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We present a case of hypoglycemia in a young patient without diabetes mellitus who presented initially with enlarging neck mass and weight loss, and was found to have aggressive melanoma with metastasis to multiple organs and diffuse lymphadenopathy. He had presented to the emergency room two times with neuroglycopenic symptoms that required admission and intravenous dextrose continuously. Evaluation of hypoglycemia included C-peptide, insulin levels, insulin-like growth factor (IGF) -I and -II, and ß- hydroxybutyrate. Insulin levels were suppressed appropriately during hypoglycemia, however, IGF-II:IGF-I ratio was high, suggesting non-islet tumour induced hypoglycemia. The presence of IGF-II produced by large tumors results in a low hepatic glucose output and increased uptake by skeletal muscle, resulting in hypoglycemia especially in a patient with extremely low appetite such as our patient. Treating the culprit malignancy leads to resolution of hypoglycemia, but corticosteroids have been used to suppress IGF-II levels and alleviate symptoms.

OBJECTIVE The objective of this study was to determine the frequency with which brain biopsy for presumed CNS relapse of systemic hematological malignancies yields new, actionable diagnostic information. Hematological malignancies represent a disparate group of genetic and histopathological disorders. Proclivity for brain involvement is dependent on the unique entity and may occur synchronously or metasynchronously with the systemic lesion. Diffuse large B-cell lymphomas (DLBCLs) have a high propensity for brain involvement. Patients in remission from systemic DLBCL may present with a lesion suspicious for brain relapse. These patients often undergo brain biopsy. The authors’ a priori hypothesis was that brain biopsy in patients with a history of systemic DLBCL and a new brain MRI lesion would have lower diagnostic utility compared with patients with non-DLBCL systemic malignancies. METHODS The authors performed a retrospective review of patients who underwent brain biopsy between 2000 and 2019. Inclusion criteria were patients ≥ 18 years of age with a prior systemic hematological malignancy in remission presenting with a new brain MRI lesion concerning for CNS relapse. Patients with a history of any CNS neoplasms, demyelinating disorders, or active systemic disease were excluded. The main outcome was the proportion of patients with a distinct histopathological brain diagnosis compared with the systemic malignancy. The authors secondarily assessed overall survival, procedure-related morbidity, and 30-day mortality. RESULTS Sixty patients met inclusion criteria (40 males and 20 females); the median age at brain biopsy was 67 years (range 23–88 years). The median follow-up was 8.5 months (range 0.1–231 months). Thirty-nine (65.0%) patients had DLBCL and 21 (35%) had non-DLBCL malignancies. Thirty-five of 36 (97.2%) patients with prior systemic DLBCL and a diagnostic biopsy had histopathological confirmation of the original systemic disease versus 0 of 21 patients with non-DLBCL systemic malignancies (p < 0.001). Morbidity and 30-day mortality were 8.3% and 10.0%, respectively; 2 of 6 30-day mortalities were directly attributable to the biopsy. The median overall survival following brain biopsy was 10.8 months. CONCLUSIONS Patients with a history of systemic DLBCL and presumed CNS relapse gained minimal clinical benefit from brain biopsy but were at high risk of morbidity and mortality. In patients with a history of non-DLBCL systemic malignancies, brain biopsy remained critical given the high likelihood for discovery of distinct diagnostic entities. It was determined that patients with a prior systemic DLBCL and presumed brain relapse should likely receive empirical therapy obviating treatment delay and the risks of brain biopsy.

Type 2 diabetes is a disease characterized by impaired insulin secretion and defective glucagon suppression in the postprandial period. We examined the effect of impaired glucagon suppression on glucose concentrations and endogenous glucose production (EGP) at different degrees of insulin secretory impairment. The contribution of anthropometric characteristics, peripheral, and hepatic insulin action to this variability was also examined. To do so, we studied 54 nondiabetic subjects on two occasions in which endogenous hormone secretion was inhibited by somatostatin, with glucagon infused at a rate of 0.65 ng/kg/min, at 0 min to prevent a fall in glucagon (nonsuppressed day) or at 120 min to create a transient fall in glucagon (suppressed day). Subjects received glucose (labeled with [3-(3)H]-glucose) infused to mimic the systemic appearance of 50-g oral glucose. Insulin was infused to mimic a prandial insulin response in 18 subjects, another 18 received 80% of the dose, and the remaining 18 received 60%. EGP was measured using the tracer-dilution technique. Decreased prandial insulin resulted in greater % increase in peak glucose but not in integrated glucose concentrations attributable to nonsuppressed glucagon. The % change in integrated EGP was unaffected by insulin dose. Multivariate regression analysis, adjusted for age, sex, weight, and insulin dose, did not show a relationship between the EGP response to impaired suppression of glucagon and insulin action as measured at the time of screening by oral glucose tolerance. A similar analysis for hepatic insulin action also did not show a relationship with the EGP response. These data indicate that the effect of impaired glucagon suppression on EGP is independent of anthropometric characteristics and insulin action. NEW & NOTEWORTHY In prediabetes, anthropometric characteristics as well as insulin action do not alter the hepatic response to glucagon. The postprandial suppression or lack of suppression of glucagon secretion is an important factor governing postprandial glucose tolerance independent of insulin secretion.

INTRODUCTION We examined national Google Trends and local healthcare utilization after 3 high-impact gastroenterology publications. METHODS Changes in US Google Trends and Olmsted County health utilization were studied. RESULTS Publication views within 30 days were 51,458 (Imperiale), 49,759 (Pimentel), and 18,750 (Gomm). Colonoscopy searches (P = 0.04) and Cologuard tests performed (P < 0.01) increased while colonoscopies decreased (P < 0.01). Searches for rifaximin (P = 0.05), irritable bowel syndrome (P < 0.01), diarrhea (P < 0.01), and rifaximin prescriptions (P = 0.02) increased. Increase in hydrogen-2 blocker searches (P = 0.02) and prescriptions (P < 0.01) and gastroesophageal reflux disease (P < 0.01) and dementia office visits (P < 0.01) occurred. DISCUSSION High-impact gastroenterology publications influence Google searches and local population-based healthcare utilization.

Undiagnosed dilated cardiomyopathy (DC) can be asymptomatic or present as sudden cardiac death, therefore pre-emptively identifying and treating patients may be beneficial. Screening for DC with echocardiography is expensive and labor intensive and standard electrocardiography (ECG) is insensitive and non-specific. The performance and applicability of artificial intelligence-enabled electrocardiography (AI-ECG) for detection of DC is unknown. Diagnostic performance of an AI algorithm in determining reduced left ventricular ejection fraction (LVEF) was evaluated in a cohort that comprised of DC and normal LVEF control patients. DC patients and controls with 12-lead ECGs and a reference LVEF measured by echocardiography performed within 30 and 180 days of the ECG respectively were enrolled. The model was tested for its sensitivity, specificity, negative predictive (NPV) and positive predictive values (PPV) based on the prevalence of DC at 1% and 5%. The cohort consisted of 421 DC cases (60% males, 57±15 years, LVEF 28±11%) and 16,025 controls (49% males, age 69 ±16 years, LVEF 62±5%). For detection of LVEF≤45%, the area under the curve (AUC) was 0.955 with a sensitivity of 98.8% and specificity 44.8%. The NPV and PPV were 100% and 1.8% at a DC prevalence of 1% and 99.9% and 8.6% at a prevalence of 5%, respectively. In conclusion AI-ECG demonstrated high sensitivity and negative predictive value for detection of DC and could be used as a simple and cost-effective screening tool with implications for screening first degree relatives of DC patients.

Objectives The aim of this study was to examine the effect of CYP2C19 genotype on clinical outcomes in patients with coronary artery disease (CAD) who predominantly underwent percutaneous coronary intervention (PCI), comparing those treated with ticagrelor or prasugrel versus clopidogrel. Background The effect of CYP2C19 genotype on treatment outcomes with ticagrelor or prasugrel compared with clopidogrel is unclear. Methods Databases through February 19, 2020, were searched for studies reporting the effect of CYP2C19 genotype on ischemic outcomes during ticagrelor or prasugrel versus clopidogrel treatment. Study eligibility required outcomes reported for CYP2C19 genotype status and clopidogrel and alternative P2Y12 inhibitors in patients with CAD with at least 50% undergoing PCI. The primary analysis consisted of randomized controlled trials (RCTs). A secondary analysis was conducted by adding non-RCTs to the primary analysis. The primary outcome was a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia. Meta-analysis was conducted to compare the 2 drug regimens and test interaction with CYP2C19 genotype. Results Of 1,335 studies identified, 7 RCTs were included (15,949 patients, mean age 62 years; 77% had PCI, 98% had acute coronary syndromes). Statistical heterogeneity was minimal, and risk for bias was low. Ticagrelor and prasugrel compared with clopidogrel resulted in a significant reduction in ischemic events (relative risk: 0.70; 95% confidence interval: 0.59 to 0.83) in CYP2C19 loss-of-function carriers but not in noncarriers (relative risk: 1.0; 95% confidence interval: 0.80 to 1.25). The test of interaction on the basis of CYP2C19 genotype status was statistically significant (p = 0.013), suggesting that CYP2C19 genotype modified the effect. An additional 4 observational studies were found, and adding them to the analysis provided the same conclusions (p value of the test of interaction Conclusions The effect of ticagrelor or prasugrel compared with clopidogrel in reducing ischemic events in patients with CAD who predominantly undergo PCI is based primarily on the presence of CYP2C19 loss-of-function carrier status. These results support genetic testing prior to prescribing P2Y12 inhibitor therapy.

