Measuring dengue illness intensity: Development and content validity of the dengue virus daily diary (DENV-DD).

BACKGROUND: Dengue is the most prevalent arboviral infection causing an estimated 50-60 million cases of febrile illness globally per year, exacting considerable disease burden. Few instruments exist to assess the patient illness experience, with most based on healthcare provider assessment, lacking standardization in timepoints and symptom assessment. This study aimed to evaluate the content validity of the novel 'Dengue Virus Daily Diary (DENV-DD)', designed to measure symptom intensity and disease burden within outpatient infant to adult populations. METHODS: The Dengue Illness Index Report Card was used as a foundation to create the DENV-DD, consisting of patient- and observer-reported outcome (PRO/ObsRO) instruments. In two South American dengue-endemic communities, qualitative combined concept elicitation and cognitive debriefing interviews were conducted among individuals and caregivers of children with symptomatic laboratory-confirmed dengue. Interviews were conducted across two rounds allowing DENV-DD modifications. A small-scale quantitative assessment of the DENV-DD was also conducted with data from an independent Dengue Human Infection Model (DHIM) to generate early evidence of feasibility of DENV-DD completion, instrument performance and insight into the sign/symptom trajectory over the course of illness. RESULTS: Forty-eight participants were interviewed (20 adults, 20 older children/adolescents with their caregivers, 8 caregivers of younger children). A wide spectrum of signs/symptoms lasting 3-15 days were reported with fever, headache, body ache/pain, loss of appetite, and body weakness each reported by > 70% participants. DENV-DD instructions, items and response scales were understood, and items were considered relevant across ages. DHIM data supported feasibility of DENV-DD completion. CONCLUSIONS: Findings demonstrate content validity of the DENV-DD (PRO/ObsRO instruments) in dengue-endemic populations. Psychometric and cultural validity studies are ongoing to support use of the DENV-DD in clinical studies.

Dengue is the most common viral infection transmitted to humans by mosquitos, and affects an estimated 50­60 million individuals globally per year. However, there are few resources for understanding and capturing the patient experience of dengue throughout illness. Most research studies are based on healthcare provider assessment, which lack consistency in terms of assessment time points and the signs/symptoms assessed. The 'Dengue Illness Index Report Card (DII-RC)' was used as a foundation to create the new 'Dengue Virus Daily Diary (DENV-DD)' to better capture the patient experience of symptom intensity and dengue disease burden for the duration of illness. Forty-eight individuals and caregivers of younger children from Peru and Ecuador who recently had symptomatic dengue were interviewed to understand the patient experience over the time of illness and to test whether the DENV-DD is understood by patients and caregivers and includes all relevant and important signs/symptoms and health-related quality of life impacts. Nine individuals with active dengue infection also completed the DENV-DD daily for 28-days as part of a clinical study. We found that > 70% of patients experienced fever, headache, body ache/pain, loss of appetite and body weakness. The DENV-DD instructions, questions and response option(s) were well understood, feasible to complete and the concepts assessed by the DENV-DD were relevant to the dengue experience. Our study adds to the understanding of the dengue illness experience and supports the DENV-DD for use in future dengue studies as an assessment of signs/symptoms throughout the duration of illness.

Fluid intelligence and naturalistic task impairments after focal brain lesions.

Classical executive tasks, such as Wisconsin card-sorting and verbal fluency, are widely used as tests of frontal lobe control functions. Since the pioneering work of Shallice and Burgess (1991), it has been known that complex, naturalistic tasks can capture deficits that are missed in these classical tests. Matching this finding, deficits in several classical tasks are predicted by loss of fluid intelligence, linked to damage in a specific cortical "multiple-demand" (MD) network, while deficits in a more naturalistic task are not. To expand on these previous results, we examined the effect of focal brain lesions on three new tests-a modification of the previously-used Hotel task, a new test of task switching after extended delays, and a test of decision-making in imagined real-life scenarios. As potential predictors of impairment we measured volume of damage to a priori MD and default mode (DMN) networks, as well as cortical damage outside these networks. Deficits in the three new tasks were substantial, but were not explained by loss of fluid intelligence, or by volume of damage to either MD or DMN networks. Instead, deficits were associated with diverse lesions, and not strongly correlated with one another. The results confirm that naturalistic tasks capture cognitive deficits beyond those measured by fluid intelligence. We suggest, however, that these deficits may not arise from specific control operations required by complex behaviour. Instead, like everyday activities, complex tasks combine a rich variety of interacting cognitive components, bringing many opportunities for processing to be disturbed.

The limited reach of surprise: Evidence against effects of surprise on memory for preceding elements of an event.

