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Purpose In response to the outbreak of COVID-19 in Ireland, the government implemented a nationwide stay-at-home order, with the closure of all non-essential businesses. During this period, there was a significant increase in supermarket expenditure. It has been shown that stress, anxiety and boredom are triggers for unhealthy eating habits. Fat consumption is a risk factor for both the development of gallstones and, additionally, the development of acute calculous cholecystitis. The aim of this study was to assess the incidence of acute calculous cholecystitis during the nationwide lockdown and compare it to the same period one year prior. Methods A retrospective review of all emergency abdominal imaging performed during the first 5 weeks of the lockdown was completed using the hospital PACS (picture archiving and communication system). All cases of acute calculous cholecystitis were identified and compared with the same period 1 year prior. Results Eighteen cases of acute calculous cholecystitis were identified from 24 March to 27 April 2020. Eleven cases were identified during the same period in 2019. This represented an increase of 63%. Non-COVID-19-related emergency presentations decreased during this period, and imaging of emergency presentations decreased by 24%. The rate of scans positive for acute cholecystitis more than doubled (p

We implemented the BioFire® FilmArray® Meningitis/Encephalitis Panel (MEP) with guidance for use based on patient age, cerebrospinal fluid (CSF) white blood cell (WBC) count and immune system status. MEPs results over 2 years (1/1/2017 to 12/31/18) were reviewed and clinical significance of positive MEP results in patients with CSF WBC ≤ 10 evaluated. Overall, 12% (51/453) of MEPs were positive with 4/184 (2%) positive in nonimmunocompromised (non-IC) with ≤ 10 CSF WBCs. Among positive results in non-IC patient with ≤10 CSF WBCs, none were judged clinically significant. Four of 6 results in immunocompromised patients with ≤10 CSF WBCs were clinically significant. Redundant testing was common and guideline adherence could have safely decreased MEPs use 41% saving$56,000. Guideline adherence was poor and MEP use can be safely avoided in non-IC adults with10 CSF WBC, but clinically significant results did occur in IC patients with low CSF WBC. Clinical decision support could reduce unneeded testing and result in significant cost savings.

Lipid-related metabolic disorders (LRMD) are prevalent in early lactation dairy cows, and have detrimental effects on productivity and health. Our objectives were to identify cows resistant or susceptible to LRMD using a ketosis induction protocol (KIP) to discover differentially expressed liver genes and metabolic pathways associated with disposition. Clustering cows based on postpartum lipid metabolite concentrations within dietary treatments identified cows more or less susceptible (MS vs. LS) to LRMD within the control treatment, and more or less resistant (MR vs. LR) within the KIP treatment. Whole-transcriptome RNA sequencing was performed on liver samples (−28, +1, and +14 days relative to calving) to assess differential gene and pathway expression (LS vs. MS, MR vs. LR, n = 3 cows per cluster). Cows within the MS and LR clusters had evidence of greater blood serum β-hydroxybutyrate concentration and liver triglyceride content than the LS and MR clusters, respectively. The inferred metabolism of differentially expressed genes suggested a role of immune response (i.e., interferon-inducible proteins and major histocompatibility complex molecules). Additionally, unique roles for glutathione metabolism and eicosanoid metabolism in modulating susceptibility and resistance, respectively, were implicated. Overall, this research provides novel insight into the role of immunometabolism in LRMD pathology, and suggests the potential for unique control points for LRMD progression and severity.

BACKGROUND: The extent to which obesity and genetics determine post-operative complications is incompletely understood. METHODS: We performed a retrospective study using two population cohorts with electronic health record (EHR) data. The first included 736,726 adults with body mass index (BMI) recorded between 1990-2017 at Vanderbilt University Medical Center. The second cohort consisted of 65,174 individuals from 12 institutions contributing EHR and genome-wide genotyping data to the Electronic Medical Records & Genomics (eMERGE) Network. Pairwise logistic regression analyses were used to measure the association of BMI categories with postoperative complications derived from International Classification of Disease-9 codes, including postoperative infection, incisional hernia, and intestinal obstruction. A genetic risk score (GRS) was constructed from 97 obesity-risk single nucleotide polymorphisms for a Mendelian randomization study to determine the association of genetic risk for obesity on postoperative complications. Logistic regression analyses were adjusted for sex, age, site, and race/principal components. RESULTS: Individuals with overweight or obese BMI (≥25 kg/m(2)) had increased risk for incisional hernia (Odds ratio [OR] 1.7-5.5, p

Background Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver illness with a genetically heterogeneous background that can be accompanied by considerable morbidity and attendant health care costs. The pathogenesis and progression of NAFLD is complex with many unanswered questions. We conducted genome-wide association studies (GWASs) using both adult and pediatric participants from the Electronic Medical Records and Genomics (eMERGE) Network to identify novel genetic contributors to this condition. Methods First, a natural language processing (NLP) algorithm was developed, tested, and deployed at each site to identify 1106 NAFLD cases and 8571 controls and histological data from liver tissue in 235 available participants. These include 1242 pediatric participants (396 cases, 846 controls). The algorithm included billing codes, text queries, laboratory values, and medication records. Next, GWASs were performed on NAFLD cases and controls and case-only analyses using histologic scores and liver function tests adjusting for age, sex, site, ancestry, PC, and body mass index (BMI). Results Consistent with previous results, a robust association was detected for the PNPLA3 gene cluster in participants with European ancestry. At the PNPLA3-SAMM50 region, three SNPs, rs738409, rs738408, and rs3747207, showed strongest association (best SNP rs738409 p = 1.70 × 10− 20). This effect was consistent in both pediatric (p = 9.92 × 10− 6) and adult (p = 9.73 × 10− 15) cohorts. Additionally, this variant was also associated with disease severity and NAFLD Activity Score (NAS) (p = 3.94 × 10− 8, beta = 0.85). PheWAS analysis link this locus to a spectrum of liver diseases beyond NAFLD with a novel negative correlation with gout (p = 1.09 × 10− 4). We also identified novel loci for NAFLD disease severity, including one novel locus for NAS score near IL17RA (rs5748926, p = 3.80 × 10− 8), and another near ZFP90-CDH1 for fibrosis (rs698718, p = 2.74 × 10− 11). Post-GWAS and gene-based analyses identified more than 300 genes that were used for functional and pathway enrichment analyses. Conclusions In summary, this study demonstrates clear confirmation of a previously described NAFLD risk locus and several novel associations. Further collaborative studies including an ethnically diverse population with well-characterized liver histologic features of NAFLD are needed to further validate the novel findings. Electronic supplementary material The online version of this article (10.1186/s12916-019-1364-z) contains supplementary material, which is available to authorized users.

Background Inherited trimethylaminuria (TMAU), a rare genetic disorder of hepatic metabolism of trimethylamine (TMA) causing excessive accumulation of malodorous trimethylamine (TMA), is a socially distressing disorder. Diagnosis is made by biochemical analysis of urine, with the calculation of flavin monooxygenase trimethylamine conversion capacity. Genetic testing, sequencing the entire coding region of the FMO3 gene has been recommended for affected individuals who convert less than 90% of the total TMA load to TMAO. Methods Genetic analysis was undertaken for 13 Irish patients with TMAU of varying phenotypic severity (three severe, six moderate, and four mild). Results A genetic diagnosis was made for seven patients, including for five of the nine moderate to severely affected cases. We noted the c.913G>T;p.(Glu305*) and c.458C>T;p.(Pro153Leu) mutations in this Irish population with severe TMAU which is consistent with our earlier findings in Australian and North American families of Irish and British descent. Three individuals were noted to be homozygous for the common variant haplotype c.472G>A;923A>G;p.(Glu158Lys);(Glu308Gly). We also identified three novel variants in this population, which are likely to be pathogenic: c.682G>A;p(Gly228Ser), c.694G>T:p(Asp232Tyr), and c.989G>A;p.(Gly330Glu). Conclusion Urinary biochemical analysis probably remains the first line diagnostic approach to classify the various types of TMAU. FMO3 gene analysis is likely only to be informative for certain presentations of TMAU.

ObjectivesTo perform an international comparison of the trajectory of laboratory values among hospitalized patients with COVID-19 who develop severe disease and identify optimal timing of laboratory value collection to predict severity across hospitals and regions.DesignRetrospective cohort study.SettingThe Consortium for Clinical Characterization of COVID-19 by EHR (4CE), an international multi-site data-sharing collaborative of 342 hospitals in the US and in Europe.ParticipantsPatients hospitalized with COVID-19, admitted before or after PCR-confirmed result for SARS-CoV-2.Primary and secondary outcome measuresPatients were categorized as “ever-severe” or “never-severe” using the validated 4CE severity criteria. Eighteen laboratory tests associated with poor COVID-19-related outcomes were evaluated for predictive accuracy by area under the curve (AUC), compared between the severity categories. Subgroup analysis was performed to validate a subset of laboratory values as predictive of severity against a published algorithm. A subset of laboratory values (CRP, albumin, LDH, neutrophil count, D-dimer, and procalcitonin) was compared between North American and European sites for severity prediction.ResultsOf 36,447 patients with COVID-19, 19,953 (43.7%) were categorized as ever-severe. Most patients (78.7%) were 50 years of age or older and male (60.5%). Longitudinal trajectories of CRP, albumin, LDH, neutrophil count, D-dimer, and procalcitonin showed association with disease severity. Significant differences of laboratory values at admission were found between the two groups. With the exception of D-dimer, predictive discrimination of laboratory values did not improve after admission. Sub-group analysis using age, D-dimer, CRP, and lymphocyte count as predictive of severity at admission showed similar discrimination to a published algorithm (AUC=0.88 and 0.91, respectively). Both models deteriorated in predictive accuracy as the disease progressed. On average, no difference in severity prediction was found between North American and European sites.ConclusionsLaboratory test values at admission can be used to predict severity in patients with COVID-19. Prediction models show consistency across international sites highlighting the potential generalizability of these models.

