Optimisation of stochastic networks with blocking: a functional-form approach

This paper introduces a class of stochastic networks with blocking, motivated by applications arising in cellular network planning, mobile cloud computing, and spare parts supply chains. Blocking results in lost revenue due to customers or jobs being permanently removed from the system. We are interested in striking a balance between mitigating blocking by increasing service capacity, and maintaining low costs for service capacity. This problem is further complicated by the stochastic nature of the system. Owing to the complexity of the system there are no analytical results available that formulate and solve the relevant optimization problem in closed form. Traditional simulation-based methods may work well for small instances, but the associated computational costs are prohibitive for networks of realistic size. We propose a hybrid functional-form based approach for finding the optimal resource allocation, combining the speed of an analytical approach with the accuracy of simulation-based optimisation. The key insight is to replace the computationally expensive gradient estimation in simulation optimisation with a closed-form analytical approximation that is calibrated using a single simulation run. We develop two implementations of this approach and conduct extensive computational experiments on complex examples to show that it is capable of substantially improving system performance. We also provide evidence that our approach has substantially lower computational costs compared to stochastic approximation

Factors of resilience in informal caregivers of people with dementia from integrative international data analysis

Background/Aims: Although caring for a person with dementia can be stressful, some caregivers appear to experience few negative consequences to their well-being. This study aimed to examine what proportion of caregivers demonstrates resilience under different challenging circumstances and to identify factors related to their resilience. Methods: Baseline data from 4 studies from the Netherlands and UK among informal caregivers of people with dementia were harmonized and integrated. Caregiver resilience was defined as high levels of psychological well-being despite different types of high caregiving demands. Multivariate regression analyses identified factors significantly related to caregiver resilience. Results: The integrated data set included 15 harmonized variables with data from 1,048 caregivers facing a high care demand. The prevalence of resilience varied between 35 and 43%, depending on the demand for high care. Being a male caregiver, caring for a female, living apart from your relative, and low caregiver burden were positively related to caregiver resilience. Conclusion: Caregivers have the capacity to demonstrate resilience despite significant challenges. This study demonstrates how harmonization of data from multiple existing studies can be used to increase power and explore the consistency of findings. This contributes to a better understanding of which factors are likely to facilitate caregiver resilience and offers insights for developing services

Early Response to Dexamethasone as Prognostic Factor: Result from Indonesian Childhood WK-ALL Protocol in Yogyakarta

Early response to treatment has been shown to be an important prognostic factor of childhood acute lymphoblastic leukemia (ALL) patients in Western studies. We studied this factor in the setting of a low-income province in 165 patients treated on Indonesian WK-ALL-2000 protocol between 1999 and 2006. Poor early response, defined as a peripheral lymphoblasts count of ≥1000/μL after 7 days of oral dexamethasone plus one intrathecal methotrexate (MTX), occurred in 19.4% of the patients. Poor responders showed a higher probability of induction failures compared to good responders (53.1% versus 23.3%, P < 0.01), higher probability of resistant disease (15.6% versus 4.5%, P = 0.02), shorter disease-free survival (P = 0.034; 5-year DFS: 24.9% ± 12.1% versus 48.6% ± 5.7%), and shorter event-free survival (P = 0.002; 5-year EFS: 9.7% ± 5.3% versus 26.3% ± 3.8%). We observed that the percentage of poor responders in our setting was higher than reported for Western countries with prednisone or prednisolone as the steroids. The study did not demonstrate a significant additive prognostic value of early response over other known risk factors (age and white blood cell count) for DFS and only a moderately added value for EFS

Comparing the sensitivities of two screening tests in nonblinded randomized paired screen-positive trials with differential screening uptake

Before a new screening test can be used in routine screening, its performance needs to be compared to the standard screening test. This comparison is generally done in population screening trials with a screen-positive design where participants undergo one or both screening tests after which disease verification takes place for those positive on at least one screening test. We consider the randomized paired screen-positive design of Alonzo and Kittelson where participants are randomized to receive one of the two screening tests and only participants with a positive screening test subsequently receive the other screening test followed by disease verification. The tests are usually offered in an unblinded fashion in which case the screening uptake may differ between arms, in particular when one test is more burdensome than the other. When uptake is associated with disease, the estimator for the relative sensitivity derived by Alonzo and Kittelson may be biased and the type I error of the associated statistical test is no longer guaranteed to be controlled. We present methods for comparing sensitivities of screening tests in randomized paired screen-positive trials that are robust to differential screening uptake. In a simulation study, we show that our methods adequately control the type I error when screening uptake is associated with disease. We apply the developed methods to data from the IMPROVE trial, a nonblinded cervical cancer screening trial comparing the accuracy of HPV testing on self-collected versus provider-collected samples. In this trial, screening uptake was higher among participants randomized to self-collection