When reflecting on the past, some of our strongest memories are for experiences that took us by surprise. Extensive research has backed this intuition that we are more likely to remember surprising moments than mundane ones. But what about the moments leading up to the surprise? Are we more likely to remember those as well? While surprise is a well-established modulator of memory, it is unknown whether memory for the entire event will be enhanced, or only for the surprising occurrence itself. We developed a novel paradigm utilising stop-motion films, depicting of a sequence of narrative events, in which specific occurrences could be replaced with surprising ones, while keeping the rest of the film unaltered. Using this design, we tested whether surprise exerts retroactive effects on memory, and specifically whether any potential effect would be confined to elements in the same event as the surprising occurrence. In a large cohort of participants (n = 340), we found strong evidence that surprise did not retroactively modulate memory, neither when participants were tested immediately after study nor when they were tested 24 hours later. We suggest two possible accounts for these findings: (1) that the components of an event are encoded as independent episodic elements (not as a cohesive unit), or (2) that surprise segments experience, sectioning off the preceding elements as a separate event.

Roles of the Default Mode and Multiple-Demand Networks in Naturalistic versus Symbolic Decisions.

The default mode network (DMN) is often associated with representing semantic, social, and situational content of contexts and episodes. The DMN may therefore be important for contextual decision-making, through representing situational constraints and simulating common courses of events. Most decision-making paradigms, however, use symbolic stimuli and instead implicate cognitive control regions, such as the multiple demand (MD) system. This fMRI study aimed to contrast the brain mechanisms underlying decision-making based on rich naturalistic contexts or symbolic cues. While performing an ongoing task, 40 human participants (25 female) responded to different sounds. For one sound, the stimulus-response mapping was fixed; responses for the other sounds depended on the visual context: either lifelike scenes or letter symbols, varying across participants. Despite minimal behavioral differences between the groups, posterior DMN regions showed increased activity during context-dependent decision-making using the naturalistic scenes only, compared with symbolic cues. More anterior temporal and frontal DMN regions showed a different pattern, with sensitivity to the need for contextual control, but not to the type of context. Furthermore, in the scenes group, widespread DMN regions showed stronger representation of not just the context but also the sound whose significance it modulated. In comparison, the MD system showed strong univariate activity for every decision, but, intriguingly, somewhat reduced activity in the case of a scene-based but demanding context-dependent decision. Depending on context, we suggest, either DMN or MD regions may play a prominent role in selection and control of appropriate behavior.SIGNIFICANCE STATEMENT Contextual knowledge is widely believed to be important for guiding real-world goal-directed behavior. Much remains to be understood, however, regarding the underlying brain mechanisms. Using a novel paradigm to contrast decisions based on richly meaningful naturalistic scenes with decisions based on symbolic cues, we find that both multiple demand regions and default mode regions may contribute to the cognitive control of behavior. Rich semantic context enhances representation not just of the context itself, but also of the contents of the decision that it controls. Dependence of a decision on naturalistic context can also reverse the common pattern of multiple demand regions responding more, and default mode regions responding less, to more difficult decisions.

The effect of rule retrieval on activity in the default mode network.

The default mode network (DMN) is often associated with internally-directed cognition, distinct from the constraints of the external environment. However, a recent finding is that the DMN shows strong activation after large task switches during a demanding externally-directed task (Crittenden et al., 2015; Smith et al., 2018). Following other proposals, we have suggested that the DMN encodes cognitive or environmental context, and that context representations are momentarily strengthened during large cognitive switches, perhaps so that new activity can be checked against current environmental constraints. An alternative account, consistent with the role of the DMN in episodic memory, might be that switches to a substantially new task increase demands on rule retrieval. To test this alternative, we directly manipulated rule retrieval demands. Contrary to the retrieval account, increased retrieval demand led to reduced DMN activity, accompanied by increased activation in prefrontal and lateral parietal cognitive control areas. Unlike episodic retrieval, with its rich contextual representations, rule retrieval does not drive DMN activity. Accordingly, it cannot explain increased DMN activity during large cognitive switches.

Role of the Default Mode Network in Cognitive Transitions.

A frequently repeated finding is that the default mode network (DMN) shows activation decreases during externally focused tasks. This finding has led to an emphasis in DMN research on internally focused self-relevant thought processes. A recent study, in contrast, implicates the DMN in substantial externally focused task switches. Using functional magnetic resonance imaging, we scanned 24 participants performing a task switch experiment. Whilst replicating previous DMN task switch effects, we also found large DMN increases for brief rests as well as task restarts after rest. Our findings are difficult to explain using theories strictly linked to internal or self-directed cognition. In line with principal results from the literature, we suggest that the DMN encodes scene, episode or context, by integrating spatial, self-referential, and temporal information. Context representations are strong at rest, but rereference to context also occurs at major cognitive transitions.