Paper and electronic versions of HM-PRO, a novel patient-reported outcome measure for hematology: an equivalence study.

© 2019 Goswami, Oliva, Ionova et al.Aim:To determine measurement equivalence of paper and electronic application of the hematologi-cal malignancy-patient-reported outcome (HM-PRO), a specific measure for the evaluation of patient-reported outcomes in HMs.Patients & methods:Following International Society of Pharmacoeconomicsand Outcomes Research ePRO Good Research Practice Task Force guidelines, a total of 193 adult patientswith different HMs were recruited into a multicenter prospective study. The paper and the electronic ver-sion of the instrument were completed in the outpatient clinics in a randomized crossover design with a30-min time interval to minimize the learning effect. Those who completed the paper version first, com-pleted the electronic version after 30 min and vice versa. Instrument version and order effects were testedon total score of the two parts of the HM-PRO (Part A: quality of life and Part B: signs & symptoms) in atwo-way ANOVA with patients as random effects. Intraclass correlation coefficients (95% CI) and Spear-man’s rank correlation coefficients were used to evaluate test–retest reliability and reproducibility. Theeffects of instrument version and order were tested on total score of the two parts of HM-PRO.Results:The questionnaire version and administration order effects were not significant at the 5% level. Therewere no interactions found between these two factors for HM-PRO (Part A [quality of life]; p=0.95); and(part B [signs and symptoms]; p=0.72]. Spearman’s rank correlation coefficients were greater than 0.9, andintraclass correlation coefficients ranged from 0.94 to 0.98; furthermore, the scores were not statisticallydifferent between the two versions, showing acceptable reliability indexes. Noteworthy, the differencebetween the completion time for both paper (mean=6:38 min) and electronic version (mean=7:29 min)was not statistically significant (n=100; p=0.11). Patients did not report any difficulty in completing theelectronic version during cognitive interviews and were able to understand and respond spontaneously.Conclusion:Measurement equivalence has been demonstrated for the paper and electronic applicationof the HM-PRO.Peer reviewe

Development of a Novel Hematological Malignancy Specific Patient-Reported Outcome Measure (HM-PRO) : Content Validity

Copyright © 2020 Goswami, Oliva, Ionova, Else, Kell, Fielding, Jennings, Karakantza, Al-Ismail, Collins, McConnell, Langton and Salek.Background: The quality of life of patients at all stages of hematological malignancy is greatly affected by the disease and its treatment. There is a wide range of health-related quality of life (HRQoL) issues important to these patients. Any new instrument developed to measure HRQoL of such patients should be content valid, i.e., the items should be comprehensively relevant to the patients and their health condition. The aim of the present study was to examine content validity of a hematological malignancy specific patient reported outcome measure (HM-PRO) developed for use in routine clinical practice. Methods: Following literature review and semi-structured interviews, the generated themes and sub-themes were discussed to develop the prototype version of the HM-PRO. A 4-step approach was used for content validation: initial testing and cognitive interviewing; item rating; content validity panel meeting; final field testing and cognitive interviewing. Additional questions related to patients' perception of recall period and preferred sentence structure (i.e., question or statement) of the items were also asked during cognitive interviews. Results: The content analysis of 129 transcribed semi-structured interviews resulted in the prototype version of the instrument consisting of 58 items grouped into two parts: Part A (impact/HRQoL - 34 items) and Part B (signs and symptoms - 24 items). The initial testing showed intra-class correlation coefficient (ICC) of >0.8 for both Part A and Part B. Item rating for language clarity, completeness, relevance, and response scale by experts and patients showed content validity index for scales average >0.8 for both Part A and Part B, except 0.64 for relevance for Part A by the patient panel. The final testing of the revised version of the instrument showed the Cronbach's alpha value of 0.91 for Part A and 0.76 for Part B, suggesting high internal consistency, and ICC of 0.91 for Part A and 0.76 for Part B. The recall period of "today" for Part-A and "last 3 days" for Part-B were the patients' preferred "recall period." Furthermore, the patients expressed preference to the HM-PRO items as statements. Conclusion: The findings of this study confirm that the HM-PRO possesses a strong content validity, includes all the issues important to patients and is easy to read, understand and respond to spontaneously.Peer reviewedFinal Published versio