Simple Summary Treatment decisions represent a significant dilemma for patients diagnosed with prostate cancer. The prediction of early treatment failure would inform appropriate decision making and allow the clinician and patient to consider appropriate primary treatments and adjuvant therapies. We have developed and validated a serum biomarker-based model for predicting risk of biochemical reoccurrence in prostate cancer after radical prostatectomy. This study shows that the pre-operative biomarker PEDF can improve the accuracy of the clinical factors to predict risk of biochemical reoccurrence. PEDF has anti-inflammatory effects impacting on cytokine production. This non-invasive tool can be employed prior to treatment and demonstrates significant benefit over current clinical practice, impacting on patients’ outcomes and quality of life. Abstract This study undertook to predict biochemical recurrence (BCR) in prostate cancer patients after radical prostatectomy using serum biomarkers and clinical features. Three radical prostatectomy cohorts were used to build and validate a model of clinical variables and serum biomarkers to predict BCR. The Cox proportional hazard model with stepwise selection technique was used to develop the model. Model evaluation was quantified by the AUC, calibration, and decision curve analysis. Cross-validation techniques were used to prevent overfitting in the Irish training cohort, and the Austrian and Norwegian independent cohorts were used as validation cohorts. The integration of serum biomarkers with the clinical variables (AUC = 0.695) improved significantly the predictive ability of BCR compared to the clinical variables (AUC = 0.604) or biomarkers alone (AUC = 0.573). This model was well calibrated and demonstrated a significant improvement in the predictive ability in the Austrian and Norwegian validation cohorts (AUC of 0.724 and 0.606), compared to the clinical model (AUC of 0.665 and 0.511). This study shows that the pre-operative biomarker PEDF can improve the accuracy of the clinical factors to predict BCR. This model can be employed prior to treatment and could improve clinical decision making, impacting on patients’ outcomes and quality of life.

Introduction The rising prevalence of heart failure due to an aging population, higher post–myocardial infarction survival and the increasing burden of cardio–metabolic diseases, presents public health and economic challenges. Optimisation of heart failure therapy is essential in preventing the morbidity and mortality associated with this disease. The landmark DAPA–HF trial identified a 26% relative reduction in a composite primary outcome of worsening heart failure or death with use of dapagliflozin in patients with heart failure and reduced ejection fraction (HFrEF), irrespective of diabetic status. Although this class of drug is not yet incorporated into ESC guidelines, such a marked benefit may prompt consideration. The objective of this study is to determine the proportion of patients eligible for dapagliflozin at our site, based on inclusion and exclusion criteria of the DAPA–HF trial. Methods This retrospective observational study was conducted at Our Lady of Lourdes Hospital, Heart Failure Clinic. Data was collected on all patients referred from January 2018 to December 2019. We employed four data sources: CELLMA, a programme used to record clinical information; PACS (radiology); WinPath (blood work); and patient charts. This multipronged approach served to limit missing data. Eligibility required: EF ≤40%; NYHA ≥II; absence of type 1 diabetes mellitus (T1DM); SBP ≥95 mmHg; eGFR ≥30 ml/min; commensurate elevated BNP levels; and taking at least an ACE inhibitor, ARB or sacubitril/valsartan combined with a beta blocker (BB). Complete case analysis was used, as data was complete for >90% patients. Results In all, there were 587 referrals during this period, of which 278 (47.4%) had HFrEF and 130 (22.1%) had an EF Conclusion In a real–life Heart Failure Clinic almost one quarter of HFrEF patients fulfilled the DAPA–HF inclusion criteria. These patients may stand to benefit from dapagliflozin in terms of reduced hospitalisations and mortality, were this drug prescribed in addition to guideline–recommended heart failure therapies.

Introduction Heart failure with preserved ejection fraction (HFpEF) is a common but heterogenous clinical syndrome. Transthyretin amyloidosis cardiomyopathy (ATTR-CM) can now be diagnosed non-invasively with high sensitivity incorporating Technitium-99m, 3,3-diphosphono-1,2-propanodicarboxylic acid (Tc-DPD) scintigraphy. ATTR-CM has been found as the underlying aetiology of heart failure in 13% in HFpEF syndrome with left ventricular hypertrophy (LVH). Timely diagnosis of ATTR-CM has become even more relevant given the recent availability of targeted treatments. However, the prevalence and spectrum of ATTR-CM has not previously been studied in all-comer HFpEF cohort. Aims To determine the prevalence and spectrum of ATTR-CM in an undifferentiated multicentre HFpEF population using the non-invasive diagnostic pathway incorporating Tc-DPD scintigraphy. Methods Consecutive patients ≥60 years attending the heart failure services with a diagnosis of HFpEF and New York Heart Association class II-IV symptoms across 4 sites were prospectively enrolled. Severe valvular pathology or a prior history of symptomatic myeloma, AL amyloidosis or monoclonal gammopathy of unknown significance (MGUS) were excluded. Transthoracic 2D strain echocardiography, 12 lead electrocardiogram (ECG), biomarker analysis and Tc-DPD scintigraphy were performed. Tc-DPD findings were graded visually according to the Perugini classification (grades 0–3). Those patients with Perugini grade 2–3 on Tc-DPD (moderate-severe uptake; highly suggestive of ATTR-CM) underwent additional laboratory and haematological assessment and transthyretin (TTR) gene sequencing. Results To date, 45 patients (49% female, mean age 77.6 ± 7.9 years) have been prospectively enrolled. A history of atrial fibrillation and hypertension were present in 60% and 80% respectively. In keeping with ATTR-CM, no participant had a low voltage pattern on ECG. Three patients (6.7%) had Perugini grade 3 uptake on Tc-DPD and 6 patients (13.3%) had grade 1 uptake (mild uptake, inferior to bone; diagnostic significance undetermined). No patients had grade 2 uptake. All those with grade 3 uptake had AL amyloid excluded on further haematological testing and no mutation was detected in the TTR gene confirming wild type ATTR-CM. Significant differences across Tc-DPD uptake grades were seen according to increasing age and LV wall thickness (figure 1). Conclusion ATTR-CM, characterised by high grade uptake (Perugini 3) on Tc-DPD scintigraphy and negative haematological markers, was present in 6.7% of this undifferentiated HFpEF cohort and was associated with older age, and increased left ventricular wall thickness. Low grade uptake (Perugini grade 1) was present in a further 13.3%. While the diagnostic significance of this phenotype is undetermined, this may represent early ATTR-CM, suggesting that Tc-DPD scintigraphy may be able to identify a spectrum of disease according to uptake that correlates with wall thickness. Further follow up in this study will explore this potential.

Lower respiratory tract infections, including hospital-acquired and ventilator-associated pneumonia, are common in hospitalized patient populations. Standard methods frequently fail to identify the infectious etiology due to the polymicrobial nature of respiratory specimens and the necessity of ordering specific tests to identify viral agents. The potential severity of these infections combined with a failure to clearly identify the causative pathogen results in administration of empirical antibiotic agents based on clinical presentation and other risk factors., Lower respiratory tract infections, including hospital-acquired and ventilator-associated pneumonia, are common in hospitalized patient populations. Standard methods frequently fail to identify the infectious etiology due to the polymicrobial nature of respiratory specimens and the necessity of ordering specific tests to identify viral agents. The potential severity of these infections combined with a failure to clearly identify the causative pathogen results in administration of empirical antibiotic agents based on clinical presentation and other risk factors. We examined the impact of the multiplexed, semiquantitative BioFire FilmArray Pneumonia panel (PN panel) test on laboratory reporting for 259 adult inpatients submitting bronchoalveolar lavage (BAL) specimens for laboratory analysis. The PN panel demonstrated a combined 96.2% positive percent agreement (PPA) and 98.1% negative percent agreement (NPA) for the qualitative identification of 15 bacterial targets compared to routine bacterial culture. Semiquantitative values reported by the PN panel were frequently higher than values reported by culture, resulting in semiquantitative agreement (within the same log10 value) of 43.6% between the PN panel and culture; however, all bacterial targets reported as >105 CFU/ml in culture were reported as ≥105 genomic copies/ml by the PN panel. Viral targets were identified by the PN panel in 17.7% of specimens tested, of which 39.1% were detected in conjunction with a bacterial target. A review of patient medical records, including clinically prescribed antibiotics, revealed the potential for antibiotic adjustment in 70.7% of patients based on the PN panel result, including discontinuation or de-escalation in 48.2% of patients, resulting in an average savings of 6.2 antibiotic days/patient.

Decreased adipose tissue oxygen tension and increased HIF-1α expression can trigger adipose tissue inflammation and dysfunction in obesity. Our current understanding of obesity-associated decreased adipose tissue oxygen tension is mainly focused on changes in oxygen supply and angiogenesis. Here, we demonstrate that increased adipocyte O2 demand, mediated by ANT2 activity, is the dominant cause of adipocyte hypoxia. Deletion of adipocyte Ant2 improves obesity-induced intracellular adipocyte hypoxia by decreasing obesity-induced adipocyte oxygen demand, without effects on mitochondrial number or mass, or oligomycin-sensitive respiration. This led to decreased adipose tissue HIF-1α expression and inflammation with improved glucose tolerance and insulin resistance in both a preventative or therapeutic setting. Our results suggest that ANT2 may be a target for the development of insulin sensitizing drugs and that ANT2 inhibition might have clinical utility.

