A psychometric investigation of health-related quality of life measures for paediatric neurodevelopment assessment: Reliability and concurrent validity of the PEDS-QL, CHU-9D, and the EQ-5D-Y.

There is a need for tools that can provide a brief assessment of functioning for children with neurodevelopmental conditions, including health-related quality of life (HR-QoL). This study evaluated the psychometric properties of three commonly used and well known HR-QoL measures in a cohort of children presenting to clinical developmental assessment services. The most common diagnoses received in these assessment services were autism spectrum disorders. Findings showed good internal consistency for the PedsQL and the CHU-9D, but not the EQ-5D-Y. This research also found that the CHU-9D, EQ-5D-Y, and PedsQL correlated with relevant functioning domains assessed by the VABS-III. Overall, the measures showed that children with neurodevelopmental conditions experienced poor HR-QoL. The majority of children (>86%) met cut-off criteria for significant health concerns on the PedsQL. On the EQ-5D-Y and CHU-9D, they showed reduced HR-QoL particularly on domains relating to school and homework, being able to join in activities, looking after self, and doing usual activities. This study supports the use of the CHU-9D and PedsQL in this population to assess and potentially track HR-QoL in a broad neurodevelopment paediatric population.

Racial and ethnic differences in clonal hematopoiesis, tumor markers, and outcomes of patients with multiple myeloma.

Multiple myeloma (MM) incidence, mortality, and survival vary by race and ethnicity, but the causes of differences remain unclear. We investigated demographic, clinical, and molecular features of diverse MM patients to elucidate mechanisms driving clinical disparities. This study included 495 MM patients (self-reported Hispanic, n = 45; non-Hispanic Black, n = 52; non-Hispanic White, n = 398). Hispanic and non-Hispanic Black individuals had an earlier age of onset than non-Hispanic White individuals (53 and 57 vs 63 years, respectively, P < .001). There were no differences in treatment by race and ethnicity groups, but non-Hispanic Black patients had a longer time to hematopoietic cell transplant than non-Hispanic White patients (376 days vs 248 days; P = .01). Overall survival (OS) was improved for non-Hispanic Black compared with non-Hispanic White patients (HR, 0.50; 95% CI, 0.31-0.81; P = .005), although this association was attenuated after adjusting for clinical features (HR, 0.62; 95% CI, 0.37-1.03; P = .06). Tumor mutations in IRF4 were most common in Hispanic patients, and mutations in SP140, AUTS2, and SETD2 were most common in non-Hispanic Black patients. Differences in tumor expression of BCL7A, SPEF2, and ANKRD26 by race and ethnicity were observed. Clonal hematopoiesis was detected in 12% of patients and associated with inferior OS in non-Hispanic Black patients compared with patients without clonal hematopoiesis (HR, 4.36; 95% CI, 1.36-14.00). This study provides insight into differences in molecular features that may drive clinical disparities in MM patients receiving comparable treatment, with the novel inclusion of Hispanic individuals.

Kyasanur Forest disease, India, 2011-2012.

To determine the cause of the recent upsurge in Kyasanur Forest disease, we investigated the outbreak that occurred during December 2011-March 2012 in India. Male patients >14 years of age were most commonly affected. Although vaccination is the key strategy for preventing disease, vaccine for boosters was unavailable during 2011, which might be a reason for the increased cases.

Modulation of Ets-1 expression in B lymphocytes is dependent on the antigen receptor-mediated activation signals and cell cycle status.

