Citation Advantage of Promoted Articles in a Cross-Publisher Distribution Platform: 36-Month Follow-up to a Randomized Controlled Trial.

BACKGROUND: There are limited evidence-based strategies that have been shown to increase the rate at which peer-reviewed articles are cited. In a previously reported randomized controlled trial, we demonstrated that promotion of article links in an online cross-publisher distribution platform (TrendMD) persistently augments citation rates after 12 months, leading to a statistically significant 50% increase in citations relative to the control. OBJECTIVE: This study aims to investigate if the citation advantage of promoted articles upholds after 36 months. METHODS: A total of 3200 published articles in 64 peer-reviewed journals across 8 subject areas were block randomized at the subject level to either the TrendMD group (n=1600) or the control group (n=1600) of the study. Articles were promoted in the TrendMD Network for 6 months. We compared the citation rates in both groups after 36 months. RESULTS: At 36 months, we found the citation advantage endured; articles randomized to TrendMD showed a 28% increase in mean citations relative to the control. The difference in mean citations at 36 months for articles randomized to TrendMD versus the control was 10.52 (95% CI 3.79-17.25) and was statistically significant (P=.001). CONCLUSIONS: To our knowledge, this is the first randomized controlled trial to demonstrate how a postpublication article promotion intervention can be used to persistently augment citations of peer-reviewed articles. TrendMD is an efficient digital tool for knowledge translation and dissemination to targeted audiences to facilitate the uptake of research.

Online distribution channel increases article usage on Mendeley: a randomized controlled trial.

Prior research shows that article reader counts (i.e. saves) on the online reference manager, Mendeley, correlate to future citations. There are currently no evidenced-based distribution strategies that have been shown to increase article saves on Mendeley. We conducted a 4-week randomized controlled trial to examine how promotion of article links in a novel online cross-publisher distribution channel (TrendMD) affect article saves on Mendeley. Four hundred articles published in the Journal of Medical Internet Research were randomized to either the TrendMD arm (n = 200) or the control arm (n = 200) of the study. Our primary outcome compares the 4-week mean Mendeley saves of articles randomized to TrendMD versus control. Articles randomized to TrendMD showed a 77% increase in article saves on Mendeley relative to control. The difference in mean Mendeley saves for TrendMD articles versus control was 2.7, 95% CI (2.63, 2.77), and statistically significant (p < 0.01). There was a positive correlation between pageviews driven by TrendMD and article saves on Mendeley (Spearman's rho r = 0.60). This is the first randomized controlled trial to show how an online cross-publisher distribution channel (TrendMD) enhances article saves on Mendeley. While replication and further study are needed, these data suggest that cross-publisher article recommendations via TrendMD may enhance citations of scholarly articles.

The putative impact of metabolic health on default mode network activity and functional connectivity in neuropsychiatric disorders.

The default mode network (DMN) describes a distributed network of brain regions that are predominantly activated and engaged during periods of spontaneous, stimulus independent thought (i.e., at rest) and remain quiescent during attention-demanding, goal-directed tasks. Replicated evidence in functional neuroimaging studies suggests that midline cortical and subcortical brain regions responsible for memory, self-relevant emotional and mental processes, as well as information integration comprise the DMN. The DMN is posited to represent self-referential mental activity via a dynamic interplay of cognitive and emotional processes by integrating information from the external environment with introspective thoughts to generate an autobiographical concept of the self. It has been amply documented that irregularities in the DMN and its functional connectivity are associated with various neuropsychiatric disorders. Moreover, accumulating evidence also suggests that individuals with select medical disorders (i.e., metabolic disorders) demonstrate alterations in DMN activity and functional connectivity. However, there is a paucity of data evaluating whether individuals with metabolically-based medical conditions, exhibiting altered DMN activity and functional connectivity, are at increased risk for developing neuropsychiatric disorders. Likewise, potential mechanisms (e.g., altered brain metabolism, insulin resistance) mediating these changes and their implications for novel treatment approaches have yet to be elucidated. Taken together, the overarching aim of this review is to provide a synthetic overview that suggests that this neural circuit may represent a common (or convergent) substrate affected in individuals with select neuropsychiatric and metabolic disorders.

Inter-hospital transfers and outcomes of critically ill patients with severe acute kidney injury: a multicenter cohort study.

