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The emphasis on team science in clinical and translational research increases the importance of collaborative biostatisticians (CBs) in healthcare. Adequate training and development of CBs ensure appropriate conduct of robust and meaningful research and, therefore, should be considered as a high-priority focus for biostatistics groups. Comprehensive training enhances clinical and translational research by facilitating more productive and efficient collaborations. While many graduate programs in Biostatistics and Epidemiology include training in research collaboration, it is often limited in scope and duration. Therefore, additional training is often required once a CB is hired into a full-time position. This article presents a comprehensive CB training strategy that can be adapted to any collaborative biostatistics group. This strategy follows a roadmap of the biostatistics collaboration process, which is also presented. A TIE approach (Teach the necessary skills, monitor the Implementation of these skills, and Evaluate the proficiency of these skills) was developed to support the adoption of key principles. The training strategy also incorporates a “train the trainer” approach to enable CBs who have successfully completed training to train new staff or faculty.
Reducing stigma is a perennial target of mental health advocates, but effectively addressing stigma relies on the ability to correctly understand and accurately measure culture-specific and location-specific components of stigma and discrimination.
We developed two culture-sensitive measures that assess the core components of stigma. The 40-item Interpersonal Distance Scale (IDS) asks respondents about their willingness to establish four different types of relationships with individuals with 10 target conditions, including five mental health-related conditions and five comparison conditions. The 40-item Occupational Restrictiveness Scale (ORS) asks respondents how suitable it is for individuals with the 10 conditions to assume four different types of occupations. The scales – which take 15 min to complete – were administered as part of a 2013 survey in Ningxia Province, China to a representative sample of 2425 adult community members.
IDS and ORS differentiated the level of stigma between the 10 conditions. Of the total, 81% of respondents were unwilling to have interpersonal relationships with individuals with mental health-related conditions and 91% considered them unsuitable for various occupations. Substantial differences in attitudes about the five mental health-related conditions suggest that there is no community consensus about what constitutes a ‘mental illness’.
Selection of comparison conditions, types of social relationships, and types of occupations considered by the IDS and ORS make it possible to develop culture-sensitive and cohort-specific measures of interpersonal distance and occupational restrictiveness that can be used to compare the level and type of stigma associated with different conditions and to monitor changes in stigma over time.
OBJECTIVES/GOALS: We sought to examine: 1) variability in center acceptance patterns for heart allografts offered to the highest-priority candidates, 2) impact of this acceptance behavior on candidate survival, and 3) post-transplantation outcomes in candidates who accepted first rank offer vs. previously declined offer. METHODS/STUDY POPULATION: In this retrospective cohort study, the US national transplant registry was queried for all match runs of adult candidates listed for isolated heart transplantation between 2007-2017. We examined center acceptance rates for heart allografts offered to the highest-priority candidates and accounted for covariates in multivariable logistic regression. Competing risks analysis was performed to assess the relationship between center acceptance rate and waitlist mortality. Post-transplantation outcomes (patient survival and graft failure) between candidates who accepted their first-rank offers vs those who accepted previously declined offers were compared using Fine-Gray subdistribution hazards model. RESULTS/ANTICIPATED RESULTS: Among 19,703 unique organ offers, 6,302 (32%) were accepted for first-ranked candidates. After adjustment for donor, recipient, and geographic covariates, transplant centers varied markedly in acceptance rates (12%-62%) of offers made to first-ranked candidates. Lowest acceptance rate centers (<25%) associated with highest cumulative incidence of waitlist mortality. For every 10% increase in adjusted center acceptance rate, waitlist mortality risk decreased by 27% (SHR 0.73, 95% CI 0.67-0.80). No significant difference was observed in 5-year adjusted post-Tx survival and graft failure between hearts accepted at the first-rank vs lower-rank positions. DISCUSSION/SIGNIFICANCE OF IMPACT: Wide variability in heart acceptance rates exists among centers, with candidates listed at low acceptance rate centers more likely to die waiting. Similar post-Tx survival suggests previously declined allografts function as well as those accepted at first offer. Center-level decision is a modifiable behavior associated with waitlist mortality.
Fluid intelligence expresses the capacity for interpretation of novel stimuli and flexible behavioral adaptation to such cues. Phasic dopamine firing closely matches a temporal difference prediction error (PE) signal important for learning and rapid behavioral adaptation. Both fluid intelligence and dopaminergic neurotransmission decline with age. So far, no study investigated the relationship between fluid IQ, PE signal and direct measures of dopaminergic neurotransmission. Here we used a multimodal imaging approach that combines positron emission tomography and functional magnetic resonance imaging.
