Citations

Context.— Organ weights are an essential part of autopsy analysis. Deviations from normal organ weights provide important clues to disease processes. The assessment of normal organ weights depends on reliable reference tables, but most widely available reference tables are based on data that are either decades old or derived from relatively small sample sizes. Objective.— To provide an updated reference table of organ weights based on contemporary sources and a large sample size. Design.— Organ weights from 4197 carefully screened autopsies performed on adults at the Palm Beach County Medical Examiner's Office in West Palm Beach, Florida, and the Mayo Clinic Hospital in Rochester, Minnesota. Results.— Height and body weight data in this study reflect the well-recognized increases in both variables, but most particularly in body weight, seen during the last decades. The study data show a strong positive association between organ weight and body weight for the heart, liver, and spleen. There is a similar but weaker association between body weight and the weight of the lungs and kidneys. Brain weight is independent of body weight but shows a strong negative association with age. Even when controlling for body weight, men's organs are heavier, except for the weight of the liver, which is comparable in men and women. These associations are in agreement with the findings of previous studies. The current study suggests that, for some of the commonly weighed organs, there has been an increase in median organ weight when compared with existing references. Conclusions.— The tables presented here provide an updated reference that should prove useful to autopsy pathologists in the forensic and hospital settings.

Genome-wide association studies (GWAS) have identified more than 200 susceptibility loci for breast cancer, but these variants explain less than a fifth of the disease risk. Although gene–environment interactions have been proposed to account for some of the remaining heritability, few studies have empirically assessed this. We obtained genotype and risk factor data from 46,060 cases and 47,929 controls of European ancestry from population-based studies within the Breast Cancer Association Consortium (BCAC). We built gene expression prediction models for 4,864 genes with a significant (P < 0.01) heritable component using the transcriptome and genotype data from the Genotype-Tissue Expression (GTEx) project. We leveraged predicted gene expression information to investigate the interactions between gene-centric genetic variation and 14 established risk factors in association with breast cancer risk, using a mixed-effects score test. After adjusting for number of tests using Bonferroni correction, no interaction remained statistically significant. The strongest interaction observed was between the predicted expression of the C13orf45 gene and age at first full-term pregnancy (PGXE = 4.44 × 10−6). In this transcriptome-informed genome-wide gene–environment interaction study of breast cancer, we found no strong support for the role of gene expression in modifying the associations between established risk factors and breast cancer risk. Our study suggests a limited role of gene–environment interactions in breast cancer risk.

Background: Ketamine, a dissociative anesthetic, induces improvement in depressive symptoms by antagonizing glutaminergic NMDA receptors. Ketamine has been used previously in outpatient setting for treatment-resistant depression, but we showcase its utility in depression management at the Intensive Care Unit (ICU). Research Question: Can ketamine be used for depression treatment in ICU patients? Study Design and Methods: A retrospective chart review of ICU patients was done at a tertiary center from 2018 to 2021, to assess the ketamine usage. Among the patients reviewed, ketamine was used for depression in 12, and for analgesia & sedation in 2322 patients. Ketamine was administered in doses of 0.5mg/kg & 0.75mg/kg for depression. Each course consisted of 3 doses of ketamine administered over 3 days, and 7 in 12 patients received a single course of ketamine. The rest received 3–4 courses 1 week apart. Results: Ketamine was found to improve mood and affect in most of the patients with depression. 11 in 12 patients had a positive response with better sleep. It has a major advantage over conventional anti-depressants since it takes only a few hours to induce clinical improvement. Patients who were observably withdrawn from care team and family, were administered ketamine. Conclusion: A major drawback of ketamine is that the duration of clinical improvement is short, with the response lasting only up to seven days after a single dose. Hence, all the patients in our study were weaned off ketamine with a supporting antidepressant. Ketamine has been documented to cause cardio-neurotoxicity; however, only one patient had worsening lethargy in our study. To conclude, ketamine has a marked benefit in treating depression in the ICU. Although our study was associated with positive outcomes, there is a need for prospective studies with long-term follow-up assessments.