Background and Purpose— Both low serum calcium and magnesium levels have been associated with the extent of bleeding in patients with intracerebral hemorrhage, suggesting hypocalcemia- and hypomagnesemia-induced coagulopathy as a possible underlying mechanism. We hypothesized that serum albumin-corrected total calcium and magnesium levels are associated with ruptured intracranial aneurysms. Methods— The medical records of 4701 patients, including 1201 prospective patients, diagnosed at the Brigham and Women’s Hospital and Massachusetts General Hospital between 1990 and 2016 were reviewed and analyzed. One thousand two hundred seventy-five patients had available serum calcium, magnesium, and albumin values within 1 day of diagnosis. Individuals were divided into cases with ruptured aneurysms and controls with unruptured aneurysms. Univariable and multivariable logistic regression analyses were performed to determine the association between serum albumin-corrected total calcium and magnesium levels and ruptured aneurysms. Results— In multivariable analysis, both albumin-corrected calcium (odds ratio, 0.33; 95% confidence interval, 0.27–0.40) and magnesium (odds ratio, 0.40; 95% confidence interval, 0.28–0.55) were significantly and inversely associated with ruptured intracranial aneurysms. Conclusions— In this large case–control study, hypocalcemia and hypomagnesemia at diagnosis were significantly associated with ruptured aneurysms. Impaired hemostasis caused by hypocalcemia and hypomagnesemia may explain this association.

Background The relationship between inflammation and blood pressure (BP) has been studied mainly in the general population. In this study, we examined the association between inflammation and BP across a broader range of inflammation observed in rheumatoid arthritis (RA) and non-RA outpatients. Methods We studied subjects from a tertiary care outpatient population with C-reactive protein (CRP) and BP measured on the same date in 2009–2010; RA outpatients were identified using a validated algorithm. General population data were obtained from the National Health and Nutrition Examination Survey (NHANES) as comparison. To study the cross-sectional association between CRP and BP in the three groups, we constructed a generalized additive model. Longitudinal association between CRP and BP was examined using a repeated-measures linear mixed-effects model in RA outpatients with significant change in inflammation at two consecutive time points. Results We studied 24,325 subjects from the outpatient population, of whom 1811 had RA, and 5561 were from NHANES. In RA outpatients, we observed a positive relationship between CRP and systolic BP (SBP) at CRP

Bipolar disorder (BD) is a heritable mood disorder characterized by episodes of mania and depression. Although genomewide association studies (GWAS) have successfully identified genetic loci contributing to BD risk, sample size has become a rate-limiting obstacle to genetic discovery. Electronic health records (EHRs) represent a vast but relatively untapped resource for high-throughput phenotyping. As part of the International Cohort Collection for Bipolar Disorder (ICCBD), we previously validated automated EHR-based phenotyping algorithms for BD against in-person diagnostic interviews (Castro et al. Am J Psychiatry 172:363–372, 2015). Here, we establish the genetic validity of these phenotypes by determining their genetic correlation with traditionally ascertained samples. Case and control algorithms were derived from structured and narrative text in the Partners Healthcare system comprising more than 4.6 million patients over 20 years. Genomewide genotype data for 3330 BD cases and 3952 controls of European ancestry were used to estimate SNP-based heritability (h2g) and genetic correlation (rg) between EHR-based phenotype definitions and traditionally ascertained BD cases in GWAS by the ICCBD and Psychiatric Genomics Consortium (PGC) using LD score regression. We evaluated BD cases identified using 4 EHR-based algorithms: an NLP-based algorithm (95-NLP) and three rule-based algorithms using codified EHR with decreasing levels of stringency—“coded-strict”, “coded-broad”, and “coded-broad based on a single clinical encounter” (coded-broad-SV). The analytic sample comprised 862 95-NLP, 1968 coded-strict, 2581 coded-broad, 408 coded-broad-SV BD cases, and 3 952 controls. The estimated h2g were 0.24 (p = 0.015), 0.09 (p = 0.064), 0.13 (p = 0.003), 0.00 (p = 0.591) for 95-NLP, coded-strict, coded-broad and coded-broad-SV BD, respectively. The h2g for all EHR-based cases combined except coded-broad-SV (excluded due to 0 h2g) was 0.12 (p = 0.004). These h2g were lower or similar to the h2g observed by the ICCBD + PGCBD (0.23, p = 3.17E−80, total N = 33,181). However, the rg between ICCBD + PGCBD and the EHR-based cases were high for 95-NLP (0.66, p = 3.69 × 10–5), coded-strict (1.00, p = 2.40 × 10−4), and coded-broad (0.74, p = 8.11 × 10–7). The rg between EHR-based BD definitions ranged from 0.90 to 0.98. These results provide the first genetic validation of automated EHR-based phenotyping for BD and suggest that this approach identifies cases that are highly genetically correlated with those ascertained through conventional methods. High throughput phenotyping using the large data resources available in EHRs represents a viable method for accelerating psychiatric genetic research.

Background and Purpose— Previous studies have suggested a protective effect of diabetes mellitus on aneurysmal subarachnoid hemorrhage risk. However, reports are inconsistent, and objective measures of hyperglycemia in these studies are lacking. Our aim was to investigate the association between aneurysmal subarachnoid hemorrhage and antihyperglycemic agent use and glycated hemoglobin levels. Methods— The medical records of 4701 patients with 6411 intracranial aneurysms, including 1201 prospective patients, diagnosed at the Massachusetts General Hospital and Brigham and Women’s Hospital between 1990 and 2016 were reviewed and analyzed. Patients were separated into ruptured and nonruptured groups. Univariate and multivariate logistic regression analyses were performed to determine the association between aneurysmal subarachnoid hemorrhage and antihyperglycemic agents and glycated hemoglobin levels. Propensity score weighting was used to account for selection bias. Results— In both unweighted and weighted multivariate analysis, antihyperglycemic agent use was inversely and significantly associated with ruptured aneurysms (unweighted odds ratio, 0.58; 95% confidence interval, 0.39–0.87; weighted odds ratio, 0.57; 95% confidence interval, 0.34–0.96). In contrast, glycated hemoglobin levels were not significantly associated with rupture status. Conclusions— Antihyperglycemic agent use rather than hyperglycemia is associated with decreased risk of aneurysmal subarachnoid hemorrhage, suggesting a possible protective effect of glucose-lowering agents in the pathogenesis of aneurysm rupture.

Background and Purpose— Growing evidence from experimental animal models and clinical studies suggests the protective effect of statin use against rupture of intracranial aneurysms; however, results from large studies detailing the relationship between intracranial aneurysm rupture and total cholesterol, HDL (high-density lipoprotein), LDL (low-density lipoprotein), and lipid-lowering agent use are lacking. Methods— The medical records of 4701 patients with 6411 intracranial aneurysms diagnosed at the Massachusetts General Hospital and the Brigham and Women’s Hospital between 1990 and 2016 were reviewed and analyzed. Patients were separated into ruptured and nonruptured groups. Univariable and multivariable logistic regression analyses were performed to determine the effects of lipids (total cholesterol, LDL, and HDL) and lipid-lowering medications on intracranial aneurysm rupture risk. Propensity score weighting was used to account for differences in baseline characteristics of the cohorts. Results— Lipid-lowering agent use was significantly inversely associated with rupture status (odds ratio, 0.58; 95% confidence interval, 0.47–0.71). In a subgroup analysis of complete cases that includes both lipid-lowering agent use and lipid values, higher HDL levels (odds ratio, 0.95; 95% confidence interval, 0.93–0.98) and lipid-lowering agent use (odds ratio, 0.41; 95% confidence interval, 0.23–0.73) were both significantly and inversely associated with rupture status, whereas total cholesterol and LDL levels were not significant. A monotonic exposure–response curve between HDL levels and risk of aneurysmal rupture was obtained. Conclusions— Higher HDL values and the use of lipid-lowering agents are significantly inversely associated with ruptured intracranial aneurysms.

ObjectiveTo determine the association between ruptured saccular aneurysms and aspirin use/aspirin dose.MethodsFour thousand seven hundred one patients who were diagnosed at the Massachusetts General Hospital and Brigham and Women's Hospital between 1990 and 2016 with 6,411 unruptured and ruptured saccular intracranial aneurysms were evaluated. Univariable and multivariable logistic regression analyses were performed to determine the association between aneurysmal subarachnoid hemorrhage and aspirin use, including aspirin dose. Inverse probability weighting using propensity scores was used to adjust for potential differences in baseline characteristics between cases and controls. Additional analyses were performed to examine the association of aspirin use and rerupture before treatment.ResultsIn multivariate analysis with propensity score weighting, aspirin use (odds ratio [OR] 0.60, 95% confidence interval [CI] 0.45–0.80) was significantly associated with decreased risk of ruptured intracranial aneurysms. There was a significant inverse dose-response relationship between aspirin dose and aneurysmal subarachnoid hemorrhage (OR 0.65, 95% CI 0.53–0.81). In contrast, there was a significant association between aspirin use and increased risk of rerupture before treatment (OR 8.15, 95% CI 2.22–30.0).ConclusionsIn this large case-control study, aspirin therapy at diagnosis was associated with a significantly decreased risk of subarachnoid hemorrhage, with an inverse dose-response relationship among aspirin users. However, once rupture has occurred, aspirin is associated with an increased risk of rerupture before treatment.

