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Blood pressure is not a static parameter, but rather undergoes continuous fluctuations over time, as a result of the interaction between environmental and behavioural factors on one side and intrinsic cardiovascular regulatory mechanisms on the other side. Increased blood pressure variability (BPV) may indicate an impaired cardiovascular regulation and may represent a cardiovascular risk factor itself, having been associated with increased all-cause and cardiovascular mortality, stroke, coronary artery disease, heart failure, end-stage renal disease, and dementia incidence. Nonetheless, BPV was considered only a research issue in previous hypertension management guidelines, because the available evidence on its clinical relevance presents several gaps and is based on heterogeneous studies with limited standardization of methods for BPV assessment. The aim of this position paper, with contributions from members of the European Society of Hypertension Working Group on Blood Pressure Monitoring and Cardiovascular Variability and from a number of international experts, is to summarize the available evidence in the field of BPV assessment methodology and clinical applications and to provide practical indications on how to measure and interpret BPV in research and clinical settings based on currently available data. Pending issues and clinical and methodological recommendations supported by available evidence are also reported. The information provided by this paper should contribute to a better standardization of future studies on BPV, but should also provide clinicians with some indications on how BPV can be managed based on currently available data.

Objectives Peritoneal metastases of ovarian cancer (PMOC) are common at initial presentation. Cytoreductive surgery (CRS) of curative intent has been proven to be efficient in increasing the overall survival (OS) and the disease-free survival (DFS) of these patients. Nevertheless, CRS is associated with high postoperative morbidity, which makes patient selection a major concern. Appropriate prognostic factors that can predict patient outcomes after surgery are still lacking. Preoperative biomarkers and their ratios have been shown to be predictive of patient prognosis for various solid tumors. We aimed to study their correlation with the prognosis of patients undergoing CRS for PMOC. Methods This retrospective study included patients with PMOC operated by CRS. Preoperative biomarkers and other clinicopathological characteristics were studied to determine their prognostic value in terms OS and DFS. Results 216 patients were included. Patients with preoperative Hemoglobin (Hb) 0.32, and platelet-to-lymphocyte ratio (PLR) >214.5 were associated with worse OS (p=0.022, p=0.0028, and p=0.0018, respectively) and worse DFS (p=0.028, p=0.003, and p=0.019, respectively). Multivariate analysis showed that the variables mentioned above were independent predictive factors for OS and DFS. Conclusions Preoperative Hb level, NLR, MLR, and PLR are prognostic factors for OS and DFS in PMOC patients operated by curative CRS.

The present paper provides an update of previous recommendations on Home Blood Pressure Monitoring from the European Society of Hypertension (ESH) Working Group on Blood Pressure Monitoring and Cardiovascular Variability sequentially published in years 2000, 2008 and 2010. This update has taken into account new evidence in this field, including a recent statement by the American Heart association, as well as technological developments, which have occurred over the past 20 years. The present document has been developed by the same ESH Working Group with inputs from an international team of experts, and has been endorsed by the ESH. ispartof: JOURNAL OF HYPERTENSION vol:39 issue:9 pages:1742-1767 ispartof: location:Netherlands status: published

BackgroundMajor depressive disorder (MDD) is the main cause of disability worldwide, its outcome is poor, and its underlying mechanisms deserve a better understanding. Recently, peripheral acetyl-l-carnitine (ALC) has been shown to be lower in patients with major depressive episodes (MDEs) than in controls. l-Carnitine is involved in mitochondrial function and ALC is its short-chain acetyl-ester. Our first aim was to compare the plasma levels of l-carnitine and ALC, and the l-carnitine/ALC ratio in patients with a current MDE and healthy controls (HCs). Our second aim was to assess their changes after antidepressant treatment.Methodsl-Carnitine and ALC levels and the carnitine/ALC ratio were measured in 460 patients with an MDE in a context of MDD and in 893 HCs. Depressed patients were re-assessed after 3 and 6 months of antidepressant treatment for biology and clinical outcome.ResultsAs compared to HC, depressed patients had lower ALC levels (p < 0.00001), higher l-carnitine levels (p < 0.00001) and higher l-carnitine/ALC ratios (p < 0.00001). ALC levels increased [coefficient: 0.18; 95% confidence interval (CI) 0.12–0.24; p < 0.00001], and l-carnitine levels (coefficient: −0.58; 95% CI −0.75 to −0.41; p < 0.00001) and l-carnitine/ALC ratios (coefficient: −0.41; 95% CI −0.47 to −0.34; p < 0.00001), decreased after treatment. These parameters were completely restored after 6 months of antidepressant. Moreover, the baseline l-carnitine/ALC ratio predicted remission after 3 months of treatment (odds ratio = 1.14; 95% CI 1.03–1.27; p = 0.015).ConclusionsOur data suggest a decreased mitochondrial metabolism of l-carnitine into ALC during MDE. This decreased mitochondrial metabolism is restored after a 6-month antidepressant treatment. Moreover, the magnitude of mitochondrial dysfunction may predict remission after 3 months of antidepressant treatment. New strategies targeting mitochondria should be explored to improve treatments of MDD.