Interobserver variation in CD30 immunohistochemistry interpretation; consequences for patient selection for targeted treatment

AimsCD30 immunohistochemistry (IHC) in malignant lymphoma is used for selection of patients in clinical trials using brentuximab vedotin, an antibody drug-conjugate targeting the CD30 molecule. For reliable implementation in daily practice and meaningful selection of patients for clinical trials, information on technical variation and interobserver reproducibility of CD30 immunohistochemistry (IHC) staining is required. Methods and resultsWe conducted a three-round reproducibility assessment of CD30 scoring for categorised frequency and intensity, including a technical validation, a live polling' pre- and post-instruction scoring round and a web-based round including individual scoring with additional IHC information to mimic daily diagnostic practice. Agreement in all three scoring rounds was poor to fair ( = 0.12-0.35 for CD30-positive tumour cell percentage and = 0.16-0.41 for staining intensity), even when allowing for one category of freedom in percentage of tumour cell positivity ( = 0.30-0.61). The first round with CD30 staining performed in five independent laboratories showed objective differences in staining intensity. In the second round, approximately half the pathologists changed their opinion on CD30 frequency after a discussion on potential pitfalls, highlighting hesitancy in decision-making. Using fictional cut-off points for percentage of tumour cell positivity, agreement was still suboptimal ( = 0.35-0.60). ConclusionsLack of agreement in cases with heterogeneous expression is shown to influence patient eligibility for treatment with brentuximab vedotin, both in clinical practice and within the context of clinical trials, and limits the potential predictive value of the relative frequency of CD30-positive neoplastic cells for clinical response

Filamin C-related myopathies: pathology and mechanisms

The term filaminopathy was introduced after a truncating mutation in the dimerization domain of filamin C (FLNc) was shown to be responsible for a devastating muscle disease. Subsequently, the same mutation was found in patients from diverse ethnical origins, indicating that this specific alteration is a mutational hot spot. Patients initially present with proximal muscle weakness, while distal and respiratory muscles become affected with disease progression. Muscle biopsies of these patients show typical signs of myofibrillar myopathy, including disintegration of myofibrils and aggregation of several proteins into distinct intracellular deposits. Highly similar phenotypes were observed in patients with other mutations in Ig-like domains of FLNc that result in expression of a noxious protein. Biochemical and biophysical studies showed that the mutated domains acquire an abnormal structure causing decreased stability and eventually becoming a seed for abnormal aggregation with other proteins. The disease usually presents only after the fourth decade of life possibly as a result of ageing-related impairments in the machinery that is responsible for disposal of damaged proteins. This is confirmed by mutations in components of this machinery that cause a highly similar phenotype. Transfection studies of cultured muscle cells reflect the events observed in patient muscles and, therefore, may provide a helpful model for testing future dedicated therapeutic strategies. More recently, FLNC mutations were also found in families with a distal myopathy phenotype, caused either by mutations in the actin-binding domain of FLNc that result in increased actin-binding and non-specific myopathic abnormalities without myofibrillar myopathy pathology, or a nonsense mutation in the rod domain that leads to RNA instability, haploinsufficiency with decreased expression levels of FLNc in the muscle fibers and myofibrillar abnormalities, but not to the formation of desmin-positive protein aggregates required for the diagnosis of myofibrillar myopathy

Temperament Traits and Psychopathology in Young Clinically Referred Children Compared to a General Population Sample

Evidence from general population studies shows the contribution of various temperament traits to the development of child psychopathology. Little is known about which traits are associated with internalizing and externalizing problems in young clinically referred children. The current study assessed temperament and internalizing and externalizing problems in 216 referred children (M = 4.35 years, SD 0.89, 81% boys). A comparison was made with an age and gender matched general population sample. Referred children showed less effortful control than general population children. Less effortful control and more negative affectivity were associated with more internalizing and externalizing problems across groups. Surgency, and specifically temperamental impulsivity, was more strongly associated with externalizing problems in referred children compared to general population. Less soothability, less inhibitory control and more frustration predicted (sub)clinical levels of comborbid internalizing and externalizing problems in referred children. The results can be used in diagnostic and treatment procedures in early childhood