Objective Pulsatile insulin secretion is impaired in diseases such as type 2 diabetes that are characterized by insulin resistance. This has led to the suggestion that changes in insulin pulsatility directly impair insulin signaling. We sought to examine the effects of pulse characteristics on insulin action in humans, hypothesizing that a decrease in pulse amplitude or frequency is associated with impaired hepatic insulin action. Methods We studied 29 nondiabetic subjects on two occasions. On 1 occasion, hepatic and peripheral insulin action was measured using a euglycemic clamp. The deuterated water method was used to estimate the contribution of gluconeogenesis to endogenous glucose production. On a separate study day, we utilized nonparametric stochastic deconvolution of frequently sampled peripheral C-peptide concentrations during fasting to reconstruct portal insulin secretion. In addition to measuring basal and pulsatile insulin secretion, we used approximate entropy to measure orderliness and Fourier transform to measure the average, and the dispersion of, insulin pulse frequencies. Results In univariate analysis, basal insulin secretion (R2 = 0.16) and insulin pulse amplitude (R2 = 0.09) correlated weakly with insulin-induced suppression of gluconeogenesis. However, after adjustment for age, sex, and weight, these associations were no longer significant. The other pulse characteristics also did not correlate with the ability of insulin to suppress endogenous glucose production (and gluconeogenesis) or to stimulate glucose disappearance. Conclusions Overall, our data demonstrate that insulin pulse characteristics, considered independently of other factors, do not correlate with measures of hepatic and peripheral insulin sensitivity in nondiabetic humans.

Background Tailored Antiplatelet Initiation to Lessen Outcomes Due to Decreased Clopidogrel Response after Percutaneous Coronary Intervention (TAILOR-PCI) is the largest cardiovascular genotype-based randomized pragmatic trial (NCT#01742117) to evaluate the role of genotype-guided selection of oral P2Y12 inhibitor therapy in improving ischemic outcomes after PCI. The trial has been extended from the original 12- to 24-month follow-up, using study coordinator-initiated telephone visits. TAILOR-PCI Digital Study tests the feasibility of extending the trial follow-up in a subset of patients for up to 24 months using state-of-the-art digital solutions. The rationale, design, and approach of extended digital study of patients recruited into a large, international, multi-center clinical trial has not been previously described. Methods A total of 930 patients from U.S. and Canadian sites previously enrolled in the 5,302 patient TAILOR-PCI trial within 23 months of randomization are invited by mail to the Digital Study website ( http://tailorpci.eurekaplatform.org ) and by up to 2 recruiting telephone calls. Eureka, a direct-to-participant digital research platform, is used to consent and collect prospective data on patients for the digital study. Patients are asked to answer health-related surveys at fixed intervals using the Eureka mobile app and or desktop platform. The likelihood of patients enrolled in a randomized clinical trial transitioning to a registry using digital technology, the reasons for nonparticipation and engagement rates are evaluated. To capture hospitalizations, patients may optionally enable geofencing, a process that allows background location tracking and triggering of surveys if a hospital visit greater than 4 hours is detected. In addition, patients answer digital hospitalization surveys every month. Hospitalization data received from the Digital Study will be compared to data collected from study coordinator telephone visits during the same time frame. Conclusions The TAILOR-PCI Digital Study evaluates the feasibility of transitioning a large multicenter randomized clinical trial to a digital registry. The study could provide evidence for the ability of digital technology to follow clinical trial patients and to ascertain trial-related events thus also building the foundation for conducting digital clinical trials. Such a digital approach may be especially pertinent in the era of COVID-19.

Whether cardiovascular (CV) disease is associated with clinical outcomes in cancer patients receiving immunotherapy is unknown. We reviewed the Mayo Clinic database for all cancer patients who received an immune checkpoint inhibitor (ICI). Multivariate logistic regression analysis, survival analyses, and Cox proportional-hazards models were formulated. Between March, 2010 and July, 2019, 3,326 patients received ICI. Mean patient age was 63.5 years (range: 16 to 96 years). In a Cox proportional-hazards model, obesity (hazard ratio [HR] 0.65, 95% confidence level [CI] 0.55 to 0.77, p < 0.001) and hypercholesterolemia (HR 0.80, 95% CI 0.72 to 0.89, p < 0.001) were associated with lower all-cause mortality while hypertension (HR 1.32, 95% CI 1.17 to 1.49, p < 0.001) and smoking (HR 1.17, 95% CI 1.06 to 1.29, p = 0.002) were associated with higher overall mortality. Among patients with lung cancer, multivariable-adjusted hazard ratios for death from any cause for beta blocker users, as compared with patients who had never used a beta blocker, were 1.39 (95% CI 1.10 to 1.76, p = 0.006). A total of 80 patients (2.4%) experienced CV immune-related adverse events. Event-related morality for ICI-induced myocarditis was 41.7% (5/12). Multivariable-adjusted hazard ratios for ICI-induced myocarditis were 5.2 (95% CI 1.4 to 18.7, p = 0.01) for history of heart failure, 4.06 (95% CI 1.15 to 14.3, p = 0.03) for history of acute coronary syndrome, and 1.07 (per each 1-year increase, 95% CI 1.01 to 1.14, p = 0.02) for age. In conclusion, our study shows that CV factors are associated with clinical outcomes in cancer patients receiving ICI and could be used to predict mortality. In patients with lung cancer, pretreatment beta blocker use is associated with higher all-cause mortality. Three clinical factors-history of heart failure, history of acute coronary syndrome, and age greater than 80 years-help identify patients at higher risk of ICI-induced myocarditis who might benefit from more intensive cardiac surveillance.

BACKGROUND Studies demonstrate an association between aortic hemodynamics and cognitive function. The impact of pregnancy history on this association is unknown. METHODS Postmenopausal women (age 59 ± 5 years; years since last pregnancy 35 ± 3) with either a history of preeclampsia (PE; n = 34) or a history of a normotensive pregnancy (NP; n = 30) underwent cognitive testing: Letter-Number Sequencing, Digit Span, Trail Making Test, and letter and category fluency. Applanation tonometry was used to derive aortic systolic and diastolic blood pressure and augmentation index. RESULTS Distribution of cognitive scores and aortic hemodynamic measures was similar between the PE and NP groups. Principal component (PC) analysis was used to reduce the 3 aortic hemodynamic measures and the 5 cognitive variables to single summary indices, each representing a weighted average of their respective constituent variables. Using a multivariable linear model based on these PCs that adjusted for pregnancy history and body mass index, the composite index of aortic hemodynamics was associated with the summary cognitive index, whether taking into account a potential interaction with pregnancy history (P = 0.035) or not (P = 0.026) (interaction P = 0.178). Multivariable modeling of individual cognitive tests revealed a differential association for letter fluency by pregnancy history (test for interaction P = 0.023); this score correlated with the aortic hemodynamic index in the PE (partial R2 = 0.20), but not the NP (partial R2 = 0.00) group. CONCLUSIONS Elevated aortic hemodynamics may negatively impact cognitive function in postmenopausal women with specific executive functions, such as letter fluency, being impacted more by a pregnancy history of PE.

Primary central nervous system lymphoma is an aggressive form of non-Hodgkin lymphoma arising in the eyes, meninges, spinal cord, or brain. Treatment of primary CNS lymphoma with a combination of high-dose chemotherapy and autologous stem cell transplantation has been shown to have high rates of remission which is frequently sustained for multiple years. Recurrence of primary CNS lymphoma generally presents with one or multiple contrast enhancing lesions on MRI. In rare cases, lymphoma cells may proliferate diffusely within the brain parenchyma without mass formation, a pattern termed lymphomatosis cerebri. Lymphomatosis cerebri presents a significant diagnostic challenge, and has not been reported to present with parkinsonism. Here, we present a case of initially mass forming, contrast-enhancing primary CNS lymphoma which remitted following chemotherapy and autologous stem cell transplantation, and recurred 7 years post-transplant with symptoms of parkinsonism and a lack of typical lesions on imaging, with lymphomatosis cerebri confirmed at autopsy.

Skull base paragangliomas are highly vascular tumors that are often embolized before surgical resection; however, the safety and efficacy of preoperative embolization using an ethylene vinyl alcohol copolymer (Onyx; Medtronic, Dublin, Republic of Ireland) in these tumors is unknown. This retrospective cohort study evaluated patient outcomes after preoperative embolization of skull base paragangliomas using Onyx. We retrospectively analyzed data from all patients with skull base paragangliomas who underwent preoperative Onyx embolization at our institution (January 01, 2005–December 31, 2017). Patient, tumor, embolization, and outcomes data were extracted by reviewing inpatient and outpatient clinical and imaging records. Seven patients were studied (5/7 [71%] female), 6 with glomus jugulares and 1 with a glomus vagale. The median age was 52 years, and the most common presenting symptom was cranial neuropathy (6/7 [86%]). The tumor vascular supply was from the ascending pharyngeal artery in all 7 cases (100%) with additional feeders including the occipital artery in 5 (71%); internal carotid artery in 3 (43%); middle meningeal, vertebral, and internal maxillary artery each in 2 (29%); and posterior auricular artery in 1 (14%). The median postembolization tumor devascularization was 80% (range, 64–95%). The only postembolization complication was a facial palsy in 1 patient. Preoperative embolization with Onyx affords excellent devascularization for the majority of skull base paragangliomas, and it may facilitate resection of these hypervascular lesions. The advantages provided by Onyx with respect to penetration of intratumoral vessels must be weighed against the risk of cranial neuropathy.

Supplemental Digital Content is available in the text, Objective: Development of white matter hyperintensities (WMH) in the brain is associated with blood thrombogenicity in recently menopausal women. This study examined the influence of menopausal hormone treatments (MHTs) on this association. Methods: Measures of blood thrombogenicity were examined in women of the Kronos Early Estrogen Prevention Study (n = 95) who had brain magnetic resonance imaging before and during the 48 months of randomization to transdermal 17β-estradiol (n = 30), oral conjugated equine estrogen (n = 29) both with progesterone for 12 days per month or placebo pills and patch (n = 36). Principal components (PCs) analysis was used to reduce the dimensionality of 14 markers of platelet activation and blood thrombogenicity. The first 5 PCs were assessed for association with treatment and changes in WMH. Within-person slopes were obtained to capture the extent of WMH change for each woman. Results: WMH increased in all groups over the 48 months (P = 0.044). The partial effect of PC1, representing an average of six thrombogenicity variables (microvesicles derived from endothelium, leukocytes, and monocytes, and positive for tissue factor and adhesion molecules) on WMH was significant (P = 0.003). PC3, reflecting a contrast of platelet microaggregates and adenosine triphosphate secretion versus total platelet count, differed across groups (P = 0.006) with higher scores in the oral conjugated equine estrogen group. The global association between PCs and WMH increase, however, did not differ significantly by MHT (P = 0.207 for interaction between MHT and PC's). Conclusion: In recently menopausal women, the type of MHT did not significantly influence the association of markers of blood thrombogenicity with development of WMH in the brain.

We investigated causes of antler deformities in mule deer (Odocoileus hemionus) bucks from the Paunsaugunt Plateau in southern Utah, US. A total of 10 hunter-harvested and nine live-captured bucks with antler deformities and six hunter-harvested and 43 live-captured bucks with normal antlers were included in the study. All were screened by serology for exposure to epizootic hemorrhagic disease virus (EHDV) types 1, 2, and 6, bluetongue virus, Brucella abortus, Brucella ovis, caprine arthritis, encephalitis virus, and bovine viral diarrhea virus (BVDV) types 1 and 2. Serum testosterone and trace minerals concentrations were measured, and whole-blood counts evaluated. Testicular tissue from the hunter-harvested bucks was tested by quantitative PCR for EHDV-1, -2, and -6. All bucks with antler deformities had low to non-detectable serum testosterone concentrations from end-stage fibrosing orchitis, and EHDV-2 was detected by quantitative PCR in one of the testicular tissues tested. All bucks with antler deformities were seropositive for EHDV-2. In comparison, only 53% of bucks with normal antlers were EHDV-2 seropositive. More than 67% of hunter-harvested and live-captured bucks had antibodies to BVDV-1 and BVDV-2, probably because of high cattle exposure in the area. Our results support previous research linking infection with EHDV-2 to development of antler deformities; however, it remains unclear why some infected bucks develop testicular fibrosis, and others recover from the infection.

AimTo provide a contemporary analysis of incidence trends of infective endocarditis (IE) with its changing epidemiology over the past two decades in Europe.MethodsA systematic review was conducted at the Mayo Clinic, Rochester. Ovid EBM Reviews, Ovid Embase, Ovid Medline, Scopus and Web of Science were searched for studies published between 1 January 2000 and 30 November 2020. All studies were independently reviewed by four referees and those that included a population-based incidence of IE in patients, irrespective of age, in Europe were included. Least squares regression was used to estimate pooled temporal trends in IE incidence.ResultsOf 9138 articles screened, 18 studies were included in the review. Elderly men predominated in all studies. IE incidence increased 4.1% per year (95% CI 1.8% to 6.4%) in the pooled regression analysis of eight studies that included comprehensive and consistent trends data. When trends data were weighted according to population size of individual countries, an increase in yearly incidence of 0.27 cases per 100 000 people was observed. Staphylococci and streptococci were the most common pathogens identified. The rate of surgical intervention ranged from 10.2% to 60.0%, and the rate of inpatient mortality ranged from 14.3% to 17.5%. In six studies that examined the rate of injection drug use, five of them reported a rate of less than 10%.ConclusionBased on findings from our systematic review, IE incidence in Europe has doubled over the past two decades in Europe. Multiple factors are likely responsible for this striking increase.Trial registeration numberCRD42020191196.

Background The objective of this paper was to examine temporal changes of infective endocarditis (IE) incidence and epidemiology in North America. Methods A systematic review was conducted at Mayo Clinic, Rochester. Ovid EBM Reviews, Ovid Embase, Ovid Medline, Scopus, and Web of Science were searched for studies published between January 1, 2000, and May 31, 2020. Four referees independently reviewed all studies, and those that reported a population-based incidence of IE in patients aged 18 years and older in North America were included. Results Of 8588 articles screened, 14 were included. Overall, IE incidence remained largely unchanged throughout the study period, except for 2 studies that demonstrated a rise in incidence after 2014. Five studies reported temporal trends of injection drug use (IDU) prevalence among IE patients with a notable increase in prevalence observed. Staphylococcus aureus was the most common pathogen in 7 of 9 studies that included microbiologic findings. In-patient mortality ranged from 3.7% to 14.4%, while the percentage of patients who underwent surgery ranged from 6.4% to 16.0%. Conclusions The overall incidence of IE has remained stable among the 14 population-based investigations in North America identified in our systematic review. Standardization of study design for future population-based investigations has been highlighted for use in subsequent systematic reviews of IE.

Background Hypertriglyceridemia is associated with increased risk of coronary heart disease but the association is often attributed to concomitant metabolic abnormalities. We investigated the epidemiology of primary isolated hypertriglyceridemia (PIH) and associated cardiovascular risk in a population‐based setting. Methods and Results We identified adults with at least one triglyceride level ≥500 mg/dL between 1998 and 2015 in Olmsted County, Minnesota. We also identified age‐ and sex‐matched controls with triglyceride levels P = 0.022). There was no statistically significant association between PIH and cerebrovascular disease (HR, 1.06; 95% CI, 0.65‐1.73, P = 0.813), peripheral artery disease (HR, 1.27; 95% CI, 0.43‐3.75; P = 0.668), or the composite end point of all 3 (HR, 1.28; 95% CI, 0.92‐1.80; P =0.148) in adjusted models. Conclusions PIH was associated with incident coronary heart disease events (although there was attenuation after adjustment for conventional risk factors), supporting a causal role for triglycerides in coronary heart disease. The condition is relatively prevalent but awareness and control are low.

Fasting plasma glucose (FPG) concentration is a major predictor of a person’s risk of developing diabetes mellitus (DM). However, we sought to examine characteristics of individuals who develop DM despite a baseline FPG of ≤ 80mg/dL. The Rochester Epidemiology Project (REP) links the medical records of virtually all persons who have resided in Olmsted County, MN, USA between 1966 and present. Electronic laboratory data are available from 2005. Using REP, we identified individuals with ≥ 2 FPG tests from 2005-17, after excluding people who met criteria for DM on/before their first FPG. Those who developed DM (FPG > 125mg/dL) were assigned an event date as the date of their first diagnostic value. Subjects who did not develop DM were censored at their last FPG value on/before Dec 31, 2017. The entire cohort consisted of 44,815 individuals, of whom 3689 (8.2%) developed DM. Although higher baseline FPG was strongly related to development of DM, 2315 had a baseline FPG of ≤ 80mg/dL with 130 (5.6%) developing DM. Within this subset, those who progressed were older at baseline (40 ± 11 vs. 36 ± 12 years, p Disclosure A. M. Egan: None. C. Wood-wentz: None. K. R. Bailey: None. A. Vella: Research Support; Self; Novo Nordisk. Funding National Institutes of Health (DK78646, DK116231, DK126206, K12HD065987)

Objective:Little is known regarding the progression of preclinical atherosclerosis upon cessation of menopausal hormone therapy (MHT). This study evaluated changes in carotid artery intima-media thickness (CIMT) in a subgroup of participants during 4 years and 3 years after the Kronos Early

Sarcoidosis is a systemic granulomatous disease that frequently involves the myocardium. Unfortunately, the sentinel manifestations of cardiac sarcoidosis are often potentially fatal bradyarrhythmia and tachyarrhythmia. Advanced imaging modalities such as cardiac magnetic resonance have allowed for increased diagnosis of cardiac involvement. The current review article explores diagnosis and treatment strategies for arrhythmias in patients with cardiac sarcoidosis.

Arteriovenous malformations (AVMs) are a highly complex array of abnormal arteries and veins that directly fistulize without intervening capillary beds. 1 As AVMs can differ in size, location, and morphology, specific clinical management is determined for each individual patient, in conjunction with their specific goals and needs. 2 This Video demonstrates the resection of an AVM located in the language area of eloquent cortex of a 38-year-old opera singer. The patient presented to the emergency department with a new-onset seizure. Magnetic resonance imaging including task-based functional imaging demonstrated a left post temporal AVM with associated hemosiderin-stained white matter and language activation just posterior to the lesion. Awake microsurgical resection was recommended given her career as an opera singer and the high-risk location of the AVM in proximity to eloquent language cortex, with additional goals of preventing further risk of hemorrhage and reduction in the risk of epilepsy. The patient underwent a left temporoparietal craniotomy with direct electrical stimulation-based language mapping and monitoring along with microsurgical resection of the AVM with image guidance, confirmed with intraoperative indocyanine green angiography. Postoperative angiography demonstrated no residual AVM with preservation of normal arterial and venous anatomy. At follow-up, the patient was clinically intact, seizure free, and off all antiepileptic medications. At 3 months, she resumed her career as an opera singer. Awake resection with intraoperative functional mapping can be used for select small AVMs to avoid injury to functional tissue and allow more aggressive resection of potentially epileptogenic tissue.

People who use illicit drugs face significant physical risks in the acquisition, use, and aftermath of their use. This is particularly the case among those who use heroin in view of recent spikes in heroin-associated overdoses, injuries, and deaths. Using a restrictive deterrence framework, we identify the risks that women associate with chronic heroin use and the ways they seek to manage those risks. We also examine psychological and physiological disinhibitors that contribute to women reducing use of risk reduction strategies. We find from the narratives that nearly all of the women initially engaged in specific strategies to manage risk; however, as they continued using the drug, they began to abandon even the simplest of measures. Our findings shed light on the limitations of harm reduction strategies and inform the theoretical tradition of restrictive deterrence and the importance of disinhibitors.

Background Desoxycorticosterone pivalate (DOCP) is a commonly used mineralocorticoid replacement for dogs with primary hypoadrenocorticism (HA), but manufacturer-recommended dosing protocols can be cost-prohibitive. Recent reports also have raised concerns that label dose protocols could be excessive. Objective To investigate the relative efficacy and adverse effects of 2 DOCP dosages in dogs with primary glucocorticoid and mineralocorticoid deficient HA. Animals Thirty-seven dogs, including 19 test population dogs and 18 controls. Methods Randomized controlled double-blinded clinical trial. Dogs with newly diagnosed primary HA were assigned to standard (2.2 mg/kg q30d, control population) or low-dose (1.1 mg/kg q30d, test population) DOCP treatment. Clinical and laboratory variables were assessed 10 to 14 days and approximately 30 days after each DOCP treatment for 90 days. Results Mean serum sodium to potassium ratios at reevaluations were ≥32 in both populations throughout the study. No dog developed electrolyte abnormalities warranting medical treatment, although hypokalemia occurred on at least 1 occasion in 9 controls and 6 test population dogs. Urine specific gravities (median, interquartile range) were lower in control dogs (1.022, 1.016-1.029) as compared to test population dogs (1.033, 1.023-1.039; P = .006). Plasma renin activity was overly suppressed on 84 of 104 (80.8%) assessments in control dogs whereas increased renin activity occurred on 23 of 112 (20.5%) assessments in test population dogs. Conclusions and clinical importance Low-dose DOCP protocols appear to be safe and effective for treatment of HA in most dogs. Standard-dose protocols are more likely to result in biochemical evidence of overtreatment.

High-definition (HD) mapping with the Advisor HD Grid and HD Wave Solution software offers unparalleled resolution in mapping complex arrhythmias. The unique shape of a HD Grid (16 electrodes in a 4 × 4 pattern) allows for the mapping of orthogonal electrograms (EGMs). In so doing, the HD Grid catheter virtually eliminates the issue of 'bipolar blindness', a phenomenon seen when a wavefront of propagation is traveling perpendicular to a bipole pair. By improving the accuracy of the 3D electroanatomical map, HD Grid offers the potential of shorter procedure times, safer ablations and higher success rates. The following article explores the role of HD Grid in mapping a variety of arrhythmias including supraventricular tachycardias, atrial fibrillation and ventricular tachycardia. In addition, the authors explore the role of HD Grid in more recently described substrate-based advanced mapping techniques.Lay abstract Cardiac mapping is a minimally invasive procedure carried out in patients with abnormal heart rhythm arrhythmias. The procedure identifies and produces a map of the electrical activity of the heart. The unique shape of the Advisor HD Grid offers an advantage when mapping complex arrhythmias as it allows for a more detailed map of electrical activity in the heart. By improving the accuracy of the heart map, HD Grid could shorten procedure times, improve safety and increase success rates. The following article explores the role of HD Grid in mapping a variety of arrhythmias. In addition, the authors explore the role of HD Grid in more recently described substrate-based advanced mapping techniques.

AIMS. Gastric emptying is of limited utility for predicting the severity of symptoms in patients with diabetes mellitus and gastrointestinal symptoms. We evaluated the extent to which symptoms recorded during a (13)C-spirulina-based gastric emptying breath test (GEBT) or scintigraphy predicted the severity of daily symptoms in diabetes mellitus. METHODS. Gastric emptying, symptoms during a gastric emptying study, either scintigraphy (n=38) or GEBT (n=111), and daily gastrointestinal symptoms were evaluated in 149 patients with diabetes mellitus and variably severe gastrointestinal symptoms. KEY RESULTS. Gastric emptying was normal, delayed, and rapid in 37%, 52%, and 9% measured with the GEBT and 55%, 34%, and 11% of patients measured with scintigraphy; differences between GEBT and scintigraphy were not significant. Daily symptoms were moderately severe or more intense in 58% and 21% of patients undergoing scintigraphy and GEBT (P < 0.0001). Symptoms during the GEBT (46%) and emptying t(half) (3%) explained 50% of the variance in daily symptoms in the GEBT group. In the scintigraphy group, symptoms explained 29% of this variance; the t(half) was insignificant. Among patients who reported that one or more symptoms were more severe than the others during the GE study, were more likely (OR 3.98, 95% CI 2.16, 7.33) to report the same symptom(s) as being the most severe in the daily diary. CONCLUSIONS. Symptoms during a GEBT and to a lesser extent during scintigraphy, but not gastric emptying predict the severity of daily symptoms and may serve as a biomarker in patients with diabetes mellitus.

BackgroundVon Willebrand factor (VWF) is an acute phase reactant synthesized in the megakaryocytes and endothelial cells. VWF forms ultra-large multimers (ULVWF) which are cleaved by the metalloprotease ADAMTS-13, preventing spontaneous VWF–platelet interaction. After trauma, ULVWF is released into circulation as part of the acute phase reaction. We hypothesized that trauma patients would have increased levels of VWF and decreased levels of ADAMTS-13 and that these patients would have accelerated thrombin generation.MethodsWe assessed plasma concentrations of VWF antigen and ADAMTS-13 antigen, the Rapid Enzyme Assays for Autoimmune Diseases (REAADS) activity of VWF, which measure exposure of the platelet-binding A1 domain, and thrombin generation kinetics in 50 samples from 30 trauma patients and an additional 21 samples from volunteers. Samples were analyzed at 0 to 2 hours and at 6 hours from the time of injury. Data are presented as median (IQR) and Kruskal-Wallis test was performed between trauma patients and volunteers at both time points.ResultsREAADS activity was greater in trauma patients than volunteers both at 0 to 2 hours (190.0 (132.0–264.0) vs. 92.0 (71.0–114.0), pDiscussionTrauma patients have increased exposure of the VWF A1 domain and decreased levels of ADAMTS-13 compared with healthy volunteers. This suggests that the VWF burst after trauma may exceed the proteolytic capacity of ADAMTS-13, allowing circulating ULVWF multimers to bind platelets, potentially contributing to trauma-induced coagulopathy.Level of evidenceProspective case cohort study.

Drug overdose and poisoning are leading causes of emergency department visits and hospital admissions in the United States, accounting for more than 500,000 emergency department visits and 11,000 deaths each year. This chapter discusses the approach to the patient with poisoning or drug overdose, beginning with the initial stabilization period in which the physician proceeds through the ABCDs (airway, breathing, circulation, dextrose, decontamination) of stabilization. The management of some of the more common complications of poisoning and drug overdose are summarized and include coma, hypotension and cardiac dysrhythmias, hypertension, seizures, hyperthermia, hypothermia, and rhabdomyolysis. The physician should also perform a careful diagnostic evaluation that includes a directed history, physical examination, and the appropriate laboratory tests. The next step is to prevent further absorption of the drug or poison by decontaminating the skin or gastrointestinal tract and, possibly, by administering antidotes and performing other measures that enhance elimination of the drug from the body. The diagnosis and treatment of overdoses of a number of specific drugs and poisons that a physician may encounter, as well as food poisoning and smoke inhalation, are discussed. Tables present the ABCDs of initial stabilization of the poisoned patient; mechanisms of drug-induced hypotension; causes of cardiac disturbances; drug-induced seizures; drug-induced hyperthermia; autonomic syndromes induced by drugs or poison; the use of the clinical laboratory in the initial diagnosis of poisoning; methods of gastrointestinal decontamination; methods of and indications for enhanced drug removal; toxicity of common beta blockers; common stimulant drugs; corrosive agents; dosing of digoxin-specific antibodies; poisoning with ethylene glycol or methanol; manifestations of excessive acetylcholine activity; common tricyclic and other antidepressants; seafood poisonings; drugs or classes that require activated charcoal treatment; and special circumstances for use of activated charcoal. This review contains 3 figures, 22 tables, and 198 references.

Netgun capture is a commonly used capture method for mule deer (Odocoileus hemionus) in North America. Mortalities during netgun captures are generally low, and most often caused by direct trauma and occasionally fatal capture myopathy. Capture is a stressful event for a wild animal, and subclinical capture myopathy is difficult to measure. The use of tranquilizers during netgun capture is not widespread. We compared physiologic variables from 250 netgun-captured deer (57 males and 193 females) that did or did not receive midazolam and azaperone (mean, 0.14 mg/kg; SD, 0.02 mg/kg; range, 0.08-0.21 mg/kg) at time of capture and before transporting to a processing location, with the goal of evaluating whether drug administration would improve or worsen the physiologic state of the animal. Deer were captured in association with management activities between December 2018 and March 2020, with 132 deer receiving midazolam and azaperone at time of capture. Variables recorded included chase times, time from capture to arrival at the processing location, time from capture to release, serial rectal temperatures, heart rates, respiratory rates, body condition, age, sex, O2 administration, creatine kinase, aspartate aminotransferase, packed cell volume, red blood cell concentration, and hemoglobin, as well as serial venous pH, pCO2, HCO3-, and base excess (BE). All animals were collared with GPS tracking devices and monitored after release. There was no difference in survival after capture between deer that did or did not receive midazolam and azaperone. All animals experienced severe metabolic lactic acidosis, which generally worsened with increasing chase time, highlighting the critical importance of limiting chase times during captures. Drug administration did not influence the degree of metabolic acidosis; however, it appeared to have a favorable effect on several stress-related indices, including rectal temperature, heart rate, respiratory rate, and packed cell volume.

Introduction: The impact of beta blocker use on surgical outcomes of cancer patients receiving immunotherapy is unknown. Hypothesis: Beta blocker use is associated with lower post-operative mortality in cancer patients on immunotherapy. Methods: We used an institutional Advanced Cohort Explorer to identify all patients who underwent any surgical procedure less than 90 days after receiving immunotherapy. Data on the procedure performed as well as the post-operative outcome were collected and analyzed per the pre-operative beta blocker use status. Results: A total of 233 patients underwent surgery between 09/2011-06/2019. Mean age was 64.7 years (range: 16-92). The most common cancer diagnoses were lung (48, 44.4%), melanoma (49, 45.4%) and kidney (11, 10.2%). Immunotherapy medications were pembrolizumab ( 127, 54.5%), nivolumab (51, 21.9%), ipilimumab (43, 18.5%), atezolizumab (11, 4.7%) and avelumab (1, 0.43%). Pre-operative beta blocker use was documented in 140 (60.1%) patients. Most common surgical procedures were skin resection (75, 32.1%), wound repair (47, 20.2%), vascular procedures (36, 15.5%), urethral procedures 16 (6.9%) and sentinel lymph node biopsies (10, 4.3%). The 30-day mortality rate was 10.3% (24 deaths). In a multi-variable logistic regression analysis, pre-operative use of beta blockers was associated with a lower risk of death within 30 days from surgery (OR 0.34, CI 0.13-0.87, P=0.024). 30-day mortality rates were higher in patients undergoing vascular (50%, 17 of 34) versus non-vascular (3.5%, 7 of 199) procedures (P Conclusions: Beta blocker use is associated with a lower 30-day mortality rate after surgical procedures in cancer patients treated with immunotherapy. Further investigation is warranted.

Introduction: Atrial natriuretic peptide (ANP) plays an important role in blood pressure (BP) regulation via the second messenger cGMP. ANP also induces lipolysis by increasing plasma levels of non-esterified fatty acids (NEFA). MANP is a new Mayo Clinic designed ANP analog consisting of the native ANP with a novel 12-amino-acid C-terminus extension. In experimental models, MANP is more potent than ANP in reducing BP and inducing natriuresis. These actions are mediated by the activation of the pGC-A receptor and generation of cGMP. To date, the BP pressure lowering, cGMP generating and lipolytic actions of MANP remain unexplored along with its safety and tolerability in subjects with hypertension (HTN) associated with metabolic disease. Hypothesis: In subjects with HTN, obesity and metabolic syndrome (MS), MANP administration is safe, well tolerated, activates cGMP and exerts BP lowering and lipolytic properties. Methods: Double-blind, placebo-control clinical trial in 22 subjects (17 receiving MANP) with HTN, obesity and MS involving a single subcutaneous (SQ) injection of MANP (2.5 μg/Kg) or placebo. Subjects were monitored and cardiovascular, cGMP and metabolic parameters were collected during 24 hours after the injection. Results: In all subjects, MANP was safe and well-tolerated with no serious adverse side effects. MANP increased mean cGMP plasma levels after 30 minutes (delta: 4.8 ± 2.0 pmol/mL, p=0.02) and 1 hour (delta: 2.9 ±1.3 pmol/mL, p=0.03) when compared to baseline. Six hours after MANP injection systolic BP decreased by 5.7 ± 2.9 mmHg (p=0.06) whereas subjects receiving placebo had no decrease in blood pressure values compared to baseline. During fasting period, one hour after the administration of MANP, NEFA plasma levels increased by 108.2 ± 37.4 μM (p=0.01). Conclusions: In subjects with HTN, obesity and MS, SQ MANP is safe, well tolerated and activates the pGC-A receptor as measured by a significant increase in the second messenger cGMP. Subjects receiving MANP showed a borderline significant decrease in systolic BP and a significant increase in NEFA circulating levels supporting anti-hypertensive and lipolytic properties. Our findings support MANP as a potential novel therapy for HTN associated with metabolic disease.

BACKGROUND Trends in Medicare billing and procedural reimbursement for outpatient office visits remain unclear within the field of neurosurgery. OBJECTIVE To analyze financial trends of neurosurgeon reimbursement for Medicare office visits in 2010 compared to 2018. METHODS The 2010 and 2018 physician/supplier files from the Centers for Medicare and Medicaid Services website were utilized. All payments submitted by neurosurgeons (provider ID 14) were included. Trends in office visit Current Procedural Terminology codes 99201 to 99205 and 99211 to 99215 were analyzed. RESULTS Neurosurgeons billed for 1 109 979 office visits (463 611 h) in 2010 and Medicare denied 63 704 payments (totaling $11 205 283). Neurosurgeons billed for 1 189 046 office visits (508 526 h) in 2018 and Medicare denied 57 048 payments (totaling $15 103 879). This is a 7.1% increase in total neurosurgery office visits billed to Medicare, 9.7% increase in total office hours, and 34.8% increase in the payment amounts denied over 8 yr. Furthermore, after adjusting for inflation, the average amount paid to physicians by Medicare decreased by 8.3% per office visit. Additionally, Medicare paid 36.1% of the total neurosurgeon submitted charge amount for all office visits in 2010 but paid only 27.8% in 2018 (-8.3%). CONCLUSION Neurosurgeons are performing more office visits and billing for more time with patients. Meanwhile, Medicare has been paying physicians less per office visit, denying higher amounts of payments and reimbursing a decreasing percentage of submitted charges for office visits. An understanding of these trends is necessary to ensure continued equity and quality access to neurosurgical care in the United States.