INTRODUCTION: Patients with severe acute kidney injury (AKI) who are hospitalized at centers that do not provide renal replacement therapy (RRT) are frequently subjected to inter-hospital transfer for the provision of RRT. It is unclear whether such transfers are associated with worse patient outcomes as compared with the receipt of initial care in a center that provides RRT. This study examined the relationship between inter-hospital transfer and 30-day mortality among critically ill patients with AKI who received RRT. METHODS: We conducted a retrospective cohort study of all critically ill patients who commenced RRT for AKI at two academic hospitals in Toronto, Canada. The exposure of interest was inter-hospital transfer for the administration of RRT. We evaluated the relationship between transfer status and 30-day mortality (primary outcome) and RRT dependence at 30 days following RRT initiation (secondary outcome), by using multivariate logistic regression with adjustment for patient demographics, clinical factors, biochemical indices, and severity of illness. RESULTS: Of 370 patients who underwent RRT for AKI, 82 (22.2%) were transferred for this purpose from another hospital. Compared with non-transferred patients who started RRT, transferred patients were younger (61 ± 15 versus 65 ± 15 years, P = 0.03) and had a higher serum creatinine concentration at RRT initiation (474 ± 295 versus 365 ± 169 µmol/L, P = 0.002). Inter-hospital transfer was not associated with mortality (adjusted odds ratio 0.61, 95% confidence interval 0.33 to 1.12) or RRT-dependence (adjusted odds ratio 1.64, 95% confidence interval 0.70 to 3.81) at 30 days. CONCLUSIONS: Within the limitations of this observational study and the potential for residual confounding, inter-hospital transfer of critically ill patients with AKI was not associated with a higher risk of death or dialysis dependence 30 days after the initiation of acute RRT.

Early switching strategies in antidepressant non-responders: current evidence and future research directions.

Studies have found that up to two-thirds of patients with major depressive disorder (MDD) do not fully respond to the first antidepressant. While switching antidepressants is a common strategy for antidepressant non-responders, there is still a lack of consensus about the optimal timing of a switch. Many clinicians wait for 6-12 weeks before considering a switch. The objectives of this paper are to (1) review the evidence for positive and negative predictive value (NPV) of early improvement at 2-4 weeks to predict final antidepressant response; (2) review randomized controlled trials (RCTs) that examine early switching strategies; and (3) provide future research directions and clinical recommendations for timing of antidepressant switching. We conducted a literature search for English-language studies via PubMed and Google Scholar, from 1984 to May 2013, with the following terms: 'antidepressants', 'MDD', 'time course', 'trajectory', 'early response', 'onset', 'delayed response', 'early improvement', 'predictors', 'switch', 'combination therapy', and 'augmentation'. Replicated evidence indicates that lack of early improvement (e.g. <20% reduction in a depression scale score) at 2-4 weeks can be an accurate predictor to identify eventual non-responders. The NPVs suggest that only about one in five patients with lack of improvement at 4 weeks will have a response by 8 weeks. Three RCTs examined early switch strategies, but results are inconsistent and comparisons limited by methodological differences. Future studies should incorporate a standard consensus definition of early improvement, discern whether the effect of early switching is specific to certain types of antidepressants, and determine whether early switch is superior to other strategies such as augmentation or combination. Notwithstanding these limitations, there is reasonable evidence to recommend earlier assessment for improvement. If there is no indication of early improvement at 2-4 weeks after starting an antidepressant, and taking into account other patient and clinical factors, a change in management can be considered.

Advancing biomarker research: utilizing 'Big Data' approaches for the characterization and prevention of bipolar disorder.

OBJECTIVE: To provide a strategic framework for the prevention of bipolar disorder (BD) that incorporates a 'Big Data' approach to risk assessment for BD. METHODS: Computerized databases (e.g., Pubmed, PsychInfo, and MedlinePlus) were used to access English-language articles published between 1966 and 2012 with the search terms bipolar disorder, prodrome, 'Big Data', and biomarkers cross-referenced with genomics/genetics, transcriptomics, proteomics, metabolomics, inflammation, oxidative stress, neurotrophic factors, cytokines, cognition, neurocognition, and neuroimaging. Papers were selected from the initial search if the primary outcome(s) of interest was (were) categorized in any of the following domains: (i) 'omics' (e.g., genomics), (ii) molecular, (iii) neuroimaging, and (iv) neurocognitive. RESULTS: The current strategic approach to identifying individuals at risk for BD, with an emphasis on phenotypic information and family history, has insufficient predictive validity and is clinically inadequate. The heterogeneous clinical presentation of BD, as well as its pathoetiological complexity, suggests that it is unlikely that a single biomarker (or an exclusive biomarker approach) will sufficiently augment currently inadequate phenotypic-centric prediction models. We propose a 'Big Data'- bioinformatics approach that integrates vast and complex phenotypic, anamnestic, behavioral, family, and personal 'omics' profiling. Bioinformatic processing approaches, utilizing cloud- and grid-enabled computing, are now capable of analyzing data on the order of tera-, peta-, and exabytes, providing hitherto unheard of opportunities to fundamentally revolutionize how psychiatric disorders are predicted, prevented, and treated. High-throughput networks dedicated to research on, and the treatment of, BD, integrating both adult and younger populations, will be essential to sufficiently enroll adequate samples of individuals across the neurodevelopmental trajectory in studies to enable the characterization and prevention of this heterogeneous disorder. CONCLUSIONS: Advances in bioinformatics using a 'Big Data' approach provide an opportunity for novel insights regarding the pathoetiology of BD. The coordinated integration of research centers, inclusive of mixed-age populations, is a promising strategic direction for advancing this line of neuropsychiatric research.

Implications of epigenetic modulation for novel treatment approaches in patients with schizophrenia.

Schizophrenia is a heterogeneous and complex mental disorder with high rates of disability, non-recovery, and relapse. The primary pharmacological treatments for schizophrenia are antipsychotics. Notwithstanding the efficacy of antipsychotics in ameliorating positive symptoms and reducing relapse rates, cognitive deficits and negative symptoms are not sufficiently treated with available pharmaceutical agents. Moreover, schizophrenia is associated with consistent, replicable, and clinically significant deficits in cognition. The importance of cognitive deficits in schizophrenia is emphasized by reports indicating that the severity of cognitive deficits is predictive of treatment compliance, adherence, and risk of relapse among first-episode individuals. Taken together, this review highlights epigenetic modulations involving histone deacetylase (HDAC) inhibitors as a potential avenue for novel treatment toward improvements in cognition and functional outcomes in patients with schizophrenia. The combination of epigenetic modulation with pharmacological interventions that engage multiple disparate physiological systems implicated in schizophrenia are discussed, and may represent a more effective strategy in ameliorating cognitive deficits and mitigating symptoms for improved functionality.

Cognitive deficits and functional outcomes in major depressive disorder: determinants, substrates, and treatment interventions.

BACKGROUND: Few reports have aimed to describe the mediational effect of cognitive deficits on functional outcomes in major depressive disorder (MDD), and relatively few interventions are demonstrated to mitigate cognitive deficits in MDD. METHODS: Studies enrolling subjects between the ages of 18-65 were selected for review. Bibliographies from identified articles were reviewed to identify additional original reports aligned with our objectives. RESULTS: Cognitive deficits in MDD are consistent, replicable, nonspecific, and clinically significant. The aggregated estimated effect size of cognitive deficits in MDD is small to medium. Pronounced deficits in executive function (≥1 SD below the normative mean) are evident in ∼20-30% of individuals with MDD). Other replicated abnormalities are in the domains of working memory, attention, and psychomotor processing speed. Mediational studies indicate that cognitive deficits may account for the largest percentage of variance with respect to the link between psychosocial dysfunction (notably workforce performance) and MDD. No conventional antidepressant has been sufficiently studied and/or demonstrated robust procognitive effects in MDD. CONCLUSIONS: Cognitive deficits in MDD are a principal mediator of psychosocial impairment, notably workforce performance. The hazards posed by cognitive deficits in MDD underscore the need to identify a consensus-based neurocognitive battery for research and clinical purposes. Interventions (pharmacological, behavioral, neuromodulatory) that engage multiple physiological systems implicated in cognitive deficits hold promise to reduce, reverse, and prevent cognitive deficits.

Radiologic outcomes at 5 years after severe ARDS.

OBJECTIVE: Few studies have systematically evaluated high-resolution CT (HRCT) imaging of the thorax 5 years after severe ARDS to determine the association between radiologic fi ndings and functional disability. The primary aim of this study was to determine chest radiologic abnormalities at 5 years in survivors of severe ARDS from the University of Toronto ARDS cohort. The secondary aim was to determine the relationship between the observed radiologic abnormalities on HRCT scan and pulmonary symptoms, pulmonary function test abnormalities, and healthrelated quality of life at 5-year follow-up. METHODS: HRCT scans were obtained in 24 of 64 eligible patients. Three anatomically comparable levels were selected for scoring, and each level was divided into four quadrants. The extent and distribution of individual CT image patterns (ground glass opacifi cation, intense parenchymal opacifi cation, reticular pattern, and decreased attenuation) were also reported. RESULTS: Eighteen patients (75%) had abnormal fi ndings on HRCT imaging. These findings were minor and in the nondependent lung zones. No correlation was found between radiologic findings and patient symptoms, pulmonary function tests, 6-min walk distances, or heath-related quality of life measures. CONCLUSIONS: Exercise and functional limitations experienced by survivors of severe ARDS are unlikely to be related to structural lung disease and may be more consistent with extrapulmonary muscle weakness.