Background: The optimal antibiotic therapy for the treatment of hospital acquired pneumonia (HAP) caused by Methicillin-resistant Staphylococcus aureus (MARSA) is controversial especially in diabetes mellitus patients. However, certain researches recommended that linezolid is superior to vancomycin in management of HAP. Objective: To assess the effect of treatment outcomes in patients with nosocomial pneumonia caused by methicillin- resistant staph aureus in diabetic patients and non-diabetic patients. Patients and Methods: This study was conducted on 120 patients at Mansoura Chest Diseases Hospital, Mansoura, Egypt, in the period between December 2019 and August 2020 among patients whose age more than 18 years old. Group A (n=60): Diabetic cases which further subdivided into two subgroups: Group A1 (n=30): Diabetic patients with nosocomial pneumonia receiving linezolid. Group A2 (n=30): Diabetic patients with nosocomial pneumonia receiving vancomycin. Group B (n=60): Non- diabetic cases, which further subdivided into two subgroups: Group B1 (n=30): Non-diabetic patients with nosocomial pneumonia receiving linezolid. Group B2 (n=30): Non-diabetic patients with nosocomial pneumonia receiving vancomycin. Results: APACHE score and duration of hospital admission were higher in diabetic cases in comparison with non-diabetic cases with statistically significant differences. Diabetic cases were more liable for complications with a subsequent high mortality rates in comparison with non-diabetic ones irrespective of the current usage of antibiotics (weather linezolid or vancomycin). Treatment outcomes were comparable among Linezolid and vancomycin used groups. The need for mechanical ventilation was comparable among all groups with no statistically significant difference. Conclusion: Diabetic comorbidity remains the main factor that affects the outcomes and prognosis of HAP cases. Higher complications and mortality rates were more in diabetic cases owing to their renal condition and uncontrolled diabetic status. Linezolid and vancomycin have similar efficacy and safety profiles in management of HAP cases.

Background Frailty in geriatric trauma patients is commonly associated with adverse outcomes. Racial disparities in geriatric trauma patients are previously described in the literature. We aimed to assess whether race and ethnicity influence outcomes in frail geriatric trauma patients. Methods We performed a 1-year (2017) analysis of TQIP including all geriatric (age ≥ 65 years) trauma patients. The frailty index was calculated using 11-variables and a cutoff limit of 0.27 was defined for frail status. Multivariate regression analysis was performed to control for demographics, insurance status, injury parameters, vital signs, and ICU and hospital length of stay. Results We included 41,111 frail geriatric trauma patients. In terms of race, among frail geriatric trauma patients, 35,376 were Whites and 2916 were African Americans; in terms of ethnicity, 37,122 were Non-Hispanics and 2184 were Hispanics. On regression analysis, the White race was associated with higher odds of mortality (OR, 1.5; 95% CI, 1.2–2.0; p