Background Recent investigations suggest that inflammation and autoimmunity might have a role in the pathophysiology of atrial fibrillation (AF). Given that abnormal ventriculovascular coupling often coexists with AF, we hypothesize that autoimmune vasculitis plays a significant role in the pathogenetic mechanism of AF. Methods and Results A standardized retrospective population‐based case–control study was conducted to evaluate the association between autoimmune vasculitis and AF, and all‐cause mortality. The study included 8459 patients with a new diagnosis of AF and 8459 age‐, sex‐, and registration calendar year–matched controls in Olmsted County, Minnesota, between January 1, 1980 and December 31, 2010. The association of each clinical characteristic, diagnosis, and treatment was assessed using conditional logistic regression to account for the matched case–control study design. Cox proportional hazards regression models and Kaplan‐Meier curves were used to detect independent predictors of mortality and examine cumulative survival. Of a total of 16 918 patients (mean age 72.3+14.4 years; 48.7% women), 320 (1.9%) were diagnosed with autoimmune vasculitis before the index date during the 30‐year period. Among the cases, the prevalence of any autoimmune vasculitis was 2.3%, whereas the frequency of autoimmune vasculitis in controls was 1.5% ( P P =0.03). Patients with AF and autoimmune vasculitis had worse 5‐year survival than those without autoimmune vasculitis or AF (44.7% versus 77.2%; log‐rank P Conclusions Autoimmune vasculitis is significantly associated with AF and independently confers worse survival. These observations may represent one mechanism linking autoimmunity and inflammation to the pathogenesis and prognosis of AF.

Importance After percutaneous coronary intervention (PCI), patients withCYP2C19*2or*3loss-of-function (LOF) variants treated with clopidogrel have increased risk of ischemic events. Whether genotype-guided selection of oral P2Y12 inhibitor therapy improves ischemic outcomes is unknown. Objective To determine the effect of a genotype-guided oral P2Y12 inhibitor strategy on ischemic outcomes inCYP2C19LOF carriers after PCI. Design, Setting, and Participants Open-label randomized clinical trial of 5302 patients undergoing PCI for acute coronary syndromes (ACS) or stable coronary artery disease (CAD). Patients were enrolled at 40 centers in the US, Canada, South Korea, and Mexico from May 2013 through October 2018; final date of follow-up was October 2019. Interventions Patients randomized to the genotype-guided group (n = 2652) underwent point-of-care genotyping.CYP2C19LOF carriers were prescribed ticagrelor and noncarriers clopidogrel. Patients randomized to the conventional group (n = 2650) were prescribed clopidogrel and underwent genotyping after 12 months. Main Outcomes and Measures The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia at 12 months. A secondary end point was major or minor bleeding at 12 months. The primary analysis was in patients withCYP2C19LOF variants, and secondary analysis included all randomized patients. The trial had 85% power to detect a minimum hazard ratio of 0.50. Results Among 5302 patients randomized (median age, 62 years; 25% women), 82% had ACS and 18% had stable CAD; 94% completed the trial. Of 1849 withCYP2C19LOF variants, 764 of 903 (85%) assigned to genotype-guided therapy received ticagrelor, and 932 of 946 (99%) assigned to conventional therapy received clopidogrel. The primary end point occurred in 35 of 903CYP2C19LOF carriers (4.0%) in the genotype-guided therapy group and 54 of 946 (5.9%) in the conventional therapy group at 12 months (hazard ratio [HR], 0.66 [95% CI, 0.43-1.02];P = .06). None of the 11 prespecified secondary end points showed significant differences, including major or minor bleeding inCYP2C19LOF carriers in the genotype-guided group (1.9%) vs the conventional therapy group (1.6%) at 12 months (HR, 1.22 [95% CI, 0.60-2.51];P = .58). Among all randomized patients, the primary end point occurred in 113 of 2641 (4.4%) in the genotype-guided group and 135 of 2635 (5.3%) in the conventional group (HR, 0.84 [95% CI, 0.65-1.07];P = .16). Conclusions and Relevance AmongCYP2C19LOF carriers with ACS and stable CAD undergoing PCI, genotype-guided selection of an oral P2Y12 inhibitor, compared with conventional clopidogrel therapy without point-of-care genotyping, resulted in no statistically significant difference in a composite end point of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia based on the prespecified analysis plan and the treatment effect that the study was powered to detect at 12 months. Trial Registration ClinicalTrials.gov Identifier:NCT01742117

Idiopathic normal pressure hydrocephalus (iNPH) is a progressive neurological disorder characterized by gait apraxia, cognitive decline, and urinary incontinence. It can be difficult to diagnose iNPH as the symptoms may overlap with other neurodegenerative diseases including ​cervical spondylotic myelopathy. Cervical spondylotic myelopathy is a progressive degenerative disease in which compression of the cervical spinal cord causes gait disturbances and imbalance, loss of dexterity and strength in the hands, and, at late stages, urinary dysfunction. As with iNPH, increased age is associated with higher incidence and prevalence. Surgical decompression of the cervical spinal cord is the treatment of choice in patients with progressive myelopathy. Accordingly, iNPH and cervical myelopathy may both present with progressive gait impairment and incontinence, especially in the elderly. The case presented here demonstrates that both iNPH and cervical myelopathy may present simultaneously and result in gait disturbances and imbalance in some patients. For patients with suspected iNPH and myelopathic findings on examination, it is prudent to obtain a cervical spine MRI to assess for cervical stenosis. Moreover, cervical stenosis can mask the effect of cerebrospinal fluid diversion in patients with comorbid iNPH and cervical myelopathy. Therefore, the differential for patients who have symptomology suggestive of iNPH should include cervical spine myelopathy, with considerations for possible cervical decompression in addition to placement of a ventriculoperitoneal shunt.

The study of quality of life (QOL) in patients with asymptomatic diseases receiving interventional treatment provides an essential metric for the assessment of procedural benefits in the surgical patient population. In this study, we analyzed QOL data collected from patients with unruptured intracranial aneurysms (UIAs) before and after endovascular coiling in the HEAT Trial, alongside a systematic review on QOL in unruptured brain aneurysms.HEAT was a randomized controlled trial comparing recurrence rates in aneurysms treated with either bare platinum coils or hydrogel coils. Patients enrolled in this trial completed a short form-36 (SF-36) QOL questionnaire before treatment and at the 3- to 12- and 18- to 24-month follow-ups. The change in QOL before and after treatment was assessed. Regression analysis evaluated the effect of select baseline characteristics on QOL change.A total of 270 patients were eligible for analysis. There was an increase in the role physical (P = 0.043), vitality (P = 0.022), and emotional well-being (P0.001) QOL components at the 18- to 24-month follow-up compared with baseline scores. Regression analysis showed that age younger than 60 and absence of serious adverse events were associated with improved social functioning and vitality. The literature review showed a mixed effect of intervention on QOL in patients with UIAs.Our analysis has revealed that patients with 3- to 14-mm UIAs had improvements in some physical and emotional components of QOL at 18-24 months following aneurysm coiling in the HEAT study. The literature remains indeterminate on this issue. Further studies are needed to better understand the effects of the diagnosis of UIAs and their treatment on QOL.

The interaction of anthropometric variables with fasting blood glucose on progression from normal fasting glucose to overt diabetes (DM), is uncertain. In the Rochester Epidemiology Project (MN, USA), we identified 44,992 individuals with ≥ 2 fasting plasma glucose (FPG) tests from 2005-17, after excluding people who met criteria for DM (FPG > 125mg/dL) on/before their first FPG. The cohort was 58% female, had an age range of 18-65 yrs (44 ± 10, Mean ± SD) and BMI of 29 ± 7 kg/m2. Subjects who did not develop DM were censored at their last FPG value on/before Dec 31, 2017. Those who developed DM were assigned an event date as the first diagnostic value. Over a median follow-up of 7 yrs, 3888 (8.6%) developed DM. The Kaplan-Meier 10-year cumulative risk of incident DM was 12.8% (CI 12.4%-13.3%). As expected, multivariable Cox modeling identified elevated initial FPG [100-109mg/dL (HR 2.0; 1.9-2.2); 110-125mg/dL (HR 5.8; 5.4-6.3)] as conferring increased risk. Other independent risks were male sex (HR 1.30; 95% CI 1.22-1.38) and abnormal BMI [ Disclosure A.M. Egan: None. C. Wood-Wentz: None. K.R. Bailey: None. A. Vella: Advisory Panel; Self; vTv Therapeutics, Zealand Pharma A/S. Research Support; Self; Novo Nordisk A/S, Xeris Pharmaceuticals, Inc.