Cognitive enhancement in Canadian medical students.

BACKGROUND: Cognitive enhancing agents are substances that may augment functions such as memory, attention, concentration, wakefulness, and intelligence. METHODS: An anonymous, online survey containing a series of questions on the actual and hypothetical use of cognitive enhancers was sent via email to 647 medical students across all four years in one Canadian MD program. RESULTS: The response rate was 50% (326/647). Overall, 49 (15%, 95% CI: 11% to 19%) students admitted to non-medical and/or off-label use of one or more pharmaceutical stimulants, of whom 14 (4%, 95% CI: 2% to 6%) had used stimulants within the last year. Senior medical students reported recent use more often than junior students (8% vs. 2%, P = 0.04). Class seniority and male gender were both associated with positive attitudes towards use of these agents; favorable attitudes were associated with recent use of pharmaceutical stimulant and high-caffeine products. CONCLUSION: A substantial proportion of Canadian medical students have engaged at some point in non-medical and/or off-label use of stimulants for purposes of cognitive enhancement. Male students and those in upper years of the MD program were more likely to have used pharmaceutical stimulants in the last year, and have favorable attitudes concerning use of cognitive-enhancing agents.

Predicting treatment response in major depressive disorder: the impact of early symptomatic improvement.

OBJECTIVE: Antidepressants (ADs) are the mainstay of treatment for major depressive disorder (MDD). Despite their widespread usage, a consensus does not exist as to the timing of clinically significant symptomatic improvement during an AD trial. The objective of this review is to provide practitioners with empirically based recommendations pertaining to the optimal duration of index (initial) AD therapy before a clinical intervention is warranted. METHODS: We conducted a nonsystematic review, using a combination of a MeSH key word search, Google Scholar, and the Scopus database. Our search strategy focused on research papers reporting on the early symptomatic response to AD therapy. RESULTS: Available evidence suggests that there are several subpopulations that exist within whole-group data assigned to an AD treatment. Among the responder subgroups, an early responder group (that is, less than 3 weeks) and later responder group (that is, 3 weeks or more) are identified. People who exhibit early partial symptomatic improvement are more likely to respond to therapy thereafter. However, the interpretability of extant evidence is complicated by the use of disparate statistical approaches with differing computational complexity and sample heterogeneity. CONCLUSIONS: Response outcomes in MDD are heterogeneous. Available data suggest that people may respond early, late, and (or) continuously over time, and may represent distinct subpopulations that provide a proximate indication for treatment response outcomes. Notwithstanding, a pragmatic recommendation would be to consider a treatment intervention (for example, dosage optimization and [or] augmentation) if, after 3 to 4 weeks, symptomatic improvement is insufficient.

Functional disability 5 years after acute respiratory distress syndrome.

BACKGROUND: There have been few detailed, in-person interviews and examinations to obtain follow-up data on 5-year outcomes among survivors of the acute respiratory distress syndrome (ARDS). METHODS: We evaluated 109 survivors of ARDS at 3, 6, and 12 months and at 2, 3, 4, and 5 years after discharge from the intensive care unit. At each visit, patients were interviewed and examined; underwent pulmonary-function tests, the 6-minute walk test, resting and exercise oximetry, chest imaging, and a quality-of-life evaluation; and reported their use of health care services. RESULTS: At 5 years, the median 6-minute walk distance was 436 m (76% of predicted distance) and the Physical Component Score on the Medical Outcomes Study 36-Item Short-Form Health Survey was 41 (mean norm score matched for age and sex, 50). With respect to this score, younger patients had a greater rate of recovery than older patients, but neither group returned to normal predicted levels of physical function at 5 years. Pulmonary function was normal to near-normal. A constellation of other physical and psychological problems developed or persisted in patients and family caregivers for up to 5 years. Patients with more coexisting illnesses incurred greater 5-year costs. CONCLUSIONS: Exercise limitation, physical and psychological sequelae, decreased physical quality of life, and increased costs and use of health care services are important legacies of severe lung injury.