Preclinical toxicology and safety pharmacology of the first-in-class GADD45β/MKK7 inhibitor and clinical candidate, DTP3

Aberrant NF-κB activity drives oncogenesis and cell survival in multiple myeloma (MM) and many other cancers. However, despite an aggressive effort by the pharmaceutical industry over the past 30 years, no specific IκBα kinase (IKK)β/NF-κB inhibitor has been clinically approved, due to the multiple dose-limiting toxicities of conventional NF-κB-targeting drugs. To overcome this barrier to therapeutic NF-κB inhibition, we developed the first-in-class growth arrest and DNA-damage-inducible (GADD45)β/mitogen-activated protein kinase kinase (MKK)7 inhibitor, DTP3, which targets an essential, cancer-selective cell-survival module downstream of the NF-κB pathway. As a result, DTP3 specifically kills MM cells, ex vivo and in vivo, ablating MM xenografts in mice, with no apparent adverse effects, nor evident toxicity to healthy cells. Here, we report the results from the preclinical regulatory pharmacodynamic (PD), safety pharmacology, pharmacokinetic (PK), and toxicology programmes of DTP3, leading to the approval for clinical trials in oncology. These results demonstrate that DTP3 combines on-target-selective pharmacology, therapeutic anticancer efficacy, favourable drug-like properties, long plasma half-life and good bioavailability, with no target-organs of toxicity and no adverse effects preclusive of its clinical development in oncology, upon daily repeat-dose administration in both rodent and non-rodent species. Our study underscores the clinical potential of DTP3 as a conceptually novel candidate therapeutic selectively blocking NF-κB survival signalling in MM and potentially other NF-κB-driven cancers

Deletion of Abi3 gene locus exacerbates neuropathological features of Alzheimer's disease in a mouse model of Aβ amyloidosis

Recently, large-scale human genetics studies identified a rare coding variant in the ABI3 gene that is associated with an increased risk of Alzheimer’s disease (AD). However, pathways by which ABI3 contributes to the pathogenesis of AD are unknown. To address this question, we determined whether loss of ABI3 function affects pathological features of AD in the 5XFAD mouse model. We demonstrate that the deletion of Abi3 locus significantly increases amyloid β (Aβ) accumulation and decreases microglia clustering around the plaques. Furthermore, long-term potentiation is impaired in 5XFAD;Abi3 knockout (“Abi3−/−”) mice. Moreover, we identified marked changes in the proportion of microglia subpopulations in Abi3−/− mice using a single-cell RNA sequencing approach. Mechanistic studies demonstrate that Abi3 knockdown in microglia impairs migration and phagocytosis. Together, our study provides the first in vivo functional evidence that loss of ABI3 function may increase the risk of developing AD by affecting Aβ accumulation and neuroinflammation

Influence of test parameters on in vitro fracture resistance of post-endodontic restorations: a structured review

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75093/1/j.1365-2842.2009.01940.x.pd

Stronger Neural Modulation by Visual Motion Intensity in Autism Spectrum Disorders

Theories of autism spectrum disorders (ASD) have focused on altered perceptual integration of sensory features as a possible core deficit. Yet, there is little understanding of the neuronal processing of elementary sensory features in ASD. For typically developed individuals, we previously established a direct link between frequency-specific neural activity and the intensity of a specific sensory feature: Gamma-band activity in the visual cortex increased approximately linearly with the strength of visual motion. Using magnetoencephalography (MEG), we investigated whether in individuals with ASD neural activity reflect the coherence, and thus intensity, of visual motion in a similar fashion. Thirteen adult participants with ASD and 14 control participants performed a motion direction discrimination task with increasing levels of motion coherence. A polynomial regression analysis revealed that gamma-band power increased significantly stronger with motion coherence in ASD compared to controls, suggesting excessive visual activation with increasing stimulus intensity originating from motion-responsive visual areas V3, V6 and hMT/V5. Enhanced neural responses with increasing stimulus intensity suggest an enhanced response gain in ASD. Response gain is controlled by excitatory-inhibitory interactions, which also drive high-frequency oscillations in the gamma-band. Thus, our data suggest that a disturbed excitatoryinhibitory balance underlies enhanced neural responses to coherent motion in ASD

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease