Predicting Treatment Responses in Patients With Osteoarthritis: Results From Two Phase III Tanezumab Randomized Clinical Trials.

Prediction of treatment responses is essential to move forward translational science. Our question was to identify patient-based variables that predicted responses to treatments. We conducted secondary analyses on pooled data from two randomized phase III clinical trials (NCT02697773 and NCT02709486) conducted in participants with moderate to severe osteoarthritis randomized to subcutaneous placebo (n = 514) or tanezumab 2.5 mg (n = 514). We used gradient boosted regression trees to identify variables that predicted Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain subscale scores at Week 16 and marginal plots to determine the directional relationship between each variable category and responses to placebo or tanezumab within the models. We also used Virtual Twins models to identify potential subgroups of response to the active treatment vs. placebo. We found that responses to placebo were predicted by baseline WOMAC Physical Function, baseline WOMAC Pain, the radiographic classification of the index joint, and the standard deviation of diary pain scores at baseline. In contrast, baseline WOMAC Pain along with failure of prior medications, duration of disease, and standard deviation of diary pain scores at baseline were predictive of tanezumab responses as expressed by the WOMAC Pain scores at Week 16. Those who responded to tanezumab vs. placebo were identified based on the radiographic classification of the index joint and either age or smoking status. These secondary-data analyses identified distinct and common patient-based variables to predict response to placebo or tanezumab. These findings will inform the design of future clinical trials, helping to move forward clinical pharmacology and translational science.

The default-interventionist model underlies premise typicality weakening the premise diversity effect during category-based induction: Event-related potentials evidence.

The diversity effect during category-based induction (CBI) means that the more diverse the evidence, the higher will be the conclusion's inductive strength. However, it is influenced by the premise typicality. Three competitive cognitive processing models account for this influence: (1) The pre-emptive conflict resolution model assumes that only premise typicality activates; (2) the parallel-competitive model assumes that premise typicality and diversity activate in parallel; and (3) the default-interventionist model assumes that a default response of premise diversity first activates and is subsequently followed by premise typicality, or premise typicality activates first, followed by premise diversity. The timing of premise typicality affecting the diversity effect during CBI was measured using event-related potentials to determine which cognitive model best explains this influence. Similar to previous studies, non-diverse premise inductive tasks involving two typical premise categories were compared with diverse premise inductive tasks involving a typical and an atypical category. The results showed that non-diverse conditions had higher "correct" response proportions, greater inductive strength, higher "definitely" response proportions, and shorter reaction times than diverse conditions, showing that premise typicality weakens the diversity effect. Moreover, the diverse premises elicited larger P2, smaller FN400, and greater frontal post-N400-positivity amplitudes than non-diverse premises, suggesting that premise diversity was facilitated during a relatively early time window and revised by premise typicality in a later window. These results support the default-interventionist in nature during thinking and reasoning.

The human mediodorsal thalamus: Organization, connectivity, and function.

The human mediodorsal thalamic nucleus (MD) is crucial for higher cognitive functions, while the fine anatomical organization of the MD and the function of each subregion remain elusive. In this study, using high-resolution data provided by the Human Connectome Project, an anatomical connectivity-based method was adopted to unveil the topographic organization of the MD. Four fine-grained subregions were identified in each hemisphere, including the medial (MDm), central (MDc), dorsal (MDd), and lateral (MDl), which recapitulated previous cytoarchitectonic boundaries from histological studies. The subsequent connectivity analysis of the subregions also demonstrated distinct anatomical and functional connectivity patterns, especially with the prefrontal cortex. To further evaluate the function of MD subregions, partial least squares analysis was performed to examine the relationship between different prefrontal-subregion connectivity and behavioral measures in 1012 subjects. The results showed subregion-specific involvement in a range of cognitive functions. Specifically, the MDm predominantly subserved emotional-cognition domains, while the MDl was involved in multiple cognitive functions especially cognitive flexibility and inhibition. The MDc and MDd were correlated with fluid intelligence, processing speed, and emotional cognition. In conclusion, our work provides new insights into the anatomical and functional organization of the MD and highlights the various roles of the prefrontal-thalamic circuitry in human cognition.

Common and distinctive cognitive processes between categorization and category-based induction: Evidence from event-related potentials.

Categorization involves forming equivalence classes of discriminable entities, whereas category-based induction (CBI) involves employing categorical knowledge to generalize novel properties. Previous studies have suggested either common or distinctive cognitive processing between categorization and CBI. However, no study has compared cognitive processes with the same stimuli sets using event-related potentials (ERPs), which help to determine the cognitive processes with a high temporal solution. In this study, we compared the ERP responses to categorization and CBI using two separate experiments (i.e., generic and specific conclusions), with the same task materials. Results from both experiments identified distinctive cognitive processing between categorization and CBI based on a greater proportion of "definitely" responses and smaller amplitudes of sustained negativity during categorization. These observations suggest that categorization involves decreased conflict monitoring and control than CBI under single-premise conditions. Contrastingly, categorization and CBI elicited similar FN400 amplitudes in both experiments, which suggests a common cognitive process between them. These findings present the common and distinctive cognitive processes between categorization and CBI.

The burden of caring for dementia patients: caregiver reports from a cross-sectional hospital-based study in China.

The impact of dementia care on caregivers' professional, personal, emotional and social well-being was measured in a cohort of 1,387 caregivers in seven regions across mainland China, using a Chinese version of the Zarit Burden Interview (ZBI) and four supplementary questions. Caregivers also estimated costs of care and medical resource utilization. Caregiver burden was generally low to moderate. Dementia care had the greatest impact on caregivers' professional lives, with 25.5% reporting a reduced work schedule in the past month. Lost work time was greater for caregivers of patients with previously diagnosed dementia than for those with newly diagnosed dementia. Average monthly out-of-pocket costs of dementia care exceeded national average monthly incomes of rural and urban residents. These findings highlight the obstacles facing the country with the fastest-growing elderly population in the world.

Clinical Characterization and the Caregiver Burden of Dementia in China.

OBJECTIVES: The prevalence of dementia in China is among the highest in the world, but systematic estimates of the rate of dementia subtypes and characterization of associated deficits are lacking. The primary aim of this study was to determine the clinical presentation of dementia and describe the caregiver burden in mainland China. METHODS: A 3-month, open-enrollment, multicenter, cross-sectional study was conducted at 48 tier-3 hospitals. Caregivers who qualified for study entry (provided amount and duration of care information), had intimate knowledge of patient status, and accompanied enrolled patients to study sites were asked to participate in an interview about patient care and caregiver burden. Caregiver burden was assessed via the Chinese version of the validated Zarit Burden Interview. RESULTS: A total of 1425 caregivers completed the survey. Patients had mild to moderate dementia (mean Clinical Dementia Rating score of 1.67±0.79), and the most common dementia subtypes were Alzheimer disease (46.7%) and vascular dementia (28.7%). Among caregivers, 57% were females, 52% were patients' spouses, and 67.3% had been caring for patients for 1 year or more. Most patients required family help and lived at home or with a family member. Caregiver awareness of dementia was limited. The mean total caregiver Zarit Burden Interview score was 26.6. Observations were similar across age, gender, education, dementia type, Clinical Dementia Rating score, and duration of care. CONCLUSIONS: China faces multiple obstacles in preparing to care for its fast-growing dementia population. Better understanding of patients and caregivers may mitigate these challenges by improving awareness and education.