Alcohol consumption may be a modifiable risk factor for rupture of intracranial aneurysms. Our aim is to evaluate the association between ruptured aneurysms and alcohol consumption, intensity, and cessation. The medical records of 4701 patients with 6411 radiographically confirmed intracranial aneurysms diagnosed at the Brigham and Women's Hospital and Massachusetts General Hospital between 1990 and 2016 were reviewed. Individuals were divided into cases with ruptured aneurysms and controls with unruptured aneurysms. Univariable and multivariable logistic regression analyses were performed to determine the association between alcohol consumption and rupture of intracranial aneurysms. In multivariable analysis, current alcohol use (OR 1.36, 95% CI 1.17-1.58) was associated with rupture status compared with never drinkers, whereas former alcohol use was not significant (OR 1.23, 95% CI 0.92-1.63). In addition, the number of alcoholic beverages per day among current alcohol users (OR 1.13, 95% CI 1.04-1.23) was significantly associated with rupture status, whereas alcohol use intensity was not significant among former users (OR 1.02, 95% CI 0.94-1.11). Current alcohol use and intensity are significantly associated with intracranial aneurysm rupture. However, this increased risk does not persist in former alcohol users, emphasizing the potential importance of alcohol cessation in patients harboring unruptured aneurysms.

Rationale Lysosomal associated membrane protein type-2 (LAMP-2) is a highly conserved, ubiquitous protein that is critical for autophagic flux. Loss of function mutations in the LAMP-2 gene cause Danon disease, a rare X-linked disorder characterized by developmental delay, skeletal muscle weakness, and severe cardiomyopathy. We previously found that human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from Danon patients exhibited significant mitochondrial oxidative stress and apoptosis. Understanding how loss of LAMP-2 expression leads to cardiomyocyte dysfunction and heart failure has important implications for the treatment of Danon disease as well as a variety of other cardiac disorders associated with impaired autophagy. Objective Elucidate the pathophysiology of cardiac dysfunction in Danon disease. Methods and results We created hiPSCs from two patients with Danon disease and differentiated those cells into hiPSC-CMs using well-established protocols. Danon hiPSC-CMs demonstrated an accumulation of damaged mitochondria, disrupted mitophagic flux, depressed mitochondrial respiratory capacity, and abnormal gene expression of key mitochondrial pathways. Restoring the expression of LAMP-2B, the most abundant LAMP-2 isoform in the heart, rescued mitophagic flux as well as mitochondrial health and bioenergetics. To confirm our findings in vivo, we evaluated Lamp-2 knockout (KO) mice. Impaired autophagic flux was noted in the Lamp-2 KO mice compared to WT reporter mice, as well as an increased number of abnormal mitochondria, evidence of incomplete mitophagy, and impaired mitochondrial respiration. Physiologically, Lamp-2 KO mice demonstrated early features of contractile dysfunction without overt heart failure, indicating that the metabolic abnormalities associated with Danon disease precede the development of end-stage disease and are not merely part of the secondary changes associated with heart failure. Conclusions Incomplete mitophagic flux and mitochondrial dysfunction are noted in both in vitro and in vivo models of Danon disease, and proceed overt cardiac contractile dysfunction. This suggests that impaired mitochondrial clearance may be central to the pathogenesis of disease and a potential target for therapeutic intervention.

The ability to provide timely identification of the causative agents of lower respiratory tract infections can promote better patient outcomes and support antimicrobial stewardship efforts. Current diagnostic testing options include culture, molecular testing, and antigen detection. These methods may require collection of various specimens, involve extensive sample treatment, and can suffer from low sensitivity and long turnaround times. This study assessed the performance of the BioFire FilmArray Pneumonia Panel (PN panel) and Pneumonia Plus Panel (PNplus panel), an FDA-cleared sample-to-answer assay that enables the detection of viruses, atypical bacteria, bacteria, and antimicrobial resistance marker genes from lower respiratory tract specimens (sputum and bronchoalveolar lavage [BAL] fluid)., The ability to provide timely identification of the causative agents of lower respiratory tract infections can promote better patient outcomes and support antimicrobial stewardship efforts. Current diagnostic testing options include culture, molecular testing, and antigen detection. These methods may require collection of various specimens, involve extensive sample treatment, and can suffer from low sensitivity and long turnaround times. This study assessed the performance of the BioFire FilmArray Pneumonia Panel (PN panel) and Pneumonia Plus Panel (PNplus panel), an FDA-cleared sample-to-answer assay that enables the detection of viruses, atypical bacteria, bacteria, and antimicrobial resistance marker genes from lower respiratory tract specimens (sputum and bronchoalveolar lavage [BAL] fluid). Semiquantitative results are also provided for the bacterial targets. This paper describes selected analytical and clinical studies that were conducted to evaluate performance of the panel for regulatory clearance. Prospectively collected respiratory specimens (846 BAL and 836 sputum specimens) evaluated with the PN panel were also tested by quantitative reference culture and molecular methods for comparison. The PN panel showed a sensitivity of 100% for 15/22 etiologic targets using BAL specimens and for 10/24 using sputum specimens. All other targets had sensitivities of ≥75% or were unable to be calculated due to low prevalence in the study population. Specificity for all targets was ≥87.2%, with many false-positive results compared to culture that were confirmed by alternative molecular methods. Appropriate adoption of this test could provide actionable diagnostic information that is anticipated to impact patient care and antimicrobial stewardship decisions.

Mounting evidence suggests that antiretroviral therapy (ART) drugs may contribute to the prevalence of HIV-associated neurological dysfunction. The HIV envelope glycoprotein (gp120) is neurotoxic and has been linked to alterations in mitochondrial function and increased inflammatory gene expression, which are common neuropathological findings in HIV+ cases on ART with neurological disorders. Tenofovir disproxil fumarate (TDF) has been shown to affect neurogenesis in brains of mice and mitochondria in neurons. In this study, we hypothesized that TDF contributes to neurotoxicity by modulating mitochondrial biogenesis and inflammatory pathways. TDF administered to wild-type (wt) and GFAP-gp120 transgenic (tg) mice caused peripheral neuropathy, as indicated by nerve conduction slowing and thermal hyperalgesia. Conversely TDF protected gp120-tg mice from cognitive dysfunction. In the brains of wt and gp120-tg mice, TDF decreased expression of mitochondrial transcription factor A (TFAM). However, double immunolabelling revealed that TFAM was reduced in neurons and increased in astroglia in the hippocampi of TDF-treated wt and gp120-tg mice. TDF also increased expression of GFAP and decreased expression of IBA1 in the wt and gp120-tg mice. TDF increased tumor necrosis factor (TNF) α in wt mice. However, TDF reduced interleukin (IL) 1β and TNFα mRNA in gp120-tg mouse brains. Primary human astroglia were exposed to increasing doses of TDF for 24 hours and then analyzed for mitochondrial alterations and inflammatory gene expression. In astroglia, TDF caused a dose-dependent increase in oxygen consumption rate, extracellular acidification rate and spare respiratory capacity, changes consistent with increased metabolism. TDF also reduced IL-1β-mediated increases in IL-1β and TNFα mRNA. These data demonstrate that TDF causes peripheral neuropathy in mice and alterations in inflammatory signaling and mitochondrial activity in the brain.

Catecholamines stimulate the mobilization of stored triglycerides in adipocytes to provide fatty acids (FAs) for other tissues. However, a large proportion is taken back up and either oxidized or re-esterified. What controls the disposition of these FAs in adipocytes remains unknown. Here, we report that catecholamines redirect FAs for oxidation through the phosphorylation of signal transducer and activator of transcription 3 (STAT3). Adipocyte STAT3 is phosphorylated upon activation of β-adrenergic receptors, and in turn suppresses FA re-esterification to promote FA oxidation. Adipocyte-specific Stat3 KO mice exhibit normal rates of lipolysis, but exhibit defective lipolysis-driven oxidative metabolism, resulting in reduced energy expenditure and increased adiposity when they are on a high-fat diet. This previously unappreciated, non-genomic role of STAT3 explains how sympathetic activation can increase both lipolysis and FA oxidation in adipocytes, revealing a new regulatory axis in metabolism.

Background: Recent studies indicate mitochondrial dysfunction is a dominant pathway in diabetic kidney disease (DKD), however underlying mechanisms are unclear. Here we examined if Crabtree effect by glucose is a cause of mitochondrial dysfunction in kidney. Methods: Lactate was measured by by YSI biochemistry analyzer. TCA cycle metabolites were measured by gas chromatography mass spectroscopy in urine samples of type 1 and type 2 DKD mouse models. Changes in oxygen consumption (OCR) and extracellular acidification i(ECAR) were analyzed on a Seahorse extracellular flux analyzer. Immunohistochemical analysis was performed on FFPE-embedded mouse kidney sections. Western blot analysis was performed on kidney cortical sections and HK2 cells. Results: Significantly increased urine and plasma lactate along with a decrease in several TCA cycle metabolites were observed in both type 1 and type 2 diabetic mice. Mitochondrial functional analysis in different kidney cells showed a profound respiratory inhibition and stimulation of lactate by glucose in proximal tubules, but not in mesangial cells and podocytes. Pyruvate at above physiological concentration reversed the glucose-induced inhibition of OCR. Western blotting of kidney cortical tissue sections showed a significant increase in phospho PDH in diabetic kidney tissues and in HK2 cells treated with high glucose. In normal conditions, phospho PDH was predominantly on distal tubules, however in diabetic conditions a significant increase in phospho PDH was noted in proximal tubule cells. Dichloroacetate, an inhibitor of PDK completely reversed the glucose induced respiratory inhibition in proximal tubule epithelial cells. Conclusions: Mitochondrial dysfunction in proximal tubule epithelial cells may potentially be due to high-glucose induced PDH phosphorylation resulting in limited pyruvate oxidation into mitochondria and enhanced lactate production. Disclosure M. Darshi: None. J.J. Kim: None. V. Drel: None. A.N. Murphy: Advisory Panel; Self; Cytokinetics Inc. Consultant; Self; Agilent Technologies. Funding JDRF; U.S. Department of Veterans Affairs