Background: Seizures are a known complication of ischemic stroke. Some studies have reported a higher risk of post-stroke seizure with cardioembolic strokes, whereas others have not. The risk of post-stroke seizure for different stroke mechanisms is unclear. Objective: To compare different stroke etiologies and the risk of post-stroke seizure in a population-based study. Methods: Utilizing the Rochester Epidemiology Project medical records linkage system, we ascertained all first ischemic strokes occurring among Rochester, MN residents from 1990-1994, and followed the patients in the comprehensive medical record through March 2014 for occurrence of seizure. TOAST stroke subtype classification was determined by a consensus of cerebrovascular neurologists. New post-stroke seizure was identified by physician diagnosis and/or EEG report. Patients with a seizure before the index stroke were not included. Pre-morbid stroke risk factors were recorded. Associations between seizure after index ischemic stroke as outcome and other variables of interest were assessed using univariate logistic regression. Results: A total of 490 patients met inclusion criteria, with median follow-up of 6.5 years. Out of 490 patients, 35 had new onset seizures (7.1%). Median age was significantly lower at index stroke for patients with seizures (73 v. 77 years, p=0.017). The most common TOAST stroke subtype was cryptogenic (46.8%) followed by cardioembolic (24.9%). There was no significant difference in TOAST stroke subtypes between patients with post-stroke seizure and those without (p=0.35). There was also no difference between the two groups when comparing combined cardioembolic and large-vessel to small-vessel (p=0.28) or cryptogenic to small-vessel (p=0.9) mechanisms. There was also no difference in pre-morbid stroke risk factors between the two groups, including hypertension (p=0.22), total cholesterol (p=0.95), type 2 diabetes mellitus (p=0.13), tobacco use (p=0.27), atrial fibrillation (p=0.9), or previous myocardial infarction (p=0.67). Conclusion: This study suggests that the long-term risk of post-stroke seizures does not differ by ischemic stroke etiology.

Introduction: The long term effectiveness of preventive intracranial treatment of unruptured aneurysms for hemorrhage and aneurysm-related morbidity and mortality has been hypothesized. No randomized trial has been done. Propensity adjusted comparison within The International Study of Unruptured Intracranial Aneurysms was undertaken to compare long-term effectiveness. Hypothesis: The purpose of this analysis was to compare the long-term outcome in the treatment cohorts (surgery and endovascular) with those of the untreated subgroup. Methods: Patients were subdivided into the initial treatment and untreated cohorts based upon observation or treatment practices in 61 centers from 1991-1998. 1691 patients were in the observational cohort, 471 were in the endovascular cohort and 1917 patients were in the surgical cohort. The cohorts were followed for a median follow-up of 9.2 years. Outcomes were determined prospectively and with central review. The data were grouped together and analyzed to determine treatment decisions. Comparison of outcomes was done using covariate adjustment and using propensity analysis where equivalent probability groups were constructed. Similar main predictors of treatment and outcome were observed. Analysis of hemorrhage, mortality and short-term and long-term morbidity and mortality were assessed. Risk-benefit ratios were also calculated. Results: Significant differences in baseline variables between treatment and observed patients were aneurysm size, symptoms, age, prior SAH or not group, geographical region, family history, hypertension and myocardial infarction history. The results show comparability of groups using the patient propensity-based score subset. Using the propensity score method, the results showed a benefit in prevention of hemorrhage by surgery and endovascular treatment versus observation (p<.01). No difference was found between endovascular versus surgery. However when procedure-related outcomes are included, no significant difference at 1 year, 5 years or 10 years in the combined aneurysm or procedure related endpoint was evident between cohorts. Conclusions: Propensity score matching to achieve comparability resulted in balanced groups. Comparison of long-term results showed that intervention demonstrated a benefit in reducing hemorrhage risk. However, peri-procedural risk negates any short-term benefit for 10 years.