BACKGROUND The fasting proinsulin to insulin ratio is elevated in people with type 2 diabetes and has been suggested as a marker of β-cell health. However, its utility in discriminating between individuals with varying degrees of β-cell dysfunction is unclear. Proinsulin has a very different half-life to insulin and unlike insulin does not undergo hepatic extraction prior to reaching the systemic circulation. Given these limitations, we sought to examine the relationship between fasting and postprandial concentrations of β-cell polypeptides (proinsulin, insulin and C-peptide) in people with normal and impaired glucose tolerance in differing metabolic environments. DESIGN Subjects were studied on two occasions in random order while undergoing an oral challenge. During one study day, free fatty acids were elevated (to induce insulin resistance) by infusion of Intralipid with heparin. Proinsulin to insulin and proinsulin to C-peptide ratios were calculated for the 0-, 30-, 60- and 240-minute time points. Insulin action (Si) and β-cell responsivity (Φ) indices were calculated using the oral minimal model. RESULTS The fasting proinsulin to c-peptide or fasting proinsulin to insulin ratios did not differ between groups and did not predict subsequent β-cell responsivity to glucose during the glycerol or Intralipid study days in either group. CONCLUSIONS Among nondiabetic individuals, the fasting proinsulin to insulin ratio is not a useful marker of β-cell function.

This cohort study compares the sex- and age-adjusted incidence of cerebral venous sinus thrombosis before the COVID-19 pandemic with that during the first 92 days after Ad26.COV2.S vaccination.

Background Radioactive iodine therapy is considered the treatment of choice for hyperthyroidism in cats, but the availability of this modality is limited by costs and hospitalization requirements. Administration of recombinant human thyroid stimulating hormone (rh-TSH) to humans with thyroid neoplasia or nodular goiter can increase thyroidal iodine uptake, thereby allowing the use of lower radioactive iodine doses for treatment. Veterinary studies of this subject are limited, and results are conflicting. Objective To investigate the effects of rh-TSH administration on thyroidal iodine uptake in hyperthyroid cats. Animals Ten client-owned hyperthyroid cats. Methods In this prospective clinical study, cats were administered saline (placebo), 50 μg rh-TSH (low-dose), and 100 μg rh-TSH (high-dose) in randomized crossover design with treatments separated by 7-10 days. After each treatment, thyroid scintigraphy was performed by administering 300 μCi 123 I and assessing radionuclide uptake 8 and 24 hours later. Serum thyroid hormone concentrations were measured at each visit. Results Thyroidal percent iodine uptakes (mean ± SD at 8 and 24 hours) in cats treated with placebo (25.2 ± 13.4%, 30.0 ± 12.8%), low-dose (24.1 ± 12.5%, 29.4 ± 13.7%), and high-dose rh-TSH (24.2 ± 16.3%, 30.8 ± 15.3%) were not different (P = .76). Independent of rh-TSH administration, percent iodine uptakes were positively correlated with serum thyroid hormone concentrations. Conclusions and clinical importance One-time administration of rh-TSH, even at high doses, would not be expected to lower radioactive iodine doses needed for treatment of hyperthyroidism in cats. Investigations of alternate strategies to increase thyroidal uptake of radioactive iodine are warranted.

Background Although large randomized clinical trials have found that primary prevention use of an implantable cardioverter-defibrillator (ICD) improves survival in patients with cardiomyopathy and heart failure symptoms, patients who receive ICDs in practice are often older and have more comorbidities than patients who were enrolled in the clinical trials. In addition, there is a debate among clinicians on the usefulness of electrophysiological study for risk stratification of asymptomatic patients with Brugada syndrome. Aim Our analysis has 2 objectives. First, to evaluate whether ventricular arrhythmias (VAs) induced with programmed electrostimulation in asymptomatic patients with Brugada syndrome identify a higher risk group that may require additional testing or therapies. Second, to evaluate whether implantation of an ICD is associated with a clinical benefit in older patients and patients with comorbidities who would otherwise benefit on the basis of left ventricular ejection fraction and heart failure symptoms. Methods Traditional statistical approaches were used to address 1) whether programmed ventricular stimulation identifies a higher-risk group in asymptomatic patients with Brugada syndrome and 2) whether ICD implantation for primary prevention is associated with improved outcomes in older patients (>75 years of age) and patients with significant comorbidities who would otherwise meet criteria for ICD implantation on the basis of symptoms or left ventricular function. Results Evidence from 6 studies of 1138 asymptomatic patients were identified. Brugada syndrome with inducible VA on electrophysiological study was identified in 390 (34.3%) patients. To minimize patient overlap, the primary analysis used 5 of the 6 studies and found an odds ratio of 2.3 (95% CI: 0.63–8.66; p=0.2) for major arrhythmic events (sustained VAs, sudden cardiac death, or appropriate ICD therapy) in asymptomatic patients with Brugada syndrome and inducible VA on electrophysiological study versus those without inducible VA. Ten studies were reviewed that evaluated ICD use in older patients and 4 studies that evaluated unique patient populations were identified. In our analysis, ICD implantation was associated with improved survival (overall hazard ratio: 0.75; 95% confidence interval: 0.67–0.83; p

Background Although large randomized clinical trials have found that primary prevention use of an implantable cardioverter-defibrillator (ICD) improves survival in patients with cardiomyopathy and heart failure symptoms, patients who receive ICDs in practice are often older and have more comorbidities than patients who were enrolled in the clinical trials. In addition, there is a debate among clinicians on the usefulness of electrophysiological study for risk stratification of asymptomatic patients with Brugada syndrome. Aim Our analysis has 2 objectives. First, to evaluate whether ventricular arrhythmias (VAs) induced with programmed electrostimulation in asymptomatic patients with Brugada syndrome identify a higher risk group that may require additional testing or therapies. Second, to evaluate whether implantation of an ICD is associated with a clinical benefit in older patients and patients with comorbidities who would otherwise benefit on the basis of left ventricular ejection fraction and heart failure symptoms. Methods Traditional statistical approaches were used to address 1) whether programmed ventricular stimulation identifies a higher-risk group in asymptomatic patients with Brugada syndrome and 2) whether ICD implantation for primary prevention is associated with improved outcomes in older patients (>75 years of age) and patients with significant comorbidities who would otherwise meet criteria for ICD implantation on the basis of symptoms or left ventricular function. Results Evidence from 6 studies of 1138 asymptomatic patients were identified. Brugada syndrome with inducible VA on electrophysiological study was identified in 390 (34.3%) patients. To minimize patient overlap, the primary analysis used 5 of the 6 studies and found an odds ratio of 2.3 (95% CI: 0.63–8.66; p=0.2) for major arrhythmic events (sustained VAs, sudden cardiac death, or appropriate ICD therapy) in asymptomatic patients with Brugada syndrome and inducible VA on electrophysiological study versus those without inducible VA. Ten studies were reviewed that evaluated ICD use in older patients and 4 studies that evaluated unique patient populations were identified. In our analysis, ICD implantation was associated with improved survival (overall hazard ratio: 0.75; 95% confidence interval: 0.67–0.83; p

To understand why the population-based incidence of diverticulitis has increased over time, we studied temporal changes in age, body mass index (BMI), and diverticulitis in Olmsted County, Minnesota.We compared the BMIs of 2967 patients with diverticulitis and 9795 people without diverticulitis from January 1, 1980, through December 31, 2007. Because BMI is a surrogate for adipose tissue, computed tomographic estimations of abdominal fat content were compared between 381 diverticulitis cases and 381 age- and sex-matched controls.Between 1980 and 2007, the prevalence of obesity increased from 12% to 49% in the population and from 19% to 40% in patients with diverticulitis (P.001 for both). Temporal trends in age, BMI, and the increased incidence of diverticulitis in people with normal BMI accounted for 48%, 47%, and 20%, respectively, of corresponding trends in diverticulitis. The secular decline in the proportion of people with normal BMI was partly offset by an increased incidence of diverticulitis in such people. In the case-control study, BMI was greater in cases than in controls (P=.001). However, after incorporating abdominal visceral (odds ratio [OR], 2.4; 95% CI, 1.6-3.7) and subcutaneous (OR, 2.9; 95% CI, 1.7-5.2) fat content (both associated with diverticulitis), BMI was associated with lower risk (OR, 0.8; 95% CI, 0.7-0.8) of diverticulitis.Aging, increasing obesity, and the increased incidence of diverticulitis in people with normal BMI account for the temporal increase in diverticulitis. Rather than BMI per se, increased abdominal visceral and subcutaneous fat are independently associated with diverticulitis. The incidence of diverticulitis, which is among the most common gastrointestinal diagnoses in hospitalized patients, has increased markedly since 2000. This study suggests that aging, increasing obesity, and the increased incidence of diverticulitis in people with normal BMI account for the temporal increase in diverticulitis.

