overtraining

The overtraining syndrome describes the condition of prolonged imbalance between training load and recovery, with increased incidence in high level performance sports. Is very important to manage this syndrome not...

Factors of Working Conditions and Prolonged Fatigue among Teachers at Public Elementary and Junior High Schools

Prolonged fatigue among elementary and junior high school teachers not only damages their health but also affects the quality of education. The aim of this study was to determine the factors of working conditions associated with prolonged fatigue among teachers at public elementary and junior high schools. We distributed a self-reported, anonymous questionnaire to 3,154 teachers (1,983 in elementary schools, 1,171 in junior high schools) working in public schools in a city in Japan. They were asked to assess 18 aspects of their working conditions using a seven-point Likert scale. Prolonged fatigue was measured using the Japanese version of the checklist individual strength questionnaire. Multiple regression analysis was used to examine the association between working conditions and prolonged fatigue. Gender, age, and school type were introduced as confounders. In all, 2,167 teachers participated in this study. Results showed that qualitative and quantitative workload (time pressure due to heavy workload, interruptions, physically demanding job, extra work at home), communication with colleagues (poor communication, lack of support), and career factors (underestimation of performance by the board of education or supervisors, occupational position not reflecting training, lack of prospects for work, job insecurity) were associated with prolonged fatigue.