Introduction: Mortality in patients with unruptured intracranial aneurysm (UIA) is significantly higher than the general population. However a minority of the deaths are due to subarachnoid hemorrhage. Hypothesis: There are differential characteristics of patients that might predict specific causes of death that would be informative in counseling patients about aneurysm risk. Methods: 4059 patients with UIA who were enrolled prospectively between 1991 and 1998 were followed by 61 medical centers in North America, Canada, and Europe. Patients have at least one UIA, which may or may not be symptomatic. Patients were Rankin grade 1 or 2 at enrollment. Patients were followed annually from enrollment to 2007. For patients who died a death certificate search was done and information was requested from local physicians and other contacts. A National Death Index search in 2008 determined cases who died and cause of death. Foreign centers also did a national search where possible. Patients who died before 30 days post treatment or lost to follow up before 30 days post enrollment were excluded. Results: Twenty-five percent of patients died during follow-up. The life expectancy was significantly less than age-, sex-, and country-matched expected estimates. Among the total of 4004 patients with UIA who survived 30 days after enrollment, 2331 were treated and 1673 were not. There were 965 deaths after 30 days after treatment, of which 320 died from vascular disease (252 died from non-SAH vascular disease), 114 died from respiratory tract disease, 255 died from cancer, and the rest died of other or unknown reasons. Predictors of SAH death were aneurysm size, site, age and convulsive disorders at enrollment. Factors related to vascular death were UIA treatment, age, gender, race, hypertension, Rankin at discharge and diminishing influence of aneurysm characteristics over time. Respiratory deaths were related to treatment, race, smoking, age, initial Rankin and presentation with convulsive disorder. Cancer deaths were related to gender, race, smoking and age. Conclusions: In patients with UIA, an assessment of risk for death underscores the importance of age, race and gender and several modifiable risk factors. Patient management should include not only aneurysm rupture prevention but also modification of smoking and hypertension.

Leucine-rich repeat containing (LRR) proteins facilitate protein-protein interactions critical in a number of cellular functions including ion channel regulation. Leucine-rich repeat containing protein 10 (LRRC10), a cardiac-specific protein expressed in zebrafish, mice and humans, is essential for normal cardiac physiology with loss of Lrrc10 in Lrrc10 -/- mice resulting in dilated cardiomyopathy (DCM). However, the mechanism by which LRRC10 contributes to DCM is unknown. Further, the functional role of LRRC10 in the regulation of ion channels in the heart has not been explored. Here we recorded L-type Ca 2+ channel currents (I Ca,L ) from isolated ventricular myocytes of WT and Lrrc10 -/- mice, demonstrating a significant reduction in I Ca,L in Lrrc10 -/- myocytes (-4.9 ± 0.19 pA/pF, n=10) compared to WT (-6.5 ± 0.24 pA/pF, n=8). Co-immunoprecipitation (co-IP) experiments showed an association between LRRC10 and Ca v 1.2 in WT, but not Lrrc10 -/- mouse lysates, with immunocytochemistry studies further demonstrating colocalization of LRRC10 and Ca v 1.2 in isolated ventricular myocytes from wild-type (WT) mice. Additionally, whole exome sequencing revealed a novel homozygous recessive missense variant in LRRC10 , I195T, found in a pediatric DCM patient. To determine whether the I195T variant impacts Ca v 1.2 L-type Ca 2+ channels, whole-cell patch clamp experiments were performed using HEK293 cells transiently expressing the L-type Ca 2+ channel complex (LTCC) alone or with WT or I195T LRRC10. These electrophysiology experiments demonstrated a significant increase in I Ca,L with WT LRRC10 coexpression (-81 ± 5.3 pA/pF, n=12), but a decrease in I Ca,L when I195T (-18.2 ± 3.3 pA/pF, n=9) was coexpressed compared to the LTCC alone (-34.1 ± 2.2 pA/pF, n=17). Parallel surface biotinylation experiments demonstrated that WT and I195T LRRC10 did not alter L-type Ca 2+ channel expression on the plasma membrane, while co-IP experiments using lysates prepared from the transiently transfected HEK293 cells showed the association between Ca v 1.2 and I195T LRRC10 variant. Overall, these findings newly identify LRRC10 as a cardiac-specific component of the Ca v 1.2 macromolecular complex and demonstrate dysregulation of I Ca,L by the DCM associated I195T LRRC10 variant.

Background: Health insurance coverage has been recently expanded to millions of Americans with the goal of improving access and quality of care. We evaluated long-term outcomes for patients with ST-elevation myocardial infarction (STEMI) with different insurance types. Methods: From 2004 to 2010, 970 consecutive STEMI patients who presented to 29 hospitals in Minnesota, Iowa or Wisconsin were treated according to the Mayo STEMI protocol. Demographic, clinical, procedural, and long-term follow up data were prospectively collected. 953 patients were categorized into groups by insurance type - private insurance (PI, n=430), Medicare (MC, n=420), Medicaid (MD, n=68), and uninsured (UN, n=35). Results: Median duration of follow-up was 32 months, and mean ages (years) were 55±8 for PI, 75±10 for MC, 49±10 for MD, and 52±9 for UN (p<0.001). Compared to PI patients, MC and MD patients were more likely to have diabetes (both 21% vs 10%, p<0.001); MC patients had more renal failure (4% vs <1%, p=0.012) but UN patients did not differ significantly (DM 12% and CRF 0%). All groups had similar frequency of cardiogenic shock (PI 9%, MC 14%, MD 9%, UN 6%, p=0.08) and comparable door-to-balloon (in minutes(Q1,Q3): PI 69(54,107), MC 79(61,114), MD 83(55,124), UN 76(58,94), p=0.09) and door-to-needle times (in minutes(Q1,Q3): PI 26(19,34), MC 29 (21,39), MD 27(22,34), UN 17(13,21), p=0.06). MC patients had the highest incidence of in-hospital death (7.6%; p=0.003 vs PI 3.0%). Significant differences in all cause mortality between insurance groups were present on 5-year follow-up (Figure). After risk factor adjustment for age (HR 1.89 per decade, p<0.001), female sex (HR 1.16, p=0.40), diabetes (HR 1.89, p<0.001), peripheral artery disease (HR 2.06, p=0.004), heart failure (HR 1.40, p=0.14), cardiogenic shock (4.22, p<0.001) and renal failure (HR 1.62, p=0.20); insurance type was not an independent risk factor for death (p=0.26). When compared to PI, the hazard ratio for UN was associated with a trend for worse survival (HR 2.69, 95%CI 0.94, 7.67, p=0.06) while MC (HR 0.94, 95%CI 0.55, 1.61, p=0.83) and MD patients (HR 1.37, 95%CI 0.52, 3.59, p=0.53) had similar survival after adjustment for covariates. Conclusion: Timeliness of reperfusion was similar across all insurance groups. After adjustment for baseline clinical variables, there was no significant difference in long-term survival according to insurance type.

Introduction: Quality of life changes can occur following procedural interventions and subarachnoid hemorrhage in unruptured intracranial aneurysms (UIA). The International Study of Unruptured Intracranial Aneurysms conducted quality of life assessment using the Mini-Mental State Exam, Rankin Score, and Barthel Index at baseline and the Telephone Interview Cognitive Status Exam (TICS), Rankin Score, and Barthel Index at follow-up. Hypothesis: The purpose of this analysis was to compare the 1 year and 5 year outcome in the treatment cohorts (surgery and endovascular) with those of the untreated subgroup. Methods: Patients were subdivided into the initial treated and untreated cohorts based upon observation or treatment practices in 61 centers from 1991-1998. 1691 patients were in the observational cohort and 2388 in the treated cohort. The cohorts were followed annually with measures of neurological status, Rankin Scale, Barthel Index and cognition (TICS). Outcomes were determined prospectively. Comparison of outcomes was done using continuous and categorical data. Covariate adjustment was done using general linear models. Stratified analysis was done by Rankin Score at the time of follow-up. Results: The percent of patients with a Barthel Index score of less than 60 at 1 year in the cohort was 9.4% (treated patients, 9.7%; untreated patients, 9.2%). The percent of patients at year 1 with a score of greater than 90 was 87.6%, 87.4% for treated patients and 87.8% for untreated patients. The percent of patients with a Barthel Index score of less than 60 at 5 years in the cohort was 41.4% (treated patients, 41.4%; untreated patients, 41.4%). The percent of patients at year 5 with a score of greater than 90 was 56.3%, 56.1% for treated patients and 56.5% for untreated patients. TICS and Barthel Index scores were significantly associated with each other for patients with Rankin Scores 0-2 (P<0.0001). This was seen at both year 1 and year 5 follow-up, but not for patients with Rankin Score 3-5. At both 1 year and 5 year follow-up, after controlling for Rankin Score, the distribution of Barthel Index scores of untreated patients and treated patients did not significantly differ. At both the 1 year follow-up, baseline Rankin Score, TICS and follow-up Rankin Score were significant predictors of Barthel Score (P<0.0001). At 5 years, only the follow-up Rankin Score was associated with Barthel Score (P<0.0001). Conclusions: Barthel Index Score decreased over time, but does not differ with treatment. The Rankin Score was the main predictor at follow-up of Barthel Index Score distribution.

Background: Artificial intelligence (AI)-based analysis of the electrocardiogram (ECG) can estimate the probability of having atrial fibrillation (AF) while in sinus rhythm. We evaluated the association between the probability of AF using AI-ECG and incident ischemic stroke (I-Stroke) and cardiovascular (CV) mortality. Methods: We evaluated a community-based cohort of consecutive patients that sought primary care in Olmsted County, MN, from the years 1998 to 2000 followed-up through March 2016. Inclusion criteria were ages 40-79, an electrocardiogram within 2 years and complete CHA2DS2-VASc data. We excluded those with known atherosclerotic CV disease or AF. The AI network was developed in 180,000 patients (649,931 ECG). The primary endpoint was incident I-Stroke; secondary endpoint was I-Stroke or CV mortality; validated in duplicate. Multivariate cox models adjusted for age, sex, history of hypertension, diabetes, heart failure, and in CHA2DS2-VASc Score subgroups (categorized as low=0, moderate=1, and high risk ≥2). Results: We included 14,601 patients, mean age 53.2±13.08 (51% women, 95% whites), CHA2DS2-VASc score 1.3±1.2, median follow-up of 16.3 years, IQR 14.5-17.5, 727 (4.9%) had an I-Stroke and 1309 (8.9%) had I-Stroke or died from CV causes. When comparing the 5 th vs the 1 st quintile, those with high AI-ECG AF probability had increased risk for I-Stroke (HR 3.25, 95%CI 2.55-4.14, P-for trend <.0001 Figure-A ) and ischemic stroke or CV mortality (HR 5.73, 95%CI 4.69-6.99, P-for trend <.0001 Figure-B ). This remained significant after adjustments. Furthermore, AI-ECG AF probability was associated with I-Stroke across CHA2DS2-VASc risk levels (HR 2.43 for high, 2.33 for moderate, 1.98 for low CHA2DS2-VASc risk, all P<0.01). Conclusion: The AI-ECG AF algorithm predicts long-term I-Stroke and CV mortality and may refine CHA2DS2-VASc. These results highlight the utility of the AI enabled ECG when estimating I-Stroke or CV mortality risk.