Iron and its derivatives play a significant role in various physiological and biochemical pathways, and are influenced by a wide variety of inflammatory, infectious, and immunological disorders. We hypothesized that iron and its related factors play a role in intracranial aneurysm pathophysiology and investigated if serum iron values are associated with ruptured intracranial aneurysms. 4,701 patients with 6,411 intracranial aneurysms, including 1201 prospective patients, who were diagnosed at the Massachusetts General Hospital and Brigham and Women’s Hospital between 1990 and 2016 were evaluated. A total of 366 patients with available serum iron, ferritin and total iron binding capacity (TIBC) values were ultimately included in the analysis. 89% of included patients had anemia. Patients were categorized into ruptured and non-ruptured groups. Univariable and multivariable logistic regression analyses were performed to determine the association between ruptured aneurysms and iron, ferritin, and TIBC. TIBC values (10−3 g/L) within 1 year of diagnosis (OR 0.41, 95% CI 0.28–0.59) and between 1 and 3 years from diagnosis (OR 0.52, 95% CI 0.29–0.93) were significantly and inversely associated with intracranial aneurysm rupture. In contrast, serum iron and ferritin were not significant. In this case-control study, low TIBC was significantly associated with ruptured aneurysms, both in the short- and long term. However, this association may not apply to the general population as there may be a selection bias as iron studies were done in a subset of patients only.

Objective Up-regulation of glucose metabolism has been implicated not only in tumor cell growth but also in immune cells upon activation. However, little is known about the metabolite profile in rheumatoid arthritis (RA), particularly in fibroblast-like synoviocytes (FLS). This study was undertaken to evaluate whether changes in glucose metabolism in RA FLS could play a role in inflammation and joint damage. Methods Synovium and FLS were obtained from patients with RA and patients with osteoarthritis (OA). The rate of glycolysis after stimulation of FLS with lipopolysaccharide and platelet-derived growth factor BB was measured using glycolysis stress test technology. FLS function was evaluated using a glycolysis inhibitor, 2-deoxy-d-glucose (2-DG). After stimulation of the FLS, a migration scratch assay, MTT assay, and enzyme-linked immunosorbent assay were performed to measure the effect of 2-DG on FLS migration, viability of the FLS, and cytokine secretion, respectively. IRDye 800CW 2-DG was used to assess glucose uptake in the arthritic joints and stromal cells of mice after K/BxN mouse serum transfer. The mice were injected daily, intraperitoneally, with 3-bromopyruvate (BrPa; 5 mg/kg) to assess the effect of inhibition of glycolysis in vivo. Results Compared to human OA FLS, the balance between glycolysis and oxidative phosphorylation was shifted toward glycolysis in RA FLS. Glucose transporter 1 (GLUT1) messenger RNA (mRNA) expression correlated with baseline functions of the RA FLS. Glucose deprivation or incubation of the FLS with glycolytic inhibitors impaired cytokine secretion and decreased the rate of proliferation and migration of the cells. In a mouse model of inflammatory arthritis, GLUT1 mRNA expression in the synovial lining cells was observed, and increased levels of glucose uptake and glycolytic gene expression were detected in the stromal compartment of the arthritic mouse joints. Inhibition of glycolysis by BrPa, administered in vivo, significantly decreased the severity of arthritis in this mouse model. Conclusion Targeting metabolic pathways is a novel approach to understanding the mechanisms of disease. Inhibition of glycolysis may directly modulate synoviocyte-mediated inflammatory functions and could be an effective treatment strategy for arthritis.

This study compared barium esophagram with high-resolution esophageal manometry (HRM) results to determine whether esophagram is an adequate screening examination for esophageal motility disorders, a common cause of dysphagia.Case series with chart review.Tertiary academic medical center.A retrospective review was completed of 281 patients who underwent both HRM and esophagram from March 2012 to June 2014. Inclusion criteria included a specific assessment of the presence or absence of dysmotility on both examinations.Eighty-four males and 197 females were included in the study. Average age was 57 years (range, 16-84). Average time between studies was 19 days (range, 0-90). Motility was judged to be normal in 40.2% (113 of 281) of esophagrams and 46.6% (131 of 281) of HRM studies. However, disagreement between the study findings was significant (P = .04). The sensitivity of esophagram for detecting esophageal dysmotility was 0.69, and specificity was 0.50. The positive and negative predictive values of esophagram for dysmotility were 0.61 and 0.58, respectively.Esophagram is useful in the assessment of anatomic abnormalities but is a poor screening examination for the detection of esophageal dysmotility. Patients with suspected esophageal dysphagia should be referred for HRM to evaluate motility disorders and identify potential treatment targets, regardless of esophagram results.

Background and Purpose— The effects of anticoagulation therapy and elevated international normalized ratio (INR) values on the risk of aneurysmal subarachnoid hemorrhage are unknown. We aimed to investigate the association between anticoagulation therapy, elevated INR values, and rupture of intracranial aneurysms. Methods— We conducted a case-control study of 4696 patients with 6403 intracranial aneurysms, including 1198 prospective patients, diagnosed at the Massachusetts General Hospital and the Brigham and Women’s Hospital between 1990 and 2016 who were on no anticoagulant therapy or on warfarin for anticoagulation. Patients were divided into ruptured and nonruptured groups. Univariable and multivariable logistic regression analyses were performed to evaluate the association of anticoagulation therapy, INR values, and presentation with a ruptured intracranial aneurysm, taking into account the interaction between anticoagulant use and INR. Inverse probability weighting using propensity scores was used to minimize differences in baseline demographics characteristics. The marginal effects of anticoagulant use on rupture risk stratified by INR values were calculated. Results— In unweighted and weighted multivariable analyses, elevated INR values were significantly associated with rupture status among patients who were not anticoagulated (unweighted odds ratio, 22.78; 95% CI, 10.85–47.81 and weighted odds ratio, 28.16; 95% CI, 12.44–63.77). In anticoagulated patients, warfarin use interacts significantly with INR when INR ≥1.2 by decreasing the effects of INR on rupture risk. Conclusions— INR elevation is associated with intracranial aneurysm rupture, but the effects may be moderated by warfarin. INR values should, therefore, be taken into consideration when counseling patients with intracranial aneurysms.

Left ventricular ejection fraction (LVEF) is an important prognostic indicator of cardiovascular outcomes. It is used clinically to determine the indication for several therapeutic interventions. LVEF is most commonly derived using in-line tools and some manual assessment by cardiologists from standardized echocardiographic views. LVEF is typically documented in free-text reports, and variation in LVEF documentation pose a challenge for the extraction and utilization of LVEF in computer-based clinical workflows. To address this problem, we developed a computerized algorithm to extract LVEF from echocardiography reports for the identification of patients having heart failure with reduced ejection fraction (HFrEF) for therapeutic intervention at a large healthcare system. We processed echocardiogram reports for 57,158 patients with coded diagnosis of Heart Failure that visited the healthcare system over a two-year period. Our algorithm identified a total of 3910 patients with reduced ejection fraction. Of the 46,634 echocardiography reports processed, 97% included a mention of LVEF. Of these reports, 85% contained numerical ejection fraction values, 9% contained ranges, and the remaining 6% contained qualitative descriptions. Overall, 18% of extracted numerical LVEFs were ≤ 40%. Furthermore, manual validation for a sample of 339 reports yielded an accuracy of 1.0. Our study demonstrates that a regular expression-based approach can accurately extract LVEF from echocardiograms, and is useful for delineating heart-failure patients with reduced ejection fraction.

Although physiological deficits such as altered cerebral blood flow (CBF), and autonomic nervous system (ANS) dysregulation have been reported following a concussion, the relationship between CBF and ANS with functional outcome post-injury remains unclear. Our present study was designed to examine heart-rate variability (HRV) using percentage of successive NN intervals (pNN50) and CBF on day-3 (T1), day-21 (T2), and day-90 (T3) following a concussion in collegiate athletes (N = 31) in comparison to non-injured controls (N = 31). Continuous RR-interval (3-lead electrocardiogram), middle cerebral artery blood velocity (MCAV; transcranial Doppler ultrasonography), mean arterial pressure (MAP; finger photoplethysmography) were obtained at rest. Cerebrovascular conductance index (CVCi) was estimated as a ratio of MCAV to MAP. Cognition was evaluated with standard assessment of concussion (SAC), and Trails AB. Compared to the controls, lower HRV (43 ± 15 vs. 27 ± 20%; p 0.0001) was observed at T1 with normalization at T2 and T3. No difference in MCAV between the control and the concussed groups across the three time points were observed. However, post-hoc analyses indicated a positive relationship between MCAV at T1 phase with HRV and CVCi during T2, and T3 phases. Higher MCAV at T1 was also associated with better cognition scores during the asymptomatic T2 phase in the concussed athletes. Therefore, our results indicate ANS dysregulation during the acute recovery phase after a concussion. Differences in CBF may be one of the underlying causes behind heterogeneity in clinical symptoms and functional outcomes after a concussion and future studies are warranted to validate this finding.

