The practice of qualitative parameterisation in the development of Bayesian networks

The typical phases of Bayesian network (BN) structured development include specification of purpose and scope, structure development, parameterisation and validation. Structure development is typically focused on qualitative issues and parameterisation quantitative issues, however there are qualitative and quantitative issues that arise in both phases. A common step that occurs after the initial structure has been developed is to perform a rough parameterisation that only captures and illustrates the intended qualitative behaviour of the model. This is done prior to a more rigorous parameterisation, ensuring that the structure is fit for purpose, as well as supporting later development and validation. In our collective experience and in discussions with other modellers, this step is an important part of the development process, but is under-reported in the literature. Since the practice focuses on qualitative issues, despite being quantitative in nature, we call this step qualitative parameterisation and provide an outline of its role in the BN development process.Comment: 6 pages, 2 figures, technical not

Ideographic Modeling and Data Visualization of Sleep, Affect, and Psychotic Symptoms: A Case Example

Background: 1. Psychotic disorders are heterogeneous. 2. Current diagnostic categorizations are unable to capture individuals’ unique symptom experiences. 3. Newly-developed ideographic analyses and data visualization tools may be useful in assessing individuals’ symptom experiences and stimulating data informed care.https://knowledgeconnection.mainehealth.org/lambrew-retreat-2021/1019/thumbnail.jp

Platelets kill circulating parasites of all major Plasmodium species in human malaria

Platelets are understood to assist host innate immune responses against infection, although direct evidence of this function in any human disease, including malaria, is unknown. Here we characterized platelet–erythrocyte interactions by microscopy and flow cytometry in patients with malaria naturally infected with Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, or Plasmodium knowlesi. Blood samples from 376 participants were collected from malaria-endemic areas of Papua, Indonesia, and Sabah, Malaysia. Platelets were observed binding directly with and killing intraerythrocytic parasites of each of the Plasmodium species studied, particularly mature stages, and was greatest in P vivax patients. Platelets preferentially bound to the infected more than to the uninfected erythrocytes in the bloodstream. Analysis of intraerythrocytic parasites indicated the frequent occurrence of platelet-associated parasite killing, characterized by the intraerythrocytic accumulation of platelet factor-4 and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling of parasite nuclei (PF4+TUNEL+ parasites). These PF4+TUNEL+ parasites were not associated with measures of systemic platelet activation. Importantly, patient platelet counts, infected erythrocyte-platelet complexes, and platelet-associated parasite killing correlated inversely with patient parasite loads. These relationships, taken together with the frequency of platelet-associated parasite killing observed among the different patients and Plasmodium species, suggest that platelets may control the growth of between 5% and 60% of circulating parasites. Platelet–erythrocyte complexes made up a major proportion of the total platelet pool in patients with malaria and may therefore contribute considerably to malarial thrombocytopenia. Parasite killing was demonstrated to be platelet factor-4-mediated in P knowlesi culture. Collectively, our results indicate that platelets directly contribute to innate control of Plasmodium infection in human malaria.This work was supported by the Australian National Health and Medical Research Council (Grants #1037304, #1045156, #490037, #605524, #1047082, #1047090, and #1066502, and Fellowships to N.M.A. [#1042072, #1135820], B.E.B. [#1088738], and M.J.G. [#1138860]), the Australian Research Council (grant #120100061), the Wellcome Trust (Fellowships to R.N.P. [#200909] and J.R.P. [#099875]), the Singapore National Medical Research Council (Award to T.W.Y. [CSA INV 15nov007]), and the Australian Department of Foreign Affairs and Trade

Plasmacytoid dendritic cells appear inactive during sub-microscopic Plasmodium falciparum blood-stage infection, yet retain their ability to respond to TLR stimulation

Plasmacytoid dendritic cells (pDC) are activators of innate and adaptive immune responses that express HLA-DR, toll-like receptor (TLR) 7, TLR9 and produce type I interferons. The role of human pDC in malaria remains poorly characterised. pDC activation and cytokine production were assessed in 59 malaria-naive volunteers during experimental infection with 150 or 1,800 P. falciparum-parasitized red blood cells. Using RNA sequencing, longitudinal changes in pDC gene expression were examined in five adults before and at peak-infection. pDC responsiveness to TLR7 and TLR9 stimulation was assessed in-vitro. Circulating pDC remained transcriptionally stable with gene expression altered for 8 genes (FDR < 0.07). There was no upregulation of co-stimulatory molecules CD86, CD80, CD40, and reduced surface expression of HLA-DR and CD123 (IL-3R-α). pDC loss from the circulation was associated with active caspase-3, suggesting pDC apoptosis during primary infection. pDC remained responsive to TLR stimulation, producing IFN-α and upregulating HLA-DR, CD86, CD123 at peak-infection. In clinical malaria, pDC retained HLA-DR but reduced CD123 expression compared to convalescence. These data demonstrate pDC retain function during a first blood-stage P. falciparum exposure despite sub-microscopic parasitaemia downregulating HLA-DR. The lack of evident pDC activation in both early infection and malaria suggests little response of circulating pDC to infection

High gamma activity distinguishes frontal cognitive control regions from adjacent cortical networks.