A group of healthy controls was investigated with both 6-[18F]FluoroDOPA PET and functional MRI with a probabilistic reversal task. The task required a constant behavioral adaptation to changes in reward contingencies, while choosing between two abstract stimuli. A reinforcement learning algorithm was used to compute a trial-by-trial prediction error, which was the used as a regressor in the fMRI data analysis with SPM8.
The prediction error signal was associated with functional activation in the basal ganglia including the ventral striatum and putamen. Fluid intelligence was associated with the PE signal in the ventral striatum, which correlated with age-related changes in dopamine synthesis capacity in the prefrontal cortex.
These findings provide insight into the role of age-related changes in dopaminergic neurotransmission on behavioral adaptation. The multimodal imaging approach allows the characterization of interactions between dopamine metabolism and learning-related neuronal activation and may thus be a useful tool to clarify mechanisms underlying learning and plasticity in old age, which are crucial to our understanding of successful aging.
Abnormal effort-based decision-making represents a potential mechanism underlying motivational deficits (amotivation) in psychotic disorders. Previous research identified effort allocation impairment in chronic schizophrenia and focused mostly on physical effort modality. No study has investigated cognitive effort allocation in first-episode psychosis (FEP).
Cognitive effort allocation was examined in 40 FEP patients and 44 demographically-matched healthy controls, using Cognitive Effort-Discounting (COGED) paradigm which quantified participants’ willingness to expend cognitive effort in terms of explicit, continuous discounting of monetary rewards based on parametrically-varied cognitive demands (levels N of N-back task). Relationship between reward-discounting and amotivation was investigated. Group differences in reward-magnitude and effort-cost sensitivity, and differential associations of these sensitivity indices with amotivation were explored.
Patients displayed significantly greater reward-discounting than controls. In particular, such discounting was most pronounced in patients with high levels of amotivation even when N-back performance and reward base amount were taken into consideration. Moreover, patients exhibited reduced reward-benefit sensitivity and effort-cost sensitivity relative to controls, and that decreased sensitivity to reward-benefit but not effort-cost was correlated with diminished motivation. Reward-discounting and sensitivity indices were generally unrelated to other symptom dimensions, antipsychotic dose and cognitive deficits.
This study provides the first evidence of cognitive effort-based decision-making impairment in FEP, and indicates that decreased effort expenditure is associated with amotivation. Our findings further suggest that abnormal effort allocation and amotivation might primarily be related to blunted reward valuation. Prospective research is required to clarify the utility of effort-based measures in predicting amotivation and functional outcome in FEP.
Consumption of sugar-sweetened beverages (SSB) by infants and young children are less explored in Asian populations. The Growing Up in Singapore Towards healthy Outcomes cohort study examined associations between SSB intake at 18 months and 5 years of age, with adiposity measures at 6 years of age. We studied Singaporean infants/children with SSB intake assessed by FFQ at 18 months of age (n 555) and 5 years of age (n 767). The median for SSB intakes is 28 (interquartile range 5·5–98) ml at 18 months of age and 111 (interquartile range 57–198) ml at 5 years of age. Association between SSB intake (100 ml/d increments and tertile categories) and adiposity measures (BMI standard deviation scores (sd units), sum of skinfolds (SSF)) and overweight/obesity status were examined using multivariable linear and Poisson regression models, respectively. After adjusting for confounders and additionally for energy intake, SSB intake at age 18 months were not significantly associated with later adiposity measures and overweight/obesity outcomes. In contrast, at age 5 years, SSB intake when modelled as 100 ml/d increments were associated with higher BMI by 0·09 (95 % CI 0·02, 0·16) sd units, higher SSF thickness by 0·68 (95 % CI 0·06, 1·44) mm and increased risk of overweight/obesity by 1·2 (95 % CI 1·07, 1·23) times at age 6 years. Trends were consistent with SSB intake modelled as categorical tertiles. In summary, SSB intake in young childhood is associated with higher risks of adiposity and overweight/obesity. Public health policies working to reduce SSB consumption need to focus on prevention programmes targeted at young children.
Disturbances in emotion regulation (ER) are characteristic of both patients with bipolar disorder (BD) and schizophrenia (SZ). We investigated the temporal dynamics of brain activation during cognitive ER in BD and SZ to understand the contribution of temporal characteristics of disturbed ER to their unique and shared symptomatology.
Forty-six participants performed an ER-task (BD, n = 15; SZ, n = 16; controls, n = 15) during functional magnetic resonance imaging, in which they were instructed to use cognitive reappraisal techniques to regulate their emotional responses. Finite impulse response modeling was applied to estimate the temporal dynamics of brain responses during cognitive reappraisal (v. passive attending) of negative pictures. Group, time, and group × time effects were tested using multivariate modeling.
