Validation of the Diagnostic Accuracy Levels of International Classification of Diseases, 10th Revision Codes for Diabetic Ketoacidosis: A Multicentre, Cross-sectional Study of Adults.

OBJECTIVES: International Classification of Diseases (ICD) codes are commonly used to identify cases of diabetic ketoacidosis (DKA) in health services research, but they have not been validated. Our aim in this study was to assess the accuracy of ICD, 10th revision (ICD-10) diagnosis codes for DKA. METHODS: We conducted a multicentre, cross-sectional study using data from 5 hospitals in Ontario, Canada. Each hospitalization event has a single most responsible diagnosis code. We identified all hospitalizations assigned diagnosis codes for DKA. A true case of DKA was defined using laboratory values (serum bicarbonate ≤18 mmol/L, arterial pH ≤7.3, anion gap ≥14 mEq/L, and presence of ketones in urine or blood). Chart review was conducted to validate DKA if laboratory values were missing or the diagnosis of DKA was unclear. Outcome measures included positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity of ICD-10 codes in patients with laboratory-defined DKA. RESULTS: We identified 316,517 hospitalizations. Among these, 312,948 did not have an ICD-10 diagnosis code for DKA and 3,569 had an ICD-10 diagnosis code for DKA. Using a combination of laboratory and chart review, we identified that the overall PPV was 67.0%, the NPV was 99.7%, specificity was 99.6%, and sensitivity was 74.9%. When we restricted our analysis to hospitalizations in which DKA was the most responsible discharge diagnosis (n=3,374 [94.5%]), the test characteristics were PPV 69.8%, NPV 99.7%, specificity 99.7%, and sensitivity 71.9%. CONCLUSION: ICD-10 codes can identify patients with DKA among those admitted to general internal medicine.

Schizophrenia Polygenic Risk During Typical Development Reflects Multiscale Cortical Organization.

Background: Schizophrenia is widely recognized as a neurodevelopmental disorder. Abnormal cortical development in otherwise typically developing children and adolescents may be revealed using polygenic risk scores for schizophrenia (PRS-SCZ). Methods: We assessed PRS-SCZ and cortical morphometry in typically developing children and adolescents (3-21 years, 46.8% female) using whole-genome genotyping and T1-weighted magnetic resonance imaging (n = 390) from the PING (Pediatric Imaging, Neurocognition, and Genetics) cohort. We contextualized the findings using 1) age-matched transcriptomics, 2) histologically defined cytoarchitectural types and functionally defined networks, and 3) case-control differences of schizophrenia and other major psychiatric disorders derived from meta-analytic data of 6 ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) working groups, including a total of 12,876 patients and 15,670 control participants. Results: Higher PRS-SCZ was associated with greater cortical thickness, which was most prominent in areas with heightened gene expression of dendrites and synapses. PRS-SCZ-related increases in vertexwise cortical thickness were mainly distributed in association cortical areas, particularly the ventral attention network, while relatively sparing koniocortical type cortex (i.e., primary sensory areas). The large-scale pattern of cortical thickness increases related to PRS-SCZ mirrored the pattern of cortical thinning in schizophrenia and mood-related psychiatric disorders derived from the ENIGMA consortium. Age group models illustrate a possible trajectory from PRS-SCZ-associated cortical thickness increases in early childhood toward thinning in late adolescence, with the latter resembling the adult brain phenotype of schizophrenia. Conclusions: Collectively, combining imaging genetics with multiscale mapping, our work provides novel insight into how genetic risk for schizophrenia affects the cortex early in life.

Press Releases of Drug-Related Randomized Trial Results Prior to Publication in High-Impact Journals: an Observational Study.