We have previously reported that the fractalkine (FKN)/CX3CR1 system represents a novel regulatory mechanism for insulin secretion and β cell function. Here, we demonstrate that chronic administration of a long-acting form of FKN, FKN-Fc, can exert durable effects to improve glucose tolerance with increased glucose-stimulated insulin secretion and decreased β cell apoptosis in obese rodent models. Unexpectedly, chronic FKN-Fc administration also led to decreased α cell glucagon secretion. In islet cells, FKN inhibited ATP-sensitive potassium channel conductance by an ERK-dependent mechanism, which triggered β cell action potential (AP) firing and decreased α cell AP amplitude. This results in increased glucose-stimulated insulin secretion and decreased glucagon secretion. Beyond its islet effects, FKN-Fc also exerted peripheral effects to enhance hepatic insulin sensitivity due to inhibition of glucagon action. In hepatocytes, FKN treatment reduced glucagon-stimulated cAMP production and CREB phosphorylation in a pertussis toxin-sensitive manner. Together, these results raise the possibility of use of FKN-based therapy to improve type 2 diabetes by increasing both insulin secretion and insulin sensitivity.

The relationship between inflammation and blood pressure (BP) has been studied mainly in the general population. In this study, we examined the association between inflammation and BP across a broader range of inflammation observed in rheumatoid arthritis (RA) and non-RA outpatients.We studied subjects from a tertiary care outpatient population with C-reactive protein (CRP) and BP measured on the same date in 2009-2010; RA outpatients were identified using a validated algorithm. General population data were obtained from the National Health and Nutrition Examination Survey (NHANES) as comparison. To study the cross-sectional association between CRP and BP in the three groups, we constructed a generalized additive model. Longitudinal association between CRP and BP was examined using a repeated-measures linear mixed-effects model in RA outpatients with significant change in inflammation at two consecutive time points.We studied 24,325 subjects from the outpatient population, of whom 1811 had RA, and 5561 were from NHANES. In RA outpatients, we observed a positive relationship between CRP and systolic BP (SBP) at CRP 6 mg/L and an inverse association at CRP ≥ 6 mg/L. A similar inverse U-shaped relationship was observed in non-RA outpatients. In NHANES, we observed a positive relationship between CRP and SBP as demonstrated by previous studies. Longitudinal analysis in RA showed that every 10 mg/L increase in CRP was associated with a 0.38 mmHg reduction in SBP.Across a broad range of CRP observed in RA and non-RA outpatients, we found an inverse U-shaped relationship between CRP and SBP, highlighting a relationship not previously observed when studying the general population.

The face of head and neck cancer has changed dramatically over the past 30 years. There has been a steady decline in the number of tobacco and alcohol related squamous cell carcinomas over the past 30 years, but and increasing incidence of human papillomavirus (HPV) related cancers. Some estimates suggest that 70-90% of new oropharyngeal cancers have evidence of HPV. These patients have different demographic patterns, in that they are more likely to be younger, white adults in their 40s and 50s who are never smokers or have reduced tobacco exposure. Studies have shown that a higher number of lifetime oral sex partners (>5) and a higher number of lifetime vaginal sex partners (>25) have been associated with increased risk of HPV positive head and neck cancer. People can also reduce their risk of HPV linked head and neck cancer by receiving the HPV vaccine series prior to becoming sexually active. Recent evidence suggests HPV related head and neck cancers present with different symptoms than those caused by tobacco. The most popular test for HPV status is the p16 immunohistochemical stain because it is cheap, simple, and studies have shown it to have comparable sensitivity and specificity to the previous standards. It is widely recommended that all cancers of the oropharynx be tested for the presence of HPV, and some recommend it for all head and neck cancers. Overall 2-year and 5-year survival for HPV positive head and neck cancer is significantly greater than for HPV negative cancers, likely due to HPV positive cancers being more responsive to treatment.

The cardiovascular response to exercise is abnormally large in hypertension. Over the past decade, it has become clear that the exercise pressor reflex (a peripheral feed-back mechanism originating in skeletal muscle) contributes significantly to the generation of this hyper-responsiveness. Further, it has been determined that overactivity of the mechanically (muscle mechanoreflex) and chemically (muscle metaboreflex) sensitive components of the exercise pressor reflex underpin its dysfunction. Given the recent attention in the literature, this review focuses upon the aberrant function of the muscle mechanoreflex in this disease. Evidence supporting a role for the mechanoreflex in the pathogenesis of the exaggerated cardiovascular response to physical activity is highlighted. The peripheral and central mechanisms that may be responsible for mechanoreflex overactivity in hypertension are likewise discussed. Particular attention is given to emerging evidence implicating a role for centrally-derived nitric oxide in this process.

Rationale: Sustained activation of Gαq transgenic (Gq) signaling during pressure overload causes cardiac hypertrophy that ultimately progresses to dilated cardiomyopathy. The molecular events that drive hypertrophy decompensation are incompletely understood. Ca 2+ /calmodulin-dependent protein kinase II δ (CaMKIIδ) is activated downstream of Gq, and overexpression of Gq and CaMKIIδ recapitulates hypertrophy decompensation. Objective: To determine whether CaMKIIδ contributes to hypertrophy decompensation provoked by Gq. Methods and Results: Compared with Gq mice, compound Gq/CaMKIIδ knockout mice developed a similar degree of cardiac hypertrophy but exhibited significantly improved left ventricular function, less cardiac fibrosis and cardiomyocyte apoptosis, and fewer ventricular arrhythmias. Markers of oxidative stress were elevated in mitochondria from Gq versus wild-type mice and respiratory rates were lower; these changes in mitochondrial function were restored by CaMKIIδ deletion. Gq-mediated increases in mitochondrial oxidative stress, compromised membrane potential, and cell death were recapitulated in neonatal rat ventricular myocytes infected with constitutively active Gq and attenuated by CaMKII inhibition. Deep RNA sequencing revealed altered expression of 41 mitochondrial genes in Gq hearts, with normalization of ≈40% of these genes by CaMKIIδ deletion. Uncoupling protein 3 was markedly downregulated in Gq or by Gq expression in neonatal rat ventricular myocytes and reversed by CaMKIIδ deletion or inhibition, as was peroxisome proliferator–activated receptor α. The protective effects of CaMKIIδ inhibition on reactive oxygen species generation and cell death were abrogated by knock down of uncoupling protein 3. Conversely, restoration of uncoupling protein 3 expression attenuated reactive oxygen species generation and cell death induced by CaMKIIδ. Our in vivo studies further demonstrated that pressure overload induced decreases in peroxisome proliferator–activated receptor α and uncoupling protein 3, increases in mitochondrial protein oxidation, and hypertrophy decompensation, which were attenuated by CaMKIIδ deletion. Conclusions: Mitochondrial gene reprogramming induced by CaMKIIδ emerges as an important mechanism contributing to mitotoxicity in decompensating hypertrophy.

Objective:Although smoking is a known risk factor for intracranial aneurysm (IA) rupture, the exact relationship between IA rupture and smoking intensity and duration, as well as duration of smoking cessation, remains unknown.Methods:In this case-control study, we analyzed 4,701 patients with 6,411 IAs diagnosed at the Brigham and Women's Hospital and Massachusetts General Hospital between 1990 and 2016. We divided individuals into patients with ruptured aneurysms and controls with unruptured aneurysms. We performed univariable and multivariable logistic regression analyses to determine the association between smoking status and ruptured IAs at presentation. In a subgroup analysis among former and current smokers, we assessed the association between ruptured aneurysms and number of packs per day, duration of smoking, and duration since smoking cessation.Results:In multivariable analysis, current (odds ratio [OR] 2.21, 95% confidence interval [CI] 1.89–2.59) and former smoking status (OR 1.56, 95% CI 1.31–1.86) were associated with rupture status at presentation compared with never smokers. In a subgroup analysis among current and former smokers, years smoked (OR 1.02, 95% CI 1.01–1.03) and packs per day (OR 1.46, 95% CI 1.25–1.70) were significantly associated with ruptured aneurysms at presentation, whereas duration since cessation among former smokers was not significant (OR 1.00, 95% CI 0.99–1.02).Conclusions:Current cigarette smoking, smoking intensity, and smoking duration are significantly associated with ruptured IAs at presentation. However, the significantly increased risk persists after smoking cessation, and smoking cessation does not confer a reduced risk of aneurysmal subarachnoid hemorrhage beyond that of reducing the cumulative dose.

Background Some internal medicine residency programs on X+Y schedules have modified clinic preceptor schedules to mimic those of the resident cohort (resident matched). This is in contrast to a traditional model, in which preceptors supervise on the same half-day each week. Objective We assessed preceptor and resident perceptions of the 2 precepting models. Methods We surveyed 44 preceptors and 97 residents at 3 clinic sites in 2 academic medical centers. Two clinics used the resident-matched model, and 1 used a traditional model. Surveys were completed at 6 months and 1 year. We assessed resident and preceptor perceptions in 5 domains: relationships between residents and preceptors; preceptor familiarity with complex patients; preceptor ability to assess milestone achievements; ability to follow up on results; and quality of care. Results There was no difference in perceptions of interpersonal relationships or satisfaction with patient care. Preceptors in the resident-matched schedule reported they were more familiar with complex patients at both 6 months and 1 year, and felt more comfortable evaluating residents' milestone achievements at 6 months, but not at 1 year. At 1 year, residents in the resident-matched model perceived preceptors were more familiar with complex patients than residents in the traditional model. The ability to discuss patient results between clinic weeks was low in both models. Conclusions The resident-matched model increased resident and preceptor perceptions of familiarity with complex patients and early preceptor perceptions of comfort in assessment of milestone achievements.