We observed a group × time interaction during ER in the ventrolateral prefrontal cortex (VLPFC), supplementary motor area (SMA) and inferior occipital gyrus. Patients with SZ demonstrated initial hyper-activation of the VLPFC and SMA activation that was not sustained in later regulatory phases. Response profiles in the inferior occipital gyrus in SZ showed abnormal activation in the later phases of regulation. BD-patients showed general blunted responsivity in these regions.
These results suggest that ER-disturbances in SZ are characterized by an inefficient initialization and failure to sustain regulatory control, whereas in BD, a failure to recruit regulatory resources may represent initial deficits in formulating adequate representations of the regulatory needs. This may help to further understand how ER-disturbances give rise to symptomatology of BD and SZ.
Although relapse in psychosis is common, a small proportion of patients will not relapse in the long term. We examined the proportion and predictors of patients who never relapsed in the 10 years following complete resolution of positive symptoms from their first psychotic episode.
Patients who previously enrolled in a 12-month randomized controlled trial on medication discontinuation and relapse following first-episode psychosis (FEP) were followed up after 10 years. Relapse of positive symptoms was operationalized as a change from a Clinical Global Impression scale positive score of <3 for at least 3 consecutive months to a score of ⩾3 (mild or more severe). Baseline predictors included basic demographics, premorbid functioning, symptoms, functioning, and neurocognitive functioning.
Out of 178 first-episode patients, 37 (21%) never relapsed during the 10-year period. Univariate predictors (p ⩽ 0.1) of patients who never relapsed included a duration of untreated psychosis (DUP) ⩽30 days, diagnosed with non-schizophrenia spectrum disorders, having less severe negative symptoms, and performing better in logical memory immediate recall and verbal fluency tests. A multivariate logistic regression analysis further suggested that the absence of any relapsing episodes was significantly related to better short-term verbal memory, shorter DUP, and non-schizophrenia spectrum disorders.
Treatment delay and neurocognitive function are potentially modifiable predictors of good long-term prognosis in FEP. These predictors are informative as they can be incorporated into an optimum risk prediction model in the future, which would help with clinical decision making regarding maintenance treatment in FEP.
Major depressive disorder (MDD) is a highly heterogeneous condition in terms of symptom presentation and, likely, underlying pathophysiology. Accordingly, it is possible that only certain individuals with MDD are well-suited to antidepressants. A potentially fruitful approach to parsing this heterogeneity is to focus on promising endophenotypes of depression, such as neuroticism, anhedonia, and cognitive control deficits.
Within an 8-week multisite trial of sertraline v. placebo for depressed adults (n = 216), we examined whether the combination of machine learning with a Personalized Advantage Index (PAI) can generate individualized treatment recommendations on the basis of endophenotype profiles coupled with clinical and demographic characteristics.
Five pre-treatment variables moderated treatment response. Higher depression severity and neuroticism, older age, less impairment in cognitive control, and being employed were each associated with better outcomes to sertraline than placebo. Across 1000 iterations of a 10-fold cross-validation, the PAI model predicted that 31% of the sample would exhibit a clinically meaningful advantage [post-treatment Hamilton Rating Scale for Depression (HRSD) difference ⩾3] with sertraline relative to placebo. Although there were no overall outcome differences between treatment groups (d = 0.15), those identified as optimally suited to sertraline at pre-treatment had better week 8 HRSD scores if randomized to sertraline (10.7) than placebo (14.7) (d = 0.58).
A subset of MDD patients optimally suited to sertraline can be identified on the basis of pre-treatment characteristics. This model must be tested prospectively before it can be used to inform treatment selection. However, findings demonstrate the potential to improve individual outcomes through algorithm-guided treatment recommendations.
Two middle Permian (Capitanian) to Early Triassic (Griesbachian) rugosochonetidae brachiopod genera, Fusichonetes Liao in Zhao et al., 1981 and Tethyochonetes Chen et al., 2000, have been regarded as two distinct taxa and used as such for a wide range of discussions including biostratigraphy, paleoecology, paleobiogeography, and the Permian-Triassic boundary mass extinction. However, the supposed morphological distinctions between the two taxa are subtle at best and appear to represent two end members of a continuum of morphological variations. In this study, we applied a range of quantitative and analytical procedures (bivariate plots, Kolmogorov-Smirnov test, categorical principle component analysis, and cladistic analysis) to a dataset of 15 quantified morphological variables, integrating both key external and internal characters, measured from 141 specimens of all well-known Fusichonetes and Tethyochonetes in order to test whether or not these two genera could be distinguished in view of the chosen characters. The results indicate that these two genera are morphologically indistinguishable and that the species classification previously applied to these two genera appears to represent polyphyletic groupings within the genus Fusichonetes. Consequently, Tethyochonetes is concluded to be a junior synonym of Fusichonetes. The diagnosis and key characteristics of Fusichonetes are clarified and refined based on a new suite of well-preserved specimens from the Permian−Triassic Xinmin section in South China.