In this report, we tested the hypothesis that Ets-1 transcription factor is modulated at the mRNA level during B cell antigen receptor (BCR)-induced cell-signalling events. Quiescent B cells express high levels of Ets-1 mRNA. Stimulation through the BCR results in time-dependent inhibition of Ets-1 mRNA expression in primary splenic B cells with maximal inhibition observed by 16-h post-stimulation. Inhibition of Ets-1 expression is specific to antigen receptor but not CD40-mediated activation. Antigen receptor-induced inhibition of Ets-1 mRNA can be mimicked by phorbol myristate acetate (PMA) and/or ionomycin. PMA but not ionomycin-induced inhibition of Ets-1 expression is rescued by the inhibitors of protein kinase C and MEK. Extended time-course analysis revealed a time-dependent cyclical pattern in the re-expression of Ets-1 mRNA. While resting cells revealed maximal Ets-1 mRNA expression, activation events that induced exit from G(0) /G(1) or cells blocked in early S phase exhibited decreased Ets-1 mRNA levels. Interestingly, cells arrested at late G2 or M phase of the cell cycle failed to down modulate Ets-1 mRNA expression. Overexpression of Ets-1 in 70Z/3 B cell line caused abnormal accumulation of cells in S phase associated with increased cyclin A expression. Consistent with a requirement for Ets-1 in BCR-induced cell cycle entry, splenic B cells from mice deficient in Ets-1 showed defective antigen receptor-induced DNA synthesis and S phase entry. These results suggest a critical role for Ets-1 regulation during B cell activation and cell cycle entry.

Getting away with murder. How law courts and police fail victims of domestic violence.

PIP: In 1986, major amendments were introduced to the Indian penal law, in which two new sections were added to the penal code. These sections made violence leading to murder of women within 7 years of marriage, as well as harassment by a husband or his relatives leading to suicide, punishable. At the same time, the Indian Evidence Act was also amended, shifting the burden of proof for such deaths on the accused, which meant that, contrary to normal practice, the husband and his family would be presumed guilty unless proven innocent. Despite such amendments, the Vimochana, a leading voluntary organization working on cases of domestic violence in Bangalore, indicates that the number of cases registered by the police and eventually punished by the courts has not increased. It seems to have only discredited the legal process as an ineffective method of protecting weak citizens within the democratic framework. According to the Vimochana, this may be because every stage of the recording and investigation of an incident of domestic violence, even when it leads to death is poorly handled. This paper presents the experiences of the Vimochana, which show how the law, courts, and police fail victims of domestic violence in the region. Moreover, it provides recommended strategies on addressing this issue.^ieng

Hyperphosphorylation of the cytoskeletal protein Tau by the MAP-kinase PK40erk2: regulation by prior phosphorylation with cAMP-dependent protein kinase A.

PK40erk2 is a MAP kinase which phosphorylates recombinant hTau40 up to 14 moles of phosphate/mole, markedly slowing its electrophoretic mobility. PK40erk2 acting on TAU is expected to cause the appearance of Alzheimer's disease-specific phosphoepitopes, detectable by specific antibodies. Maximal phosphorylation in vitro of hTau40 by PKAcat incorporates only 2-3 moles of phosphate/mole. Consequent, but smaller, reduction in electrophoretic mobility is seen, but not the formation of Alzheimer-specific or hyperphosphorylation-specific epitopes. Phosphorylation of hTau40 by PKAcat sharply reduces the number of phosphates that can now be introduced by PK40erk2 to 5-6 moles/mole, instead of the expected 11 moles/mole. Thus, prior phosphorylation by PKA, a non-proline-directed protein kinase, regulates the conformation of the protein substrate Tau so as to make some sites very much less accessible to phosphorylation by the proline-directed kinase, PK40erk2.

Hyperphosphorylation of human TAU by brain kinase PK40erk beyond phosphorylation by cAMP-dependent PKA: relation to Alzheimer's disease.

Abnormal hyperphosphorylation of the cytoskeletal protein TAU is seen in the characteristic paired helical filaments [neurofibrillary tangles] of Alzheimer's disease [AD]. A recently described protein kinase, PK40erk, (1) a member of the ERK family of kinases, can produce in vitro many of the properties of Alzheimer-like hyperphosphorylated TAU. cAMP-dependent protein kinase A [PKA] phosphorylates TAU to a lesser extent; however, the product is not like the hyperphosphorylated TAU of AD in several important respects. We now report that in vitro PK40erk, a candidate for the enzyme responsible for TAU hyperphosphorylation in AD, will further phosphorylate TAU that was previously saturated by protein kinase A, provided that the concentrations of free uncomplexed ATP are low. Interestingly, the actions of different kinases on TAU are not independent, but may depend on the order in which they work on TAU; i.e., prior phosphorylation by PKA partially inhibits the action of PK40erk.