Epistatic effects of IGHG and FCGRIIB genes on the development of Alzheimer's disease in African Americans.

Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified a large number of susceptibility genes, but most of AD heritability remains unexplained, implying the existence of additional genes. Furthermore, the majority of the GWAS have been conducted in people of European descent, and the genes important for AD susceptibility in people of African descent have been underexplored. In this hypothesis-generating prospective cohort study, we genotyped 191 African Americans (AAs) from three longitudinal cohorts on aging for the IgG3 allotype GM6, which is expressed exclusively in people of African descent, and assessed its interaction with IGHG, FCGRIIB, and HLA-DRB1 genes. Cox proportional hazards modeling showed that GM6 by itself was not significantly associated with AD development. However, there was evidence of epistatic interaction: The risk of developing AD associated with GM6 positivity was significantly different (p = 0.0098) in non-GM17/GM17 participants compared with GM 17/GM17 participants. Specifically, in non-GM17/GM17 participants, the risk of AD was over fourfold higher in GM6-positive participants compared with GM 6-negative participants (HR = 4.63). Similarly, risk of developing AD associated with GM6 positivity was marginally different in non-FCGRIIB TT participants compared with FCGRIIB TT participants. In non-FCGRIIB TT participants, the risk of developing AD was over twofold higher in GM6-positive participants compared with GM6-negative participants (HR = 2.44). This is the first report suggesting that immunoglobulin GM allotypes might play a role in AD etiology among AAs; however, since this was largely a hypothesis-generating study, replication in larger cohorts would be required to confirm this finding.

Comparison of three magnetic resonance imaging measures of brain iron in healthy and cocaine use disorder participants.

Several magnetic resonance imaging (MRI) measures for quantifying endogenous nonheme brain iron have been proposed. These correspond to distinct physical properties with varying sensitivities and specificities to iron. Moreover, they may depend not only on tissue iron concentration, but also on the intravoxel spatial pattern of iron deposition, which is complex in many brain regions. Here, the three MRI brain iron measures of R 2 * , magnetic field correlation (MFC), and magnetic susceptibility are compared in several deep gray matter regions for both healthy participants (HPs) and individuals with cocaine use disorder (CUD). Their concordance is assessed from their correlations with each other and their relative dependencies on age. In addition, associations between the iron measures and microstructure in adjacent white matter regions are investigated by calculating their correlations with diffusion MRI measures from the internal capsule, and associations with cognition are determined by using results from a battery of standardized tests relevant to CUD. It is found that all three iron measures are strongly correlated with each other for the considered gray matter regions, but with correlation coefficients substantially less than one indicating important differences. The age dependencies of all three measures are qualitatively similar in most regions, except for the red nucleus, where the susceptibility has a significantly stronger correlation with age than R 2 * . Weak to moderate correlations are seen for the iron measures with several of the diffusion and cognitive measures, with the strongest correlations being obtained for R 2 * . The iron measures differ little between the HP and CUD groups, although susceptibility is significantly lower in the red nucleus for the CUD group. For the comparisons made, the iron measures behave similarly in most respects, but with notable quantitative differences. It is suggested that these differences may be, in part, attributable to a higher sensitivity to the spatial pattern of iron deposition for R 2 * and MFC than for susceptibility. This is supported most strongly by a sharp contrast between the values of the iron measures in the globus pallidus relative to those in the red nucleus. The observed correlations of the iron measures with diffusion and cognitive scores point to possible connections between gray matter iron, white matter microstructure, and cognition.

A study of collagen refractility in dermatofibroma and dermatofibrosarcoma protuberans using diffractive microscopy.

BACKGROUND: Diffractive microscopy creates contrast within samples that are otherwise uniform under bright light. This technique can highlight subtle differences in refractive indices within birefringent samples containing varying amounts of mature collagen. Dermatofibroma (DF) and dermatofibrosarcoma protuberans (DFSP) possess differences in their mature collagen content and, therefore, may be distinguishable using diffractive microscopy. METHODS: Two hundred forty-two DF and 85 DFSP hematoxylin-eosin (H&E)-stained specimens were analyzed using diffractive microscopy. Data regarding the distribution pattern and strength of refractility was recorded. RESULTS: DFSP was more frequently found to be focally, weakly, or non-refractile (82.9%; n = 68) under diffractive microscopy, while DF more often showed diffusely bright refractility (52.9%; n = 128). DFSP samples with diffuse refractility in portions of the lesion (17.1%; n = 14) also exhibited a unique checkerboard pattern distinct from that which was seen in DF samples. CONCLUSIONS: The absence of diffuse refractility was more closely associated with DFSP, as was the presence of a unique checkerboard diffraction pattern. Despite high sensitivity (Sn = 82.9%), absent refractility was not a specific test (Sp = 52.9%), with 47.1% (n = 114) of DF samples sharing this feature. The distinction between DF and DFSP is often diagnosed using H&E alone. In difficult cases, examination of collagen under diffractive microscopy may be useful in distinguishing DFSP from DF and provide an alternative cost-effective tool to immunohistochemical staining.

Impact of Reducing Fluoroscopy Pulse Rate on Adult Modified Barium Swallow Studies.

Modified Barium Swallow Studies (MBSS) are a critical part of the evaluation, treatment planning, and outcome assessment for persons with swallowing disorders. Since MBSSs use ionizing radiation with associated cancer risks, many clinicians have reduced radiation exposure by reducing the fluoroscopic pulse rate. However, by reducing pulse rate, we also decrease the temporal resolution of MBSSs which has been shown in pilot studies to significantly reduce diagnostic accuracy. Two hundred MBSSs from patients routinely undergoing MBSS as standard of care conducted at 30 pulses per second (pps) using the Modified Barium Swallow Study Impairment Profile (MBSImP™) standardized administration protocol were selected. A stratified sampling method ensured that a full range of swallowing impairments (etiology, type, and severity) was represented. Recordings were down sampled from 30 pps to 15, 7.5, and 4 pps. MBSSs were rated using the MBSImP components and Penetration-Aspiration Scale (PAS) score for each swallow. Percent agreement was calculated across raters for MBSImP and PAS scores by bolus type and volume. The Least-Squares Method was used for hypothesis testing. Statistically significant and clinically meaningful changes in scores of swallowing physiology and penetration/aspiration occurred when reducing pulse rate below 30pps. These changes were evident across bolus types and volumes. Given the impact on diagnostic accuracy and the low radiation risks to adults undergoing MBSSs, reducing pulse rate to 15pps or below is not aligned with the As Low As Reasonably Achievable (ALARA) principle and should not be used as a viable method to reduce radiation exposure from MBSSs.

Greater Diffusion Restriction in White Matter in Preclinical Alzheimer Disease.

OBJECTIVE: The Alzheimer's continuum is biologically defined by beta-amyloid deposition, which at the earliest stages is superimposed upon white matter degeneration in aging. However, the extent to which these co-occurring changes is characterized is relatively underexplored. The goal of this study was to use diffusional kurtosis imaging (DKI) and biophysical modeling to detect and describe amyloid-related white matter changes in preclinical Alzheimer disease. METHODS: Cognitively unimpaired participants ages 45 to 85 years completed brain magnetic resonance imaging, amyloid positron emission tomography (florbetapir), neuropsychological testing, and other clinical measures at baseline in a cohort study. We tested whether beta-amyloid-negative (AB-) and -positive (AB+) participants differed on DKI-based conventional (ie, fractional anisotropy [FA], mean diffusivity [MD], mean kurtosis) and modeling (ie, axonal water fraction [AWF], extra-axonal radial diffusivity [De,⊥ ]) metrics, and whether these metrics were associated with other biomarkers. RESULTS: We found significantly greater diffusion restriction (higher FA/AWF, lower MD/De,⊥ ) in white matter in AB+ than AB- (partial η2 =0.08-0.19), more notably in the extra-axonal space within primarily late myelinating tracts. Diffusion metrics predicted amyloid status incrementally over age (area under the curve = 0.84) with modest yet selective associations, where AWF (a marker of axonal density) correlated with speed/executive functions and neurodegeneration, whereas De,⊥ (a marker of gliosis/myelin repair) correlated with amyloid deposition and white matter hyperintensity volume. INTERPRETATION: These results support prior evidence of a nonmonotonic change in diffusion behavior, where an early increase in diffusion restriction is hypothesized to reflect inflammation and myelin repair prior to an ensuing decrease in diffusion restriction, indicating glial and neuronal degeneration. ANN NEUROL 2022;91:864-877.

Cytologic atypia of benign inflammatory versus neoplastic cutaneous squamous lesions.

BACKGROUND: Cytologic atypia encompasses several features of abnormal cellular morphology. We sought to quantify these features in benign and premalignant/malignant squamous cell lesions to better characterize criteria for malignancy. METHODS: We conducted a rater-blinded observational study in which histopathology slides were evaluated under light microscopy, and the presence and relative quantity of 24 distinct cytological features were recorded, along with respective diagnoses. Each slide was evaluated, and the ratings were recorded and analyzed. RESULTS: The most helpful findings, whose presence in high numbers indicates an increased likelihood that the tissue sample is premalignant/malignant, were: (1) pleomorphic parakeratosis; (2) pleomorphic nuclei in the epithelium; (3) irregular nuclei; (4) thick refractile nuclear envelope; (5) presence of nuclear hyperchromasia (dark gray); (6) peripheral nucleoli; and (7) nucleolar stems. Higher values of round or oval nuclear shape and vesicular nuclei increase the likelihood that the tissue sample is benign. CONCLUSIONS: Certain nuclear features have a higher association with premalignancy/malignancy and may guide histologic evaluation of a given lesion. These findings can be used in combination with architectural features and clinical history to add to a complete diagnostic picture.

Dermatofibroma Versus Dermatofibrosarcoma Protuberans: A Nuclear Morphology Study.

ABSTRACT: The locally invasive soft-tissue sarcoma, dermatofibrosarcoma protuberans (DFSPs), shares certain histologic features of the much more common and benign dermatofibroma (DF). While immunohistochemical stains, specifically cluster of differentiation 34 and Factor XIIIa, can be used to distinguish the 2 entities using microscopy, these markers are not entirely sensitive nor specific. Three-dimensionally, DFSP nuclei resemble a "puck" or "coin"-like shape. As hematoxylin/eosin-stained slides are prepared, these "puck" nuclei are fixed in an infinite number of orientations depending on their current position in rotation about their axes within the tumor cells. Under histological examination, this random nuclear positioning produces the appearance of 2 predominate morphologies: an ovoid "disk" shape (en face) and a narrow spindled shape (side view), which distribute in a roughly 50:50 ratio throughout the tumor sample slide. Nuclear morphology was analyzed in 324 DFSP and DF samples at high magnification (×400) to determine the presence or absence of a predominant morphology in which nuclei appear to alternate between an ovoid (en face) and spindled (side view) throughout most of the tumor sample. An alternating ovoid-spindled nuclear morphology was the predominant cytology in 98% of DFSP and was not predominant in 100% of DF samples (P < 0.001). This morphology was found to be highly specific (Sp = 1) and sensitive (Sn = 0.98) for DFSP. This unique nuclear morphology may be a more sensitive and specific diagnostic tool in identifying DFSP from DF in comparison with costly immunohistochemical stains.

A Modification of Time-Driven Activity-Based Costing for Comparing Cost of Telehealth and In-Person Visits.

Introduction: Cost studies of telehealth (TH) and virtual visits are few and report mixed results of the economic impact of virtual care and TH. Largely missing from the literature are studies that identify the cost of delivering TH versus in-person care. The objective was to demonstrate a modified time-driven activity-based costing (TDABC) approach to compare weighted labor cost of an in-person pediatric clinic sick visit before COVID-19 to the same virtual and in-person sick-visit during COVID-19. Methods: We examined visits before and during COVID-19 using: (1) recorded structured interviews with providers; (2) iterative workflow mapping; (3) electronic health records time stamps for validation; (4) standard cost weights for wages; and (5) clinic CPT billing code mix for complexity weighs. We examined the variability in estimated time using a decision tree model and Monte Carlo simulations. Results: Workflow charts were created for the clinic before COVID-19 and during COVID-19. Using TDABC and simulations for varying time, the weighted cost of clinic labor for sick visit before COVID-19 was $54.47 versus $51.55 during COVID-19. Discussion: The estimated mean labor cost for care during the pandemic has not changed from the pre-COVID period; however, this lack of a difference is largely because of the increased use of TH. Conclusions: Our TDABC approach is feasible to use under virtual working conditions; requires minimal provider time for execution; and generates detailed cost estimates that have "face validity" with providers and are relevant for economic evaluation.

Which adults with sickle cell disease need an evaluation for pulmonary embolism?

Individuals living with sickle cell disease (SCD) are at an increased risk of venous thrombo-embolism (VTE) including pulmonary embolisms (PEs). There is a high mortality associated with PE in individuals with SCD. It can be difficult to diagnose PE since presenting symptoms of PE often mimic those of other forms of vaso-occlusive crisis in SCD. Currently, there are no validated models for predicting PEs in patients with sickle cell disease, which often leads to frequent CT scans and exposure to harmful radiation and intravenous contrast. The aim of this study was to evaluate different host variables and potential clinical biomarkers of patients with SCD including those used in the Wells score to assess predictability for PE in order to create a more accurate diagnostic algorithm to predict PE. A retrospective chart review was performed on 349 patients with SCD who underwent testing for a PE with a CT scan of the chest. Forward and backward stepwise model selection was performed to obtain a parsimonious model of the predictors of PEs. The incidence of PE in this population was 9·7%. Of the factors evaluated for this study, the Wells score was the only one with clinical significance. A Wells score greater than 4 had a sensitivity and specificity of 72·5% and 70·1%, respectively, and a score greater than 6 had a sensitivity and specificity of 50% and 87%, respectively. The Wells score is an acceptable clinical tool which may prove useful in individuals with SCD to predict who is most likely to have a PE and therefore should undergo a CT scan. A prospective study is needed to further confirm these findings.

Propensity score matching for multilevel spatial data: accounting for geographic confounding in health disparity studies.

BACKGROUND: Diabetes is a public health burden that disproportionately affects military veterans and racial minorities. Studies of racial disparities are inherently observational, and thus may require the use of methods such as Propensity Score Analysis (PSA). While traditional PSA accounts for patient-level factors, this may not be sufficient when patients are clustered at the geographic level and thus important confounders, whether observed or unobserved, vary by geographic location. METHODS: We employ a spatial propensity score matching method to account for "geographic confounding", which occurs when the confounding factors, whether observed or unobserved, vary by geographic region. We augment the propensity score and outcome models with spatial random effects, which are assigned scaled Besag-York-Mollié priors to address spatial clustering and improve inferences by borrowing information across neighboring geographic regions. We apply this approach to a study exploring racial disparities in diabetes specialty care between non-Hispanic black and non-Hispanic white veterans. We construct multiple global estimates of the risk difference in diabetes care: a crude unadjusted estimate, an estimate based solely on patient-level matching, and an estimate that incorporates both patient and spatial information. RESULTS: In simulation we show that in the presence of an unmeasured geographic confounder, ignoring spatial heterogeneity results in increased relative bias and mean squared error, whereas incorporating spatial random effects improves inferences. In our study of racial disparities in diabetes specialty care, the crude unadjusted estimate suggests that specialty care is more prevalent among non-Hispanic blacks, while patient-level matching indicates that it is less prevalent. Hierarchical spatial matching supports the latter conclusion, with a further increase in the magnitude of the disparity. CONCLUSIONS: These results highlight the importance of accounting for spatial heterogeneity in propensity score analysis, and suggest the need for clinical care and management strategies that are culturally sensitive and racially inclusive.

Diffusion MRI detects early brain microstructure abnormalities in 2-month-old 3×Tg-AD mice.

The 3×Tg-AD mouse is one of the most studied animal models of Alzheimer's disease (AD), and develops both amyloid beta deposits and neurofibrillary tangles in a temporal and spatial pattern that is similar to human AD pathology. Additionally, abnormal myelination patterns with changes in oligodendrocyte and myelin marker expression are reported to be an early pathological feature in this model. Only few diffusion MRI (dMRI) studies have investigated white matter abnormalities in 3×Tg-AD mice, with inconsistent results. Thus, the goal of this study was to investigate the sensitivity of dMRI to capture brain microstructural alterations in 2-month-old 3×Tg-AD mice. In the fimbria, the fractional anisotropy (FA), kurtosis fractional anisotropy (KFA), and radial kurtosis (K┴ ) were found to be significantly lower in 3×Tg-AD mice than in controls, while the mean diffusivity (MD) and radial diffusivity (D┴ ) were found to be elevated. In the fornix, K┴ was lower for 3×Tg-AD mice; in the dorsal hippocampus MD and D┴ were elevated, as were FA, MD, and D┴ in the ventral hippocampus. These results indicate, for the first time, dMRI changes associated with myelin abnormalities in young 3×Tg-AD mice, before they develop AD pathology. Morphological quantification of myelin basic protein immunoreactivity in the fimbria was significantly lower in the 3×Tg-AD mice compared with the age-matched controls. Our results demonstrate that dMRI is able to detect widespread, significant early brain morphological abnormalities in 2-month-old 3×Tg-AD mice.

Translating CKD Research into Primary Care Practice: a Group-Randomized Study.

BACKGROUND: Chronic kidney disease (CKD) is common in the primary care setting. Early interventions may prevent progression of renal disease and reduce risk for cardiovascular complications, yet quality gaps have been documented. Successful approaches to improve identification and management of CKD in primary care are needed. OBJECTIVE: To assess whether implementation of a primary care improvement model results in improved identification and management of CKD DESIGN: 18-month group-randomized study PARTICIPANTS: 21 primary care practices in 13 US states caring for 107,094 patients INTERVENTIONS: To promote implementation of CKD improvement strategies, intervention practices received clinical quality measure (CQM) reports at least quarterly, hosted an on-site visit and 2 webinars, and sent clinician/staff representatives to a "best practice" meeting. Control practices received CQM reports at least quarterly. MAIN MEASURES: Changes in practice adherence to a set of 11 CKD CQMs KEY RESULTS: We observed significantly greater improvements among intervention practices for annual screening for albuminuria in patients with diabetes or hypertension (absolute change 22% in the intervention group vs. - 2.6% in the control group, p < 0.0001) and annual monitoring for albuminuria in patients with CKD (absolute change 21% in the intervention group vs. - 2.0% in the control group, p < 0.0001). Avoidance of NSAIDs in patients with CKD declined in both intervention and control groups, with a significantly greater decline in the control practices (absolute change - 5.0% in the intervention group vs. - 10% in the control group, p < 0.0001). There were no other significant changes found for the other CQMs. Variable implementation of CKD improvement strategies was noted across the intervention practices. CONCLUSIONS: Implementation of a primary care improvement model designed to improve CKD identification and management resulted in significantly improved care on 3 out of 11 CQMs. Incomplete adoption of improvement strategies may have limited further improvement. Improving CKD identification and management likely requires a longer and more intensive intervention.

Statistical properties of minimal sufficient balance and minimization as methods for controlling baseline covariate imbalance at the design stage of sequential clinical trials.

When the number of baseline covariates whose imbalance needs to be controlled in a sequential randomized controlled trial is large, minimization is the most commonly used method for randomizing treatment assignments. The lack of allocation randomness associated with the minimization method has been the source of controversy, and the need to reduce even minor imbalances inherent in the minimization method has been challenged. The minimal sufficient balance (MSB) method is an alternative to the minimization method. It prevents serious imbalance from a large number of covariates while maintaining a high level of allocation randomness. In this study, the two treatment allocation methods are compared with regards to the effectiveness of balancing covariates across treatment arms and allocation randomness in equal allocation clinical trials. The MSB method proves to be equal or superior in both respects. In addition, type I error rate is preserved in analyses for both balancing methods, when using a binary endpoint.

ASSOCIATIONS BETWEEN ACCELERATED ATHEROSCLEROSIS, OXIDIZED LDL IMMUNE COMPLEXES, AND IN VITRO ENDOTHELIAL DYSFUNCTION IN SYSTEMIC LUPUS ERYTHEMATOSUS.

Systemic lupus erythematosus (SLE) is an independent risk factor for atherosclerosis. This study was designed to determine the association between atherosclerosis, oxidized LDL immune complexes (oxLDL-IC), and endothelial dysfunction in SLE. SLE patients were recruited, and carotid atherosclerotic total plaque area (TPA) was determined by ultrasound. Levels of oxLDL-IC were measured. In vitro endothelial function was measured by aortic endothelial nitric oxide (NO) production after culture of human aortic endothelial cells (HAEC) with SLE serum. Levels of oxLDL-IC are associated significantly with TPA. In vitro HAEC NO production after culture with SLE serum was positively correlated with serum complement. HAEC NO production was increased with sepiapterin to couple eNOS. To our knowledge, this is the first study to demonstrate an association between subclinical accelerated atherosclerosis and oxLDL-IC in SLE. This is also the first study to demonstrate the effect of sepiapterin on improving in vitro aortic endothelial cell function in SLE.

Equalization of four cardiovascular risk algorithms after systematic recalibration: individual-participant meta-analysis of 86 prospective studies.

AIMS: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after 'recalibration', a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied. METHODS AND RESULTS: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at 'high' 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29-39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22-24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44-51 such individuals using original algorithms, in contrast to 37-39 individuals with recalibrated algorithms. CONCLUSION: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need.

Association Between Depressive Symptoms and Incident Cardiovascular Diseases.

Importance: It is uncertain whether depressive symptoms are independently associated with subsequent risk of cardiovascular diseases (CVDs). Objective: To characterize the association between depressive symptoms and CVD incidence across the spectrum of lower mood. Design, Setting, and Participants: A pooled analysis of individual-participant data from the Emerging Risk Factors Collaboration (ERFC; 162 036 participants; 21 cohorts; baseline surveys, 1960-2008; latest follow-up, March 2020) and the UK Biobank (401 219 participants; baseline surveys, 2006-2010; latest follow-up, March 2020). Eligible participants had information about self-reported depressive symptoms and no CVD history at baseline. Exposures: Depressive symptoms were recorded using validated instruments. ERFC scores were harmonized across studies to a scale representative of the Center for Epidemiological Studies Depression (CES-D) scale (range, 0-60; ≥16 indicates possible depressive disorder). The UK Biobank recorded the 2-item Patient Health Questionnaire 2 (PHQ-2; range, 0-6; ≥3 indicates possible depressive disorder). Main Outcomes and Measures: Primary outcomes were incident fatal or nonfatal coronary heart disease (CHD), stroke, and CVD (composite of the 2). Hazard ratios (HRs) per 1-SD higher log CES-D or PHQ-2 adjusted for age, sex, smoking, and diabetes were reported. Results: Among 162 036 participants from the ERFC (73%, women; mean age at baseline, 63 years [SD, 9 years]), 5078 CHD and 3932 stroke events were recorded (median follow-up, 9.5 years). Associations with CHD, stroke, and CVD were log linear. The HR per 1-SD higher depression score for CHD was 1.07 (95% CI, 1.03-1.11); stroke, 1.05 (95% CI, 1.01-1.10); and CVD, 1.06 (95% CI, 1.04-1.08). The corresponding incidence rates per 10 000 person-years of follow-up in the highest vs the lowest quintile of CES-D score (geometric mean CES-D score, 19 vs 1) were 36.3 vs 29.0 for CHD events, 28.0 vs 24.7 for stroke events, and 62.8 vs 53.5 for CVD events. Among 401 219 participants from the UK Biobank (55% were women, mean age at baseline, 56 years [SD, 8 years]), 4607 CHD and 3253 stroke events were recorded (median follow-up, 8.1 years). The HR per 1-SD higher depression score for CHD was 1.11 (95% CI, 1.08-1.14); stroke, 1.10 (95% CI, 1.06-1.14); and CVD, 1.10 (95% CI, 1.08-1.13). The corresponding incidence rates per 10 000 person-years of follow-up among individuals with PHQ-2 scores of 4 or higher vs 0 were 20.9 vs 14.2 for CHD events, 15.3 vs 10.2 for stroke events, and 36.2 vs 24.5 for CVD events. The magnitude and statistical significance of the HRs were not materially changed after adjustment for additional risk factors. Conclusions and Relevance: In a pooled analysis of 563 255 participants in 22 cohorts, baseline depressive symptoms were associated with CVD incidence, including at symptom levels lower than the threshold indicative of a depressive disorder. However, the magnitude of associations was modest.

Racial Disparities in Arterial Stiffness Between Healthy Whites and African Americans in the United States: A Meta-analysis.