Though the lateral frontal cortex is broadly implicated in cognitive control, functional MRI (fMRI) studies suggest fine-grained distinctions within this region. To examine this question electrophysiologically, we placed electrodes on the lateral frontal cortex in patients undergoing awake craniotomy for tumor resection. Patients performed verbal tasks with a manipulation of attentional switching, a canonical control demand. Power in the high gamma range (70-250 Hz) distinguished electrodes based on their location within a high-resolution fMRI network parcellation of the frontal lobe. Electrodes within the canonical fronto-parietal control network showed increased power in the switching condition, a result absent in electrodes within default mode, language and somato-motor networks. High gamma results contrasted with spatially distributed power decreases in the beta range (12-30 Hz). These results confirm the importance of fine-scale functional distinctions within the human frontal lobe, and pave the way for increased precision of functional mapping in tumor surgeries

Tumour-infiltrated cortex participates in large-scale cognitive circuits.

The extent to which tumour-infiltrated brain tissue contributes to cognitive function remains unclear. We tested the hypothesis that cortical tissue infiltrated by diffuse gliomas participates in large-scale cognitive circuits using a unique combination of intracranial electrocorticography (ECoG) and resting-state functional magnetic resonance (fMRI) imaging in four patients. We also assessed the relationship between functional connectivity with tumour-infiltrated tissue and long-term cognitive outcomes in a larger, overlapping cohort of 17 patients. We observed significant task-related high gamma (70-250 Hz) power modulations in tumour-infiltrated cortex in response to increased cognitive effort (i.e., switch counting compared to simple counting), implying preserved functionality of neoplastic tissue for complex tasks probing executive function. We found that tumour locations corresponding to task-responsive electrodes exhibited functional connectivity patterns that significantly co-localised with canonical brain networks implicated in executive function. Specifically, we discovered that tumour-infiltrated cortex with larger task-related high gamma power modulations tended to be more functionally connected to the dorsal attention network (DAN). Finally, we demonstrated that tumour-DAN connectivity is evident across a larger cohort of patients with gliomas and that it relates to long-term postsurgical outcomes in goal-directed attention. Overall, this study contributes convergent fMRI-ECoG evidence that tumour-infiltrated cortex participates in large-scale neurocognitive circuits that support executive function in health. These findings underscore the potential clinical utility of mapping large-scale connectivity of tumour-infiltrated tissue in the care of patients with diffuse gliomas

Immunogenicity and Efficacy of Single Antigen Gp63, Polytope and PolytopeHSP70 DNA Vaccines against Visceral Leishmaniasis in Experimental Mouse Model

Polytope approach of genetic immunization is a promising strategy for the prevention of infectious disease as it is capable of generating effective cell mediated immunity by delivering the T cell epitopes assembled in series. Leishmaniasis is a significant world wide health problem for which no vaccine exists. In this study we have compared immunogenicity and efficacy of three types of DNA vaccines: single antigen Gp63 (Gp63/pcDNA), polytope (Poly/pcDNA) and Polytope fused with hsp70 (Poly/hsp/pcDNA) against visceral leishmaniasis in susceptible BALB/c mice. Mice vaccinated with these plasmids generated strong Th1 immune response as seen by dominating IFN-γ over IL-10 cytokine. Interestingly, cytotoxic responses generated by polytope DNA plasmid fused with hsp70 of Leishmania donovani were significantly higher when compared to polytope and single antigen Gp63 vaccine. Challenge studies revealed that the parasite load in liver and spleen was significantly lower with Poly/hsp/pcDNA vaccination compared to other vaccines. Therefore, our study indicates that polytope DNA vaccine is a feasible, practical and effective approach for visceral leishmaniasis

IQ Trajectory, Cognitive Reserve, and Clinical Outcome Following a First Episode of Psychosis: A 3-Year Longitudinal Study

Comparison of current and estimated premorbid IQ in schizophrenia suggests that there are subgroups with low IQ, deteriorated IQ (DIQ), or preserved IQ and that this is established by psychosis onset. There are no controlled studies examining the trajectory of these IQ subgroups longitudinally or their relationship with clinical and social outcomes. Of 129 individuals with first-episode schizophrenia or schizoaffective disorder, 25% showed stable low IQ, 31% showed stable IQ in the average/high range, and 44% demonstrated intellectual deterioration by 10 points or more. Patients in the low and deteriorated groups were equally impaired on tests of memory and executive function compared with the preserved average/high-IQ group and controls and showed more negative and disorganization symptoms than the preserved average/high-IQ group. Sixty patients and 27 controls were assessed again 1 and 3 years later. There was no evidence that those with IQ deterioration at baseline continued on a declining cognitive trajectory or that those with preserved average/high IQ experienced subsequent IQ decline. The low IQ group showed no change in IQ, whereas both the DIQ and the preserved IQ groups improved. However, the rate of improvement of these 2 subgroups was no greater than that of the healthy controls, suggesting that this reflected practice effects. Both the low and the deteriorated groups had longer index admissions, more core negative symptoms, and worse occupational outcomes at 3 years. These data suggest that following psychosis onset, IQ is stable and that it is IQ at psychosis onset rather than premorbid IQ predicts a more severe illness