We characterized evacuations related to Hurricane Sandy, which made landfall in New Jersey on October 29, 2012.
We analyzed data from the 2014 New Jersey Behavioral Risk Factor Survey. The proportion of respondents reporting evacuation was used to estimate the number of New Jersey adults who evacuated. We determined evacuation rates in heavily impacted and less-impacted municipalities, as well as evacuation rates for municipalities under and not under mandatory evacuation orders. We tested associations between demographic and health factors, such as certain chronic health conditions, and evacuation.
Among respondents, 12.7% (95% CI: 11.8%-13.6%) reported evacuating, corresponding to approximately 880,000 adults. In heavily impacted municipalities, 17.0% (95% CI: 15.2%-18.7%) evacuated, compared with 10.1% (95% CI: 9.0%-11.2%) in less-impacted municipalities. In municipalities under mandatory evacuation orders, 42.5% (95% CI: 35.1%-49.8%) evacuated, compared with 11.8% (95% CI: 10.9%-12.9%) in municipalities not under mandatory orders. Female gender (odds ratio [OR]: 1.36; 95% CI: 1.14-1.64), unmarried status (OR: 1.22; 95% CI: 1.02-1.46), shorter length of residence (OR: 1.28; 95% CI: 1.03-1.60), and living in a heavily impacted municipality (OR: 1.84; 95% CI: 1.54-2.20) were significantly associated with evacuation. History of stroke (OR: 1.61; 95% CI: 1.02-2.53) was the only chronic condition associated with evacuation.
Approximately 880,000 New Jersey adults evacuated because of Hurricane Sandy. Those in heavily impacted municipalities and municipalities under mandatory evacuation orders had higher evacuation rates; however, still fewer than half evacuated. These findings can be used for future disaster planning. (Disaster Med Public Health Preparedness. 2017;11:720–728).
The high Antarctic plateau provides exceptional conditions for infrared observations on account of the cold, dry and stable atmosphere above the ice surface. This paper describes the scientific goals behind the first program to examine the time-varying universe in the infrared from Antarctica — the Kunlun Infrared Sky Survey (KISS). This will employ a 50cm telescope to monitor the southern skies in the 2.4μmKdark window from China's Kunlun station at Dome A, on the summit of the Antarctic plateau, through the uninterrupted 4-month period of winter darkness. An earlier paper discussed optimisation of the Kdark filter for sensitivity (Li et al. 2016). This paper examines the scientific program for KISS. We calculate the sensitivity of the camera for the extrema of observing conditions that will be encountered. We present the parameters for sample surveys that could then be carried out for a range of cadences and sensitivities. We then discuss several science programs that could be conducted with these capabilities, involving star formation, brown dwarfs and hot Jupiters, exoplanets around M dwarfs, the terminal phases of stellar evolution, fast transients, embedded supernova searches, reverberation mapping of AGN, gamma ray bursts and the detection of the cosmic infrared background.
Exposures to antioxidants (AO) are associated with levels of C-reactive protein (CRP), but the pattern of evidence is mixed, due in part to studying each potential AO, one at a time, when multiple AO exposures might affect CRP levels. By studying multiple AO via a composite indicator approach, we estimate the degree to which serum CRP level is associated with serum AO level. Standardised field survey protocols for the US National Health and Nutrition Examination Survey (NHANES) 2003–2006 yielded nationally representative cross-sectional samples of adults aged 20 years and older (n 8841). NHANES latex-enhanced nephelometry quantified serum CRP levels. Liquid chromatography quantified serum concentrations of vitamins A, E and C and carotenoids. Using structural equations, we regressed CRP level on AO levels, and derived a summary estimate for a composite of these potential antioxidants (CPA), with covariates held constant. The association linking CPA with CRP was inverse, stronger for slightly elevated CRP (1·8≤CRP<10 mg/l; slope= −1·08; 95 % CI −1·39, −0·77) and weaker for highly elevated CRP (≥10 mg/l; slope= −0·52; 95 % CI −0·68, −0·35), with little change when covariates were added. Vitamins A and C, as well as lutein+zeaxanthin, were prominent contributors to the composite. In these cross-sectional data studied via a composite indicator approach, the CPA level and the CRP level were inversely related. The stage is set for more confirmatory longitudinal or intervention research on multiple vitamins. The composite indicator approach might be most useful in epidemiology when several exposure constructs are too weakly inter-correlated to be studied via formal measurement models for underlying latent dimensions.