Background Bipolar Disorder (BD) is a heritable mood disorder with about 1% lifetime prevalence in general population. Many BD-associated loci have been identified through Genome-Wide Association Studies (GWAS). However, larger sample size and more detailed clinical/phenotypic information are needed to further understand the etiology of BD. To expand to research resources for BD genetics, we seek to leverage the Electronic Health Records (EHR) database, combined with genome-wide genetic data. As part of the International Cohort Collection for Bipolar Disorder (ICCBD), we developed automated phenotyping algorithms that can identify BD patients using codified data and concepts extracted by Natural Language Processing (NLP) from clinical narratives. Using these algorithms, we identified BD cases and healthy controls in the Partners HealthCare the Research Patient Data Registry (RPDR) and genome-wide genotyped these BD cases and controls. We demonstrated that these algorithms have high positive predictive value using a gold standard of in-person structured interviews (Castro et al. Am J Psychiatry, 2015). Methods Here, we attempted to genetically validate these algorithm-identified BD cases and controls by 1) quantifying the contribution of genetic components to algorithm-identified BD and 2) estimating the genome-wide genetic similarity between algorithm-identified BD and BD ascertained by psychiatrist diagnosis or systematic interview. We evaluated BD cases identified with 4 different algorithms: an algorithm using narrative note with NLP and LASSO procedure (NLP) and 3 rule-based algorithms using codified data of patient's diagnostic and treatment history with decreasing levels of stringency – “coded-strict”, “coded-broad”, coded-broad based on a single clinical encounter (coded-SV). We used LD score regression to estimate SNP-based heritability (h2g) and genetic correlation (rg) between 4 EHR-based BD and between BD ascertained conventionally by diagnosis or interview in the Psychiatric Genomics Consortium (PGC) and ICCBD GWAS. Results We identified and genotyped 862 NLP, 1968 coded-strict, 2581 coded-broad and 408 coded-SV BD cases, and a set of 3952 controls of European ancestry. The estimated h2g were 0.24 (p=0.015), 0.09 (p=0.064), 0.13 (p=0.003), 0 (p=0.591) for NLP, coded-strict, coded-broad and coded-SV BD, respectively. These h2g were lower than those observed by the PGC+ICCBD (0.23, p=3.17E-80, total N=33181). However, the rg between conventionally ascertained BD and the EHR-based cases were high for NLP (0.66, p=3.69E-5), coded-strict (1.00, p=2.40E-4), and coded-broad (0.74, p=8.11E-7). The h2g for EHR-based cases combined was 0.11 (p=0.006) and the rg with PGC BD was 0.83 (p=2.88E-6). The rg between EHR-based BDs ranged from 0.90 to 0.98. Discussion These results provide the first genetic validation of automated EHR-based phenotyping for BD and suggest that this approach identifies cases that are highly genetically correlated with those ascertained through conventional methods. High throughput phenotyping using the large data resources available in EHRs represents a viable method for accelerating psychiatric genetic research.

We assessed adherence to European Society of Cardiology heart rate guidelines (i.e. heart rates less than 70 bpm) in patients with chronic stable heart failure. We also investigated the percent of patients on target doses of rate controlling drugs.Multicenter study involving 549 patients from 12 heart failure centers in the Republic of Ireland. Patients in sinus rhythm with stabilized heart failure treatment and without recent cardiac events were included. Resting heart rates, demographics, co-morbidities and heart failure therapies were recorded.Heart rates ≥ 70 bpm were noted in 176 (32.1%) patients with 117 (21.3%) having rates75 bpm. Non-achievement of target heart rates were unrelated to age, gender or most cardiovascular risk factors. However, 42% of patients with diabetes (p0.01), 56% of those with COPD (p0.0001) and 46% of those with NYHA Class 3 (p0.05) did not achieve target heart rates. Fifty eight (11%) subjects were not on beta-blockers and of these forty subjects (69%) (p0001) did not achieve target heart rates. Of those on beta-blockers only 25% were at target dose. However, beta-blocker dosage was unrelated to achieving target heart rates. Ivabradine was used in 11% of patients with 10% at target dosage.This study highlights that a third of "stabilized" chronic heart failure patients have not reached recommended target heart rates. Respiratory problems, diabetes and marked dyspnea were associated with poorer rate control. Guideline unawareness, inadequate beta-blocker titration and under use of ivabradine may prevent patients gaining the proven benefits of heart rate control.

Background & Aims Patients with inflammatory bowel diseases (IBDs) have increased risk for venous thromboembolism (VTE); those who require hospitalization have particularly high risk. Few hospitalized patients with IBD receive thromboprophylaxis. We analyzed the frequency of VTE after IBD-related hospitalization, risk factors for post-hospitalization VTE, and the efficacy of prophylaxis in preventing post-hospitalization VTE. Methods In a retrospective study, we analyzed data from a multi-institutional cohort of patients with Crohn's disease or ulcerative colitis and at least 1 IBD-related hospitalization. Our primary outcome was a VTE event. All patients contributed person-time from the date of the index hospitalization to development of VTE, subsequent hospitalization, or end of follow-up. Our main predictor variable was pharmacologic thromboprophylaxis. Cox proportional hazard models adjusting for potential confounders were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results From a cohort of 2788 patients with at least 1 IBD-related hospitalization, 62 patients developed VTE after discharge (2%). Incidences of VTE at 30, 60, 90, and 180 days after the index hospitalization were 3.7/1000, 4.1/1000, 5.4/1000, and 9.4/1000 person-days, respectively. Pharmacologic thromboprophylaxis during the index hospital stay was associated with a significantly lower risk of post-hospitalization VTE (HR, 0.46; 95% CI, 0.22–0.97). Increased numbers of comorbidities (HR, 1.30; 95% CI, 1.16–1.47) and need for corticosteroids before hospitalization (HR, 1.71; 95% CI, 1.02–2.87) were also independently associated with risk of VTE. Length of hospitalization or surgery during index hospitalization was not associated with post-hospitalization VTE. Conclusions Pharmacologic thromboprophylaxis during IBD-related hospitalization is associated with reduced risk of post-hospitalization VTE., National Institutes of Health (U.S.) (U54-LM008748)

Skeletal muscle sirtuin 1 (SIRT1) expression is reduced under insulin-resistant conditions, such as those resulting from high-fat diet (HFD) feeding and obesity. Herein, we investigated whether constitutive activation of SIRT1 in skeletal muscle prevents HFD-induced muscle insulin resistance. To address this, mice with muscle-specific overexpression of SIRT1 (mOX) and wild-type (WT) littermates were fed a control diet (10% calories from fat) or HFD (60% of calories from fat) for 12 wk. Magnetic resonance imaging and indirect calorimetry were used to measure body composition and energy expenditure, respectively. Whole body glucose metabolism was assessed by oral glucose tolerance test, and insulin-stimulated glucose uptake was measured at a physiological insulin concentration in isolated soleus and extensor digitorum longus muscles. Although SIRT1 was significantly overexpressed in muscle of mOX vs. WT mice, body weight and percent body fat were similarly increased by HFD for both genotypes, and energy expenditure was unaffected by diet or genotype. Importantly, impairments in glucose tolerance and insulin-mediated activation of glucose uptake in skeletal muscle that occurred with HFD feeding were not prevented in mOX mice. In contrast, mOX mice showed enhanced postischemic cardiac functional recovery compared with WT mice, confirming the physiological functionality of the SIRT1 transgene in this mouse model. Together, these results demonstrate that activation of SIRT1 in skeletal muscle alone does not prevent HFD-induced glucose intolerance, weight gain, or insulin resistance.

Background While antidepressant treatment response appears to be partially heritable, no consistent genetic associations have been identified. Large, rare copy number variants (CNVs) play a role in other neuropsychiatric diseases, so we assessed their association with treatment-resistant depression (TRD). Methods We analyzed data from two genome-wide association studies comprising 1263 Caucasian patients with major depressive disorder. One was drawn from a large health system by applying natural language processing to electronic health records (i2b2 cohort). The second consisted of a multicenter study of sequential antidepressant treatments, Sequenced Treatment Alternatives to Relieve Depression. The Birdsuite package was used to identify rare deletions and duplications. Individuals without symptomatic remission, despite two antidepressant treatment trials, were contrasted with those who remitted with a first treatment trial. Results CNV data were derived for 778 subjects in the i2b2 cohort, including 300 subjects (37%) with TRD, and 485 subjects in Sequenced Treatment Alternatives to Relieve Depression cohort, including 152 (31%) with TRD. CNV burden analyses identified modest enrichment of duplications in cases (empirical p = .04 for duplications of 100–200 kilobase) and a particular deletion region spanning gene PABPC4L (empirical p = .02, 6 cases: 0 controls). Pathway analysis suggested enrichment of CNVs intersecting genes regulating actin cytoskeleton. However, none of these associations survived genome-wide correction. Conclusions Contribution of rare CNVs to TRD appears to be modest, individually or in aggregate. The electronic health record-based methodology demonstrated here should facilitate collection of larger TRD cohorts necessary to further characterize these effects.