RationaleSupervised treadmill exercise for claudication in peripheral arterial disease is effective but poorly tolerated because of ischemic leg pain. Near infrared spectroscopy allows non-invasive detection of muscle ischemia during exercise, allowing for characterization of tissue perfusion and oxygen utilization during training.ObjectiveWe evaluated walking time, muscle blood flow, and muscle mitochondrial capacity in patients with peripheral artery disease after a traditional pain-based walking program and after a muscle oxygen-guided walking program.Method and resultsPatients with peripheral artery disease trained thrice weekly in 40-minute-long sessions for 12 weeks, randomized to oxygen-guided training ( n = 8, age 72 ± 9.7 years, 25% female) versus traditional pain-based training ( n = 10, age 71.6 ± 8.8 years, 20% female). Oxygen-guided training intensity was determined by maintaining a 15% reduction in skeletal muscle oxygenation by near infrared spectroscopy rather than relying on symptoms of pain to determine exercise effort. Pain free and maximal walking times were measured with a 12-minute Gardner treadmill test. Gastrocnemius mitochondrial capacity and blood flow were measured using near infrared spectroscopy. Baseline pain-free walking time was similar on a Gardner treadmill test (2.5 ± 0.9 vs. 3.6 ± 1.0 min, p = 0.5). After training, oxygen-guided cohorts improved similar to pain-guided cohorts (pain-free walking time 6.7 ± 0.9 vs. 6.9 ± 1.1 min, p ConclusionsOxygen-guided exercise training improves claudication comparable to pain-based training regimens. Adaptations in mitochondrial function rather than increases in limb perfusion may account for functional improvement. Increases in mitochondrial oxidative capacity may be proportional to the degree of tissue hypoxia during exercise.

To investigate the relationships among aldosterone level, use of antihypertensive (anti-HTN) medications, clinical profile, and atrial natriuretic peptide (ANP) level in individuals with HTN.In a community-based cohort, we analyzed aldosterone plasma levels based on the presence (n=477) or absence (n=1073) of HTN. In individuals with HTN, we evaluated circulating aldosterone levels according to the number of anti-HTN drugs used, analyzed the associated clinical characteristics, and determined the relationship to the counterregulatory cardiac hormone ANP. Data were collected from August 25, 1997, through September 5, 2000.Participants with HTN had higher serum aldosterone levels than those without HTN (6.4 vs 4.1 ng/dL [to convert to pmol/L, multiply by 27.74]; P.001). When individuals with HTN were stratified according to the number of anti-HTN medications used, the increase in number of medications (0, 1, 2, and ≥3) was associated with higher aldosterone levels (4.8, 6.4, 7.10, and 7.9 ng/dL, respectively; P=.002), worse metabolic profile, and higher prevalence of cardiovascular, renal, and metabolic disease. In participants with HTN, ANP plasma levels were inversely related to aldosterone levels when the latter was divided into tertiles.In this randomly selected general population cohort, aldosterone levels were higher in individuals with HTN compared with normotensive participants. Aldosterone levels increased with anti-HTN medication use. These findings also suggest a relative ANP deficiency with increasing aldosterone levels and anti-HTN drug use. These studies have pathophysiologic and therapeutic implications for targeting aldosterone in the clinical treatment of HTN.

Cerebrovascular reactivity (CVR) is reduced in patients with cognitive decline. Women with a history of preeclampsia are at increased risk for cognitive decline. This study examined an association between pregnancy history and CVR using a subgroup of 40 age- and parity-matched pairs of women having histories of preeclampsia (n=27) or normotensive pregnancy (n=29) and the association of activated blood elements with CVR. Middle cerebral artery velocity was measured by Doppler ultrasound before and during hypercapnia to assess CVR. Thirty-eight parameters of blood cellular elements, microvesicles, and cell–cell interactions measured in venous blood were assessed for association with CVR using principal component analysis. Middle cerebral artery velocity was lower in the preeclampsia compared with the normotensive group at baseline (63±4 versus 73±3 cm/s; P =0.047) and during hypercapnia ( P =0.013–0.056). CVR was significantly lower in the preeclampsia compared with the normotensive group (2.1±1.3 versus 2.9±1.1 cm·s·mm Hg; P =0.009). Globally, the association of the 7 identified principal components with preeclampsia ( P =0.107) and with baseline middle cerebral artery velocity ( P =0.067) did not reach statistical significance. The interaction between pregnancy history and principal components with respect to CVR ( P =0.084) was driven by a nominally significant interaction between preeclampsia and the individual principal component defined by blood elements, platelet aggregation, and interactions of platelets with monocytes and granulocytes ( P =0.008). These results suggest that having a history of preeclampsia negatively affects the cerebral circulation years beyond the pregnancy and that this effect was associated with activated blood elements.

Background: COVID-19-associated coagulopathy is incompletely understood. Objectives: To characterize thrombin generation, Von Willebrand Factor (VWF), neutrophil extracellular traps (NETs), and their role in COVID-19 risk stratification in the emergency department (ED). Patients/methods: Plasma samples from 67 ED COVID-19 patients were compared to 38 healthy volunteers (HVs). Thrombin generation (calibrated automated thrombogram, CAT) was expressed as lag time (LT, min), peak height (PH, min), and time to peak (ttPeak, min). Citrullinated nucleosomes and histones were quantified with ELISA, VWF antigen and activity (IU/dL) through latex immunoassay, Factor VIII (IU/dL) through one-stage optical clot detection, and VWF multimers with Western blot densitometry. Wilcoxon testing and multivariable logistic regression were performed. Results presented as median [Q1, Q3]; p

Objective Women with a history of preeclampsia are at an increased risk of hypertension and structural brain changes. However, the combined effect of both preeclampsia and late-life hypertension on brain structural changes is not known and was investigated in this study. Methods Participants were identified from the population-based Rochester Epidemiology Project cohort. Four groups of women were recruited and investigated in this study: first, women with a history of normotensive pregnancy who have late-life hypertension (n = 8, median age = 62), second, women with a history of normotensive pregnancy who do not have late-life hypertension (n = 32, median age = 59), third, women with a history of preeclampsia who have late-life hypertension (n = 24, median age = 60), and fourth, women with a history of preeclampsia who do not have late-life hypertension (n = 16, median age = 57). Cerebrovascular disease lesions on MRI, and total gray matter volumes were assessed. Results Total gray matter volumes were smaller in women with a history of preeclampsia and late-life hypertension compared with the other groups. Voxel-based morphometry demonstrated that the volume changes were localized to the posterior brain regions, particularly the occipital lobe gray matter in women with a history of preeclampsia and late-life hypertension. Conclusion Having late-life hypertension superimposed on a history of preeclampsia affects the brain structure differently than having either a history of preeclampsia alone or a history of normotensive pregnancy either with or without late-life hypertension.

Aims Standardized, population-based kinetics of C-peptide distribution and clearance are used to estimate insulin secretion from plasma C-peptide concentrations without direct measurement of C-peptide kinetics. We then compared the performance of population-based kinetics to directly measured C-peptide kinetics when used to calculate β-cell responsivity indices. To ensure that population-based kinetics apply to all conditions where β-cell function is measured, subjects were studied in the presence and absence of acute insulin resistance. Materials and Methods Somatostatin was used to inhibit endogenous insulin secretion in 56 nondiabetic subjects. Subsequently, a C-peptide bolus was administered and the changing concentrations used to calculate individual kinetic parameters of C-peptide clearance. In addition, they were studied on 2 occasions in random order using an oral glucose tolerance test (OGTT). On one occasion, free fatty acid (FFA) elevation to cause insulin resistance, was achieved by infusion of intralipid + heparin. Disposition Index (DI) was then estimated by the oral minimal model using either population-based or individual C-peptide kinetics. Results There were marked differences in the exchange parameters (k12 and k21) of the model describing C-peptide kinetics, but smaller differences in the fractional clearance, i.e. the irreversible loss from the accessible compartment (k01), obtained from population-based estimates compared to experimental measurement. Since it is predominantly influenced by k01, DI estimated using individual kinetics correlated well with those estimated using population-based kinetics. Conclusions These data support the use of population-based measures of C-peptide kinetics to estimate β-cell function during OGTT.

Background: Equine odontoclastic tooth resorption and hypercementosis (EOTRH) is a frequently diagnosed condition in adult horses. The underlying etiology is still unknown. Hematologic, biochemical, and endocrine values have not been reported in EOTRH-affected horses. Objectives: The main objective of the study was to describe the hematologic, biochemical, and endocrine parameters in horses with EOTRH. Study Design: Descriptive cross-sectional study of client-owned animals with EOTRH. Methods: A complete blood count, biochemistry panel, and endocrine profile were performed in horses diagnosed with EOTRH. Diagnosis was based on oral and radiographic examination findings and confirmed with histopathology. Results: Eighteen horses with EOTRH aged 10 to 32 years from various regions of the United States were sampled. The only consistent abnormality on the complete blood cell count and chemistry panel was hypoalbuminemia (88%). Endocrine parameters demonstrated no major abnormalities in the functioning of the thyroid and pituitary pars intermedia. The parathyroid hormone concentration was increased in 7 (47%) of 15 horses with an elevated 25-hydroxy vitamin D in 3 (17%) of 17 horses. Main Limitations: The main limitations of this study are the small sample size and lack of age-matched and management-matched control horses. Conclusions: The relevance of elevated parathyroid hormone in this study cannot be determined due to the lack of age-based controls and large population studies. With the small population evaluated in this study, there are no obvious hematological, biochemical, and endocrine changes evident. Further evaluation with signalment-matched controls will be necessary to evaluate some trends noted in the laboratory values.