Relapse is distressingly common after the first episode of psychosis, yet it is poorly understood and difficult to predict. Investigating changes in cognitive function preceding relapse may provide new insights into the underlying mechanism of relapse in psychosis. We hypothesized that relapse in fully remitted first-episode psychosis patients was preceded by working memory deterioration.
Visual memory and verbal working memory were monitored prospectively in a 1-year randomized controlled trial of remitted first-episode psychosis patients assigned to medication continuation (quetiapine 400 mg/day) or discontinuation (placebo). Relapse (recurrence of positive symptoms of psychosis), visual (Visual Patterns Test) and verbal (Letter–Number span test) working memory and stressful life events were assessed monthly.
Remitted first-episode patients (n = 102) participated in the study. Relapsers (n = 53) and non-relapsers (n = 49) had similar baseline demographic and clinical profiles. Logistic regression analyses indicated relapse was associated with visual working memory deterioration 2 months before relapse [odds ratio (OR) 3.07, 95% confidence interval (CI) 1.19–7.92, P = 0.02], more stressful life events 1 month before relapse (OR 2.11, 95% CI 1.20–3.72, P = 0.01) and medication discontinuation (OR 5.52, 95% CI 2.08–14.62, P = 0.001).
Visual working memory deterioration beginning 2 months before relapse in remitted first-episode psychosis patients (not baseline predictor) may reflect early brain dysfunction that heralds a psychotic relapse. The deterioration was found to be unrelated to a worsening of psychotic symptoms preceding relapse. Testable predictors offer insight into the brain processes underlying relapse in psychosis.
Cognitive impairment is a core feature of schizophrenia. Its relationship with duration of untreated psychosis (DUP), a potentially malleable prognostic factor, has been less studied, with inconsistent findings being observed in the literature. Previous research investigating such a relationship was mostly cross-sectional and none of those prospective studies had a follow-up duration beyond 2 years.
A total of 93 Hong Kong Chinese aged 18 to 55 years presenting with first-episode schizophrenia-spectrum disorder were studied. DUP and pre-morbid adjustment were measured using a structured interview incorporating multiple sources of information. Psychopathological evaluation was administered at intake, after clinical stabilization of the first psychotic episode, and at 12, 24 and 36 months. Cognitive functions were measured at clinical stabilization, and at 12, 24 and 36 months.
DUP exerted differential effects on various cognitive domains, with memory deficits being the most related to DUP even when potential confounders including pre-morbid adjustment and sex were adjusted. Prolonged DUP was associated with more severe impairment in visual memory at clinical stabilization and verbal memory at 24 and 36 months. Further, patients with a long DUP were found to have worse outcomes on negative symptoms at 36 months. The effects of DUP on verbal memory remained significant even when negative symptoms were taken into consideration.
Our findings provided further supportive evidence that delayed treatment to first-episode psychosis is associated with poorer cognitive and clinical outcomes. In addition, DUP may specifically affect memory function and its adverse impact on verbal memory may only become evident at a later stage of the recovery process.
Robust disease burden estimates are important for decision-making concerning introduction of new vaccines. Dengue is a major public health problem in the tropics but robust disease burden estimates are lacking. We conducted a two-sample, capture–recapture study in the largest province in Cambodia to determine disease under-recognition to the National Dengue Surveillance System (NDSS). During 2006–2008, community-based active surveillance for acute febrile illness was conducted in 0- to 19-year-olds in rural and urban areas combined with testing for dengue virus infection. Of 14 354 individuals under active surveillance (22 498 person-seasons), the annual incidence ranged from 13·4 to 57·8/1000 person-seasons. During the same period, NDSS incidence rates ranged from 1·1/1000 to 5·7/1000, which was 3·9- to 29·0-fold lower than found in the capture–recapture study. In hospitalized cases, the rate of under-recognition was 1·1- to 2·4-fold. This study shows the substantial degree of under-recognition/reporting of dengue and that reported hospitalized cases are not a good surrogate for estimating dengue disease burden.
We discuss the principles of Optical interconnects, and discuss the potential of silicon photonics to provide all the necessary building blocks to construct dense, high-bandwidth, lowpower optical links. We discuss waveguides, wavelength division multiplexing, modulators and photodetectors. We also take a look at the options for implementing light sources, a function which silicon cannot natively provide, with a focus on implementations in the IMEC silicon photonics platform.