BackgroundTargeting the mitochondria during ischemia/reperfusion (IR) can confer cardioprotection leading to improved clinical outcomes. The cardioprotective potential of (-)-epicatechin (EPI) during IR via modulation of mitochondrial function was evaluated.Methods and resultsIschemia was induced in rats via a 45 min occlusion of the left anterior descending coronary artery followed by 1 h, 48 h, or 3 week reperfusion. EPI (10 mg/kg) was administered IV 15 min prior to reperfusion for the single dose group and again 12 h later for the double dose group. Controls received water. Experiments also utilized cultured neonatal rat ventricular myocytes (NRVM) and myoblasts. A single dose of EPI reduced infarct size by 27% at 48 h and 28% at 3 week. Double dose treatment further decreased infarct size by 80% at 48 h, and 52% by 3 weeks. The protective effect of EPI on mitochondrial function was evident after 1h of reperfusion when mitochondria demonstrated less respiratory inhibition, lower mitochondrial Ca2+ load, and a preserved pool of NADH that correlated with higher tissue ATP levels. Mechanistic studies in NRVM revealed that EPI acutely stimulated maximal rates of respiration, an effect that was blocked by inhibitors of the mitochondrial pyruvate carrier, nitric oxide synthase, or soluble guanylyl cyclase. In myoblasts, knockdown of components of the mitochondrial pyruvate carrier blocked EPI-induced respiratory stimulation.ConclusionsIV EPI confers cardioprotection via preservation of mitochondrial function potentially through enhanced substrate provision. These provocative results document a novel mechanism of a natural product with potential clinical utility.

Objective Differences in lipid levels associated with cardiovascular (CV) risk between rheumatoid arthritis (RA) patients and the general population remain unclear. Determining these differences is important in understanding the role of lipids in CV risk in RA. Methods We studied 2,005 RA subjects from 2 large academic medical centers. We extracted electronic medical record data on the first low-density lipoprotein (LDL) measurement, and total cholesterol and high-density lipoprotein (HDL) measurements within 1 year of the LDL measurement. Subjects with an electronic statin prescription prior to the first LDL measurement were excluded. We compared lipid levels in RA patients to recently published levels from the general US population using the t-test and stratifying by published parameters, i.e., 2007–2010, and women. We determined lipid trends using separate linear regression models for total cholesterol, LDL cholesterol, and HDL cholesterol, testing the association between year of measurement (1989–2010) and lipid level, adjusted by age and sex. Lipid trends in RA were qualitatively compared to the published general population trends. Results Women with RA had a significantly lower total cholesterol (186 versus 200 mg/dl; P = 0.002) and LDL cholesterol (105 versus 118 mg/dl; P = 0.001) compared to the general population (2007–2010). HDL cholesterol was not significantly different in the 2 groups. In the RA cohort, total cholesterol and LDL cholesterol significantly decreased each year, while HDL cholesterol increased (all with P < 0.0001), consistent with overall trends observed in a previous study. Conclusion RA patients appear to have an overall lower total cholesterol and LDL cholesterol than the general population despite the general overall risk of CV disease in RA from observational studies.

Diabetic microvascular complications have been considered to be mediated by a glucose-driven increase in mitochondrial superoxide anion production. Here, we report that superoxide production was reduced in the kidneys of a steptozotocin-induced mouse model of type 1 diabetes, as assessed by in vivo real-time transcutaneous fluorescence, confocal microscopy, and electron paramagnetic resonance analysis. Reduction of mitochondrial biogenesis and phosphorylation of pyruvate dehydrogenase (PDH) were observed in kidneys from diabetic mice. These observations were consistent with an overall reduction of mitochondrial glucose oxidation. Activity of AMPK, the major energy-sensing enzyme, was reduced in kidneys from both diabetic mice and humans. Mitochondrial biogenesis, PDH activity, and mitochondrial complex activity were rescued by treatment with the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR). AICAR treatment induced superoxide production and was linked with glomerular matrix and albuminuria reduction in the diabetic kidney. Furthermore, diabetic heterozygous superoxide dismutase 2 (Sod2(+/-)) mice had no evidence of increased renal disease, and Ampka2(-/-) mice had increased albuminuria that was not reduced with AICAR treatment. Reduction of mitochondrial superoxide production with rotenone was sufficient to reduce AMPK phosphorylation in mouse kidneys. Taken together, these results demonstrate that diabetic kidneys have reduced superoxide and mitochondrial biogenesis and activation of AMPK enhances superoxide production and mitochondrial function while reducing disease activity.

Objectives: While genetic determinants of low density lipoprotein (LDL) cholesterol levels are well characterised in the general population, they are understudied in rheumatoid arthritis (RA). Our objective was to determine the association of established LDL and RA genetic alleles with LDL levels in RA cases compared with non-RA controls. Methods: Using data from electronic medical records, we linked validated RA cases and non-RA controls to discarded blood samples. For each individual, we extracted data on: first LDL measurement, age, gender and year of LDL measurement. We genotyped subjects for 11 LDL and 44 non-HLA RA alleles, and calculated RA and LDL genetic risk scores (GRS). We tested the association between each GRS and LDL level using multivariate linear regression models adjusted for age, gender, year of LDL measurement and RA status. Results: Among 567 RA cases and 979 controls, 80% were female and mean age at the first LDL measurement was 55 years. RA cases had significantly lower mean LDL levels than controls (117.2 vs 125.6 mg/dl, respectively, p, National Institutes of Health (U.S.) (Grant U54-LM008748)

Background The availability of monoclonal antibodies to tumor necrosis factor α has revolutionized management of Crohn's disease (CD) and ulcerative colitis. However, limited data exist regarding comparative effectiveness of these agents to inform clinical practice. Methods This study consisted of patients with CD or ulcerative colitis initiation either infliximab (IFX) or adalimumab (ADA) between 1998 and 2010. A validated likelihood of nonresponse classification score using frequency of narrative mentions of relevant symptoms in the electronic health record was applied to assess comparative effectiveness at 1 year. Inflammatory bowel disease-related surgery, hospitalization, and use of steroids were determined during this period. Results Our final cohort included 1060 new initiations of IFX (68% for CD) and 391 of ADA (79% for CD). In CD, the likelihood of nonresponse was higher in ADA than IFX (odds ratio, 1.62 and 95% CI, 1.21-2.17). Similar differences favoring efficacy of IFX were observed for the individual symptoms of diarrhea, pain, bleeding, and fatigue. However, there was no difference in inflammatory bowel disease-related surgery, hospitalizations, or prednisone use within 1 year after initiation of IFX or ADA in CD. There was no difference in narrative or codified outcomes between the 2 agents in ulcerative colitis. Conclusions We identified a modestly higher likelihood of symptomatic nonresponse at 1 year for ADA compared with IFX in patients with CD. However, there were no differences in inflammatory bowel disease-related surgery or hospitalizations, suggesting these treatments are broadly comparable in effectiveness in routine clinical practice.

Mycobacterium bovis, one of several mycobacteria of the M. tuberculosis complex, is a global zoonotic pathogen that primarily infects cattle. Humans become infected by consuming unpasteurized dairy products from infected cows; possible person-to-person airborne transmission has also been reported. In April 2014, a man in Nebraska who was born in Mexico was determined to have extensive pulmonary tuberculosis (TB) caused by M. bovis after experiencing approximately 3 months of cough and fever. Four months later, a U.S.-born Hispanic girl from a nearby town who had been ill for 4-5 months was also determined to have pulmonary TB caused by M. bovis. The only social connection between the two patients was attendance at the same church, and no common dietary exposure was identified. Both patients had pulmonary cavities on radiography and acid-fast bacilli (AFB) on sputum-smear microscopy, indicators of being contagious. Whole-genome sequencing results of the isolates were nearly indistinguishable. Initial examination of 181 contacts determined that 39 (22%) had latent infection: 10 (42%) of 24 who had close exposure to either patient, 28 (28%) of 100 who were exposed to one or both patients in church, and one (2%) of 57 exposed to the second patient at a school. Latent infection was diagnosed in six contacts on follow-up examination, 2 months after an initial negative test result, for an overall latent infection rate of 25%. No infected contacts recalled consuming unpasteurized dairy products, and none had active TB disease at the initial or secondary examination. Persons who have M. bovis TB should be asked about consumption of unpasteurized dairy products, and contact investigations should follow the same guidance as for M. tuberculosis TB.

Evidence suggests that the muscle mechanoreflex, a circulatory reflex that raises blood pressure and heart rate (HR) upon activation of mechanically sensitive afferent fibres in skeletal muscle, is overactive in hypertension. However, the mechanisms underlying this abnormal reflex function have yet to be identified. Sensory input from the mechanoreflex is processed within the nucleus tractus solitarii (NTS) in the medulla oblongata. Within the NTS, the enzymatic activity of nitric oxide synthase produces nitric oxide (NO). This centrally derived NO has been shown to modulate muscle reflex activity and serves as a viable candidate for mediating the mechanoreflex dysfunction that develops in hypertension. We hypothesized that mechanoreflex dysfunction in hypertension is mediated by abnormal alterations in NO production in the NTS. Mechanically sensitive afferent fibres were stimulated by passively stretching hindlimb muscle before and after blocking the endogenous production of NO within the NTS via microdialysis of the NO synthase inhibitor l-NAME (1 and 5 mm) in normotensive Wistar–Kyoto rats and spontaneously hypertensive rats (SHRs). Changes in HR and mean arterial pressure in response to stretch were significantly larger in SHRs compared with Wistar–Kyoto rats prior to l-NAME dialysis. Attenuating NO production via l-NAME in normotensive rats recapitulated the exaggerated cardiovascular response to stretch observed in SHRs. Dialysing l-NAME in SHRs further accentuated the increases in HR and mean arterial pressure elicited by stretch. These findings support the contention that reductions in NO production within the NTS contribute to the generation of abnormal cardiovascular control by the skeletal muscle mechanoreflex in hypertension.