IMPORTANCE: Results from high-profile randomized controlled trials (RCTs) are routinely reported through press release months prior to peer-reviewed publication. There are potential benefits to press releases (e.g., knowledge dissemination, ensuring regulatory compliance), but also potential drawbacks (e.g., selective reporting, positive "spin"). OBJECTIVE: To characterize the practice of press release predating the publication of a drug-related RCT in a peer-reviewed journal ("preemptive press release"), including factors associated with this practice. DESIGN, SETTING, AND PARTICIPANTS: We systematically reviewed all RCTs of medications published between 2015 and 2019 in the New England Journal of Medicine (NEJM), Journal of the American Medical Association (JAMA), and Lancet. Press releases were identified using a systematic search of the grey literature (e.g., press release databases, study sponsor websites). An RCT was considered to have a preemptive press release if the press release was published at least three months (90 days) prior to the date of publication in a peer-reviewed journal. MAIN OUTCOMES AND MEASURES: Presence of preemptive press release, defined as a press-release at least 90 days prior to the date of publication in a peer-reviewed journal. As secondary measures for dissemination, we also assessed citation count and Altmetric score. RESULTS: We identified 988 RCTs, of which 172 (17%) had a press release published at least 90 days before the date of peer-reviewed publication. Press releases were published a median of 246 days (interquartile range [IQR] 169-366 days) before publication in a peer-reviewed journal. In the multivariable logistic regression model, the strongest predictor of having a preemptive press release was funding by a pharmaceutical company (odds ratio 13, 95% CI 7, 25). Approximately 85% of RCTs with preemptive press releases had a positive primary outcome and, concordantly, 81% of the corresponding press releases had a positive headline. Multivariable regression models identified studies with a preemptive press release had a similar Altmetric score (median - 15, 95% CI - 33, 12) and higher median citation count (median 22 [95% CI 10 to 33] compared to studies without a preemptive press release. CONCLUSIONS AND RELEVANCE: Preemptive press releases were common, most often issued for trials funded by a pharmaceutical company, and typically preceded publication in a peer-reviewed journal by approximately eight months.

Association Between Diabetes and Mortality Among Adult Patients Hospitalized With COVID-19: A Cohort Study of Hospitalized Adults in Ontario, Canada, and Copenhagen, Denmark.

OBJECTIVES: Diabetes has been reported to be associated with an increased risk of death among patients with COVID-19. However, the available studies lack detail on COVID-19 illness severity and measurement of relevant comorbidities. METHODS: We conducted a multicentre, retrospective cohort study of patients 18 years of age and older who were hospitalized with COVID-19 between January 1, 2020, and November 30, 2020, in Ontario, Canada, and Copenhagen, Denmark. Chart abstraction emphasizing comorbidities and disease severity was performed by trained research personnel. The association between diabetes and death was measured using Poisson regression. The main outcome measure was in-hospital 30-day risk of death. RESULTS: Our study included 1,133 hospitalized patients with COVID-19 in Ontario and 305 in Denmark, of whom 405 and 75 patients, respectively, had pre-existing diabetes. In both Ontario and Denmark, patients with diabetes were more likely to be older; have chronic kidney disease, cardiovascular disease, and higher troponin levels; and be receiving antibiotics, when compared with adults without diabetes. In Ontario, 24% (n=96) of adults with diabetes died compared with 15% (n=109) of adults without diabetes. In Denmark, 16% (n=12) of adults with diabetes died in hospital compared with 13% (n=29) of those without diabetes. In Ontario, the crude mortality ratio among patients with diabetes was 1.60 (95% confidence interval [CI], 1.24 to 2.07) and in the adjusted regression model it was 1.19 (95% CI, 0.86 to 1.66). In Denmark, the crude mortality ratio among patients with diabetes was 1.27 (95% CI, 0.68 to 2.36) and in the adjusted model it was 0.87 (95% CI, 0.49 to 1.54). Meta-analysis of the 2 rate ratios from each region resulted in a crude mortality ratio of 1.55 (95% CI, 1.22 to 1.96) and an adjusted mortality ratio of 1.11 (95% CI, 0.84 to 1.47). CONCLUSION: The presence of diabetes was not strongly associated with in-hospital COVID-19 mortality independent of illness severity and other comorbidities.

Impact of presentation at conference with timed release of academic publication.

Fast-tracking publication of original research to coincide with a conference presentation ("coordinated publication") is a mechanism of rapidly disseminating new data. How often this occurs, whether its frequency is changing, and the impact of this approach on information dissemination, is unknown. Our objective was to describe the characteristics of coordinated publications, how the practice has changed over time, and evaluate its potential impact on dissemination of study results. We conducted a cross-sectional study of randomized controlled trials published in NEJM, Lancet, and JAMA between January 1, 2015, and December 31, 2019. Among the 1533 included randomized controlled trials, 502 (33%) had coordinated publications. Coordinated publications increased from 30% [n = 94] in 2015 to 37% [n = 136] in 2019. Coordinated publications were more likely to be unblinded (61% [n = 305] vs. 52% [n = 532]) and more likely to be funded by industry (50% [n = 249] vs. 30% [n = 311]). The strongest predictor of a coordinated publication was cardiovascular disease subspecialty (OR = 3.96, 95% CI [2.95, 5.36]). The median number of citations (188 vs. 98) and the median Altmetric score (318 vs. 182) were higher for coordinated publications than non-coordinated publications. These differences persisted in a multivariable regression model. Coordinated publication is increasingly common. While coordinated publications may generate greater attention, they were observed to be more likely to be unblinded and more likely to be funded by industry, raising questions about the value and intentions of such promotion.

Identifying drugs with the greatest increases and decreases in spending per beneficiary using Medicare Part D: A cross-sectional study.

IMPORTANCE: In the US, there are no effective regulations controlling how much the price of a medication can increase. A patchwork of studies examining the reasons for soaring prices has focused on medications that have received considerable media attention, like insulin, epinephrine, and colchicine. OBJECTIVE: To identify the 50 medications with the greatest increase in average spending per beneficiary and the 50 medications with the greatest decrease in average spending per beneficiary, and to identify the factors associated with spending increases. DESIGN, PARTICIPANTS: This cross-sectional study used publicly available data from the Medicare Part D Prescription Drug Program from 2014 to 2020. We included drugs dispensed to > 1000 beneficiaries in each study year and excluded those primarily administered intravenously. MAIN MEASURES: Percentage change in average spending per beneficiary from 2014 to 2020 was calculated for each drug. For each drug, we extracted the number of beneficiaries, the number of manufacturers, and the drug-specific total annual spending reported in the Medicare Part D data set. An online database search was conducted to identify the primary clinical indication, the availability of any generic versions, and the date of FDA approval for each drug. RESULTS: The 50 medications with the greatest increase in spending per beneficiary had a median increase of 362.4% (interquartile range [IQR]: 286.6%-563.0%), with a cumulative spending of almost $5 billion in 2020 alone. Most drugs with the greatest increases in spending per beneficiary had generic versions available (68%) and were approved by the FDA over 10 years ago (66%). Medications with the greatest increase in spending per beneficiary had a median of 1 manufacturer (IQR: 1-2), while medications with the greatest decrease in spending per beneficiary had a median of 9.5 manufacturers (IQR: 5-14). CONCLUSIONS: This study identified rapidly increasing costs of medications under Medicare Part D. Our findings demonstrate that off-patent medications can skyrocket in price, especially when there are few manufacturers of a given medication.

Asynchronous, online spaced-repetition training alleviates word-finding difficulties in aphasia.

Word-finding difficulties for naming everyday objects are often prevalent in aphasia. Traditionally, treating these difficulties has involved repeated drilling of troublesome items with a therapist. Spaced repetition schedules can improve the efficiency of such training. However, spaced repetition in a therapy environment can be both difficult to implement and time-consuming. The current study evaluated the potential utility of automated, asynchronous, online spaced repetition training for the treatment of word-finding difficulties in individuals with aphasia. Twenty-one participants completed a two-week training study, completing approximately 60 minutes per day of asynchronous online drilling. The training items were identified using a pretest, and word-finding difficulties were evaluated both at the end of training (i.e., a post-test) and four weeks later (i.e., a retention test). The trained items were separated into three different spaced-repetition schedules: (1) Short-spacing; (2) Long-spacing; and (3) Adaptive-spacing. At the retention-test, all trained items outperformed non-trained items in terms of accuracy and reaction time. Further, preliminary evidence suggested a potential reaction time advantage for the adaptive-spacing condition. Overall, online, asynchronous spaced repetition training appears to be effective in treating word-finding difficulties in aphasia. Further research will be required to determine if different spaced repetition schedules can be leveraged to enhance this effect.

Cortical and subcortical neuroanatomical signatures of schizotypy in 3004 individuals assessed in a worldwide ENIGMA study.

Neuroanatomical abnormalities have been reported along a continuum from at-risk stages, including high schizotypy, to early and chronic psychosis. However, a comprehensive neuroanatomical mapping of schizotypy remains to be established. The authors conducted the first large-scale meta-analyses of cortical and subcortical morphometric patterns of schizotypy in healthy individuals, and compared these patterns with neuroanatomical abnormalities observed in major psychiatric disorders. The sample comprised 3004 unmedicated healthy individuals (12-68 years, 46.5% male) from 29 cohorts of the worldwide ENIGMA Schizotypy working group. Cortical and subcortical effect size maps with schizotypy scores were generated using standardized methods. Pattern similarities were assessed between the schizotypy-related cortical and subcortical maps and effect size maps from comparisons of schizophrenia (SZ), bipolar disorder (BD) and major depression (MDD) patients with controls. Thicker right medial orbitofrontal/ventromedial prefrontal cortex (mOFC/vmPFC) was associated with higher schizotypy scores (r = 0.067, pFDR = 0.02). The cortical thickness profile in schizotypy was positively correlated with cortical abnormalities in SZ (r = 0.285, pspin = 0.024), but not BD (r = 0.166, pspin = 0.205) or MDD (r = -0.274, pspin = 0.073). The schizotypy-related subcortical volume pattern was negatively correlated with subcortical abnormalities in SZ (rho = -0.690, pspin = 0.006), BD (rho = -0.672, pspin = 0.009), and MDD (rho = -0.692, pspin = 0.004). Comprehensive mapping of schizotypy-related brain morphometry in the general population revealed a significant relationship between higher schizotypy and thicker mOFC/vmPFC, in the absence of confounding effects due to antipsychotic medication or disease chronicity. The cortical pattern similarity between schizotypy and schizophrenia yields new insights into a dimensional neurobiological continuity across the extended psychosis phenotype.

Orbitofrontal-Striatal Structural Alterations Linked to Negative Symptoms at Different Stages of the Schizophrenia Spectrum.

Negative symptoms such as anhedonia and apathy are among the most debilitating manifestations of schizophrenia (SZ). Imaging studies have linked these symptoms to morphometric abnormalities in 2 brain regions implicated in reward and motivation: the orbitofrontal cortex (OFC) and striatum. Higher negative symptoms are generally associated with reduced OFC thickness, while higher apathy specifically maps to reduced striatal volume. However, it remains unclear whether these tissue losses are a consequence of chronic illness and its treatment or an underlying phenotypic trait. Here, we use multicentre magnetic resonance imaging data to investigate orbitofrontal-striatal abnormalities across the SZ spectrum from healthy populations with high schizotypy to unmedicated and medicated first-episode psychosis (FEP), and patients with chronic SZ. Putamen, caudate, accumbens volume, and OFC thickness were estimated from T1-weighted images acquired in all 3 diagnostic groups and controls from 4 sites (n = 337). Results were first established in 1 discovery dataset and replicated in 3 independent samples. There was a negative correlation between apathy and putamen/accumbens volume only in healthy individuals with schizotypy; however, medicated patients exhibited larger putamen volume, which appears to be a consequence of antipsychotic medications. The negative association between reduced OFC thickness and total negative symptoms also appeared to vary along the SZ spectrum, being significant only in FEP patients. In schizotypy, there was increased OFC thickness relative to controls. Our findings suggest that negative symptoms are associated with a temporal continuum of orbitofrontal-striatal abnormalities that may predate the occurrence of SZ. Thicker OFC in schizotypy may represent either compensatory or pathological mechanisms prior to the disease onset.

Latent Clinical-Anatomical Dimensions of Schizophrenia.

Widespread structural brain abnormalities have been consistently reported in schizophrenia, but their relation to the heterogeneous clinical manifestations remains unknown. In particular, it is unclear whether anatomical abnormalities in discrete regions give rise to discrete symptoms or whether distributed abnormalities give rise to the broad clinical profile associated with schizophrenia. Here, we apply a multivariate data-driven approach to investigate covariance patterns between multiple-symptom domains and distributed brain abnormalities in schizophrenia. Structural magnetic resonance imaging and clinical data were derived from one discovery sample (133 patients and 113 controls) and one independent validation sample (108 patients and 69 controls). Disease-related voxel-wise brain abnormalities were estimated using deformation-based morphometry. Partial least-squares analysis was used to comprehensively map clinical, neuropsychological, and demographic data onto distributed deformation in a single multivariate model. The analysis identified 3 latent clinical-anatomical dimensions that collectively accounted for 55% of the covariance between clinical data and brain deformation. The first latent clinical-anatomical dimension was replicated in an independent sample, encompassing cognitive impairments, negative symptom severity, and brain abnormalities within the default mode and visual networks. This cognitive-negative dimension was associated with low socioeconomic status and was represented across multiple races. Altogether, we identified a continuous cognitive-negative dimension of schizophrenia, centered on 2 intrinsic networks. By simultaneously taking into account both clinical manifestations and neuroanatomical abnormalities, the present results open new avenues for multi-omic stratification and biotyping of individuals with schizophrenia.