BACKGROUND: African Americans (AAs) present with cardiovascular disease (CVD) risk factors at younger ages than whites. Consequently, CVD and stroke occur at a higher incidence and at earlier decades in life in AA populations. Arterial stiffness is a predictor of CVD outcomes and partially explains the CVD risk experienced by racial minorities. We evaluated the differences in arterial stiffness observed in AAs and whites through a systematic review and meta-analysis. METHODS: We searched PubMed and SCOPUS for comparative studies published March 1995 to November 29, 2017 comparing arterial stiffness assessments (pulse wave velocity, augmentation index, and central blood pressure) between AAs and whites. Two independent reviewers examined 195 titles/abstracts, 85 full text articles and 11 articles were included in the meta-analysis using random effects modeling approaches. MAIN RESULTS: A total of 5060 white and 3225 AAs were included across 11 relevant studies. Carotid-femoral pulse wave velocity (cfPWV) measures were statistically different between AAs and whites (mean difference = -0.44, 95% confidence interval [CI]: -[-0.67, -0.21], p = 0.0002). Aortic femoral pulse wave velocity was significantly different between AAs and whites (mean difference = -0.21, [95% CI] -0.35, -0.07, p = 0.003) regardless of sex. Augmentation index (AIx) and Augmentation index at a 75 beats per minutes heart rate (AIx @75) was also significantly different between AA and whites (mean difference = -4.36 [95% CI] = -6.59, -2,12, p = 0.0001 and -6.26, [95% CI] = -9.19, -3.33, p < 0.0001, respectively). CONCLUSIONS: Racial disparities in arterial stiffness persist among African American racial groups in the United States. The lack of homogeneity in studies capturing racial disparities in cfPWV suggest that additional studies are needed to understand the magnitude of racial differences in African Americans and whites that might be clinically relevant.

Physician Confidence in Dental Trauma Treatment and the Introduction of a Dental Trauma Decision-Making Pathway for the Pediatric Emergency Department.

OBJECTIVES: The objectives of this study were to (1) survey and report the awareness and confidence of pediatric emergency medicine physicians in the management of dental trauma and (2) determine the prevalence of dental trauma decision-making pathway utilization in the pediatric emergency department. METHODS: A survey was distributed through e-mail to the pediatric emergency medicine discussion list via Brown University LISTSERV. The survey study included 10 questions and was multiple-choice. The survey contained questions about physician confidence and their use of a dental trauma decision-making pathway. RESULTS: A total of 285 individuals responded to the survey. Somewhat confident was the most common response (61%) followed by not confident (20%) and confident (19%) by respondents in treating dental trauma. Forty-one percent of respondents felt comfortable, 39% somewhat comfortable, 19% not comfortable, and 1% not sure in replanting an avulsed tooth. Only 6% of respondents reported that their pediatric emergency department always or sometimes uses a dental trauma decision-making pathway, whereas 78% of pediatric emergency departments do not. CONCLUSIONS: We believe that the adoption of a decision-making pathway will provide timely management, improve emergency physician comfort, and enhance outcomes for pediatric patients presenting with a dental trauma. A future multicenter review will aim to evaluate these goals based on the utilization of our dental trauma decision-making pathway.

Immunoglobulin genotypes and cognitive functions in schizophrenia.

Exposure to neurotropic viruses, such as herpes simplex virus type 1 and human cytomegalovirus, has been reported to be associated with cognitive impairment in schizophrenia. These viruses have evolved highly sophisticated strategies for decreasing the efficacy of the host immune response and interfering with viral clearance. Particular immunoglobulin GM (γ marker) genotypes modulate these viral immunoevasion strategies, influence antibody responsiveness to viral proteins, and are also associated with susceptibility to schizophrenia, providing an excellent rationale for determining their possible involvement in the cognitive functions in this highly heritable neurodevelopmental disorder. In this investigation, we assessed the cognitive functions (verbal memory, working memory, motor speed, verbal fluency, attention and processing speed, and executive function) in 145 patients with schizophrenia and characterized their DNA for several GM and KM (κ marker) alleles. Particular KM and GM genotypes were significantly associated with verbal memory and attention and processing speed scores, respectively (P = 0.01 and 0.001). Epistatic effects of GM and KM genotypes on attention and processing speed, verbal fluency, and motor speed were also noted (P = 0.031, 0.047, 0.003). These results, for the first time, show that hitherto understudied immunoglobulin GM and KM genotypes-individually and epistatically-contribute to the magnitude of interindividual variability in the cognitive functions in patients with schizophrenia. Additional studies involving these highly polymorphic genes of the immune system are needed.