Introduction: Renal cell carcinoma (RCC) has various histopathological tumor subtypes which have a significant implication on the oncological outcome of these patients. We aimed to evaluate the distribution of RCC subtypes presenting at a tertiary care center in the Middle East, in comparison to the distribution reported in different geographic areas worldwide. Methods: A retrospective chart review was conducted on all patients who underwent partial or radical nephrectomy for RCC at the American University of Beirut Medical Center between January 2012 and January 2018. Data on histologic subtypes were compiled and compared to representative series from different continents. Results: One hundred and seventy-nine patients with RCC were identified, of whom 122 (68.2%) were classified as clear cell, 30 (16.8%) as papillary, 17 (9.5%) as chromophobe, and 10 (5.6%) as unclassified. When compared to other regions of the world, this Middle Eastern series demonstrated a higher prevalence of the chromophobe subtype compared to Western populations (9.5% in the Middle East vs. 5.3% in the US and 3.1% in Europe) and a lower prevalence of clear cell subtype (68.2% in the Middle East vs. 78.7% in the US and 85.8% in Europe). Conversely, there was a higher prevalence of papillary RCC in the Middle East (16.8%) compared to North America (13.1%, 95% confidence interval [CI]: 12.7–13.6), Europe (11.1%, 95% CI: 10.0–12.1), and Australia (10.2%). The prevalence of chromophobe and clear cell RCC in the Middle East was similar to that reported in South America. Conclusions: The distribution of RCC subtypes in this Middle Eastern cohort was significantly different from that reported in the Western hemisphere (Europe and the US) but similar to that reported in South America and Australia. These findings may point to a possible genetic predisposition underlying the global variation in distribution.

Background: Many cuffless blood pressure (BP) measuring devices are currently on the market claiming that they provide accurate BP measurements. These technologies have considerable potential to improve the awareness, treatment, and management of hypertension. However, recent guidelines by the European Society of Hypertension do not recommend cuffless devices for the diagnosis and management of hypertension. Objective: This statement by the European Society of Hypertension Working Group on BP Monitoring and Cardiovascular Variability presents the types of cuffless BP technologies, issues in their validation, and recommendations for clinical practice. Statements: Cuffless BP monitors constitute a wide and heterogeneous group of novel technologies and devices with different intended uses. Cuffless BP devices have specific accuracy issues, which render the established validation protocols for cuff BP devices inadequate for their validation. In 2014, the Institute of Electrical and Electronics Engineers published a standard for the validation of cuffless BP devices, and the International Organization for Standardization is currently developing another standard. The validation of cuffless devices should address issues related to the need of individual cuff calibration, the stability of measurements post calibration, the ability to track BP changes, and the implementation of machine learning technology. Clinical field investigations may also be considered and issues regarding the clinical implementation of cuffless BP readings should be investigated. Conclusion: Cuffless BP devices have considerable potential for changing the diagnosis and management of hypertension. However, fundamental questions regarding their accuracy, performance, and implementation need to be carefully addressed before they can be recommended for clinical use.

Purpose: GLP-1 receptor agonism has shown beneficial cardiovascular effects which could include the kidneys. In the human kidney, the high GLP-1 extraction and its natriuretic effect depend on the GLP-1 receptor and is accompanied by suppression of angiotensin II, independent of changes in renal plasma flow. Preclinical data showed that angiotensin II constricts the vasa recta and lowers medullary perfusion. The current randomized, controlled study was designed to test the hypothesis that GLP-1 increases renal medullary perfusion in healthy humans. Methods: Healthy male participants (n=10, 27 ± 4 years) ingested a fixed sodium intake for 4 days and were examined twice during a 1-hour infusion of either GLP-1 (1.5 pmol/kg/min) or placebo together with infusion of 0.9% NaCl (750 mL/h) . Interleaved measurements of renal artery flow, oxygenation (R2*) , and perfusion were acquired in the renal cortex and medulla during infusions, using magnetic resonance imaging. Results: GLP-1 infusion increased medullary perfusion (32 ± 7%, p Conclusions: GLP-1 increases predominantly medullary but also cortical perfusion in healthy human kidneys and maintains oxygenation during NaCl-loading. In perspective, GLP-1 may exert protective effects against renal hypoperfusion and ischemia. Disclosure B. Haddock: n/a. B. L. Jensen: None. A. Asmar: None.

In the last three decades protocols for the validation of blood pressure measuring devices have been developed by the US Association for the Advancement of Medical Instrumentation, the British Hypertension Society, the German Hypertension League, the European Society of Hypertension Working Group on blood pressure Monitoring and the International Organization for Standardization. The European Society of Hypertension International Protocol required much smaller sample size than the other protocols, aiming to reduce the time, resources and cost of validation studies and thereby increase the number of validated devices. Given its specifications, the European Society of Hypertension International Protocol was adequate for 'high- and low-accuracy' devices, yet assessment of 'moderate accuracy' devices had high uncertainty with resultant high rate of device failure. Thus, devices validated using the European Society of Hypertension International Protocol should be considered to be as accurate as those validated with the previous Association for the Advancement of Medical Instrumentation or British Hypertension Society protocols. However, the European Society of Hypertension International Protocol did not allow subgroup evaluation (arm sizes, special populations, etc). The mission of the European Society of Hypertension International Protocol to promote the concept of validation has been well achieved, as almost double studies have been published using it than all the other protocols together. However, the maintenance of different validation protocols is confusing and therefore experts from the Association for the Advancement of Medical Instrumentation, European Society of Hypertension International Protocol and International Organization for Standardization have now developed the AAMI/ESH/ISO Universal Standard (ISO 81060-2:2018) as the recommended 21st-century procedure for worldwide application. The European Society of Hypertension Working Group has published a practical guide for using the Universal Standard. It is in the interests of all scientific bodies to propagate the Universal Standard and ensure its wide implementation.

Purpose We have previously demonstrated that glucagon-like peptide-1 (GLP-1) does not affect renal hemodynamics or function under baseline conditions in healthy participants and in patients with type 2 diabetes mellitus. However, it is possible that GLP-1 promotes natriuresis under conditions with addition of salt and water to the extracellular fluid. The current study was designed to investigate a possible GLP-1-renal axis, inducing natriuresis in healthy, volume-loaded participants. Methods Under fixed sodium intake, eight healthy men were examined twice in random order during a 3-hour infusion of either GLP-1 (1.5 pmol/kg/min) or vehicle together with an intravenous infusion of 0.9% NaCl. Timed urine collections were conducted throughout the experiments. Renal plasma flow (RPF), glomerular filtration rate (GFR), and uptake and release of hormones and ions were measured via Fick's principle. Results During GLP-1 infusion, urinary sodium and osmolar excretions increased significantly compared with vehicle. Plasma renin levels decreased similarly on both days, whereas angiotensin II (ANG II) levels decreased significantly only during GLP-1 infusion. RPF and GFR remained unchanged on both days. Conclusions In volume-loaded participants, GLP-1 induces natriuresis, probably brought about via a tubular mechanism secondary to suppression of ANG II, independent of renal hemodynamics, supporting the existence of a GLP-1-renal axis.

This study was conducted to assess the clinical spectrum, management, and outcome of SARS-CoV-2-related multisystem inflammatory syndrome in children (MIS-C). We reviewed medical records of children with MIS-C diagnosis seen at the Children's Hospital of Michigan in Detroit between April and June 2020. Thirty-three children were identified including 22 who required critical care (group 1) and 11 with less intense inflammation (group 2). Children in group 1 were older (median 7.0 years) than those in group 2 (median 2.0 years). Abdominal pain was present in 68% of patients in group 1. Hypotension or shock was present in 17/22 patients in group 1. Thirteen (39.4%) had Kawasaki disease (KD)-like manifestations. Five developed coronary artery dilatation; All resolved on follow-up. Intravenous immunoglobulin (IVIG) was given to all patients in group 1 and 7/11 in group 2. Second-line therapy was needed in 13/22 (group 1) for persisting inflammation or myocardial dysfunction; 12 received infliximab. All patients recovered.Conclusion: MIS-C clinical manifestations may overlap with KD; however, MIS-C is likely a distinct inflammatory process characterized by reversible myocardial dysfunction and rarely coronary artery dilatation. Supportive care, IVIG, and second-line therapy with infliximab were associated with a favorable outcome. What is Known: • Multisystem inflammatory syndrome in children (MIS-C) manifestations include fever, gastrointestinal symptoms, shock, and occasional features of Kawasaki disease (KD). • Treatment includes immunomodulatory agents, most commonly IVIG and corticosteroids. What is New: • Spectrum of MIS-C varies from mild to severe inflammation and coronary artery dilatation occurred in 5/22 (23%) critically ill patients. • IVIG and infliximab therapy were associated with a favorable outcome including resolution of coronary dilatation; only 2/33 received corticosteroids.

Background/Objective Stroke symptoms in the absence of diagnosed stroke are common worldwide and associated with stroke risk factors and great impact on the physical and mental health functioning. The aim of this study was to assess, at the national level, the association of stroke symptoms with mental and physical health. Methods Quality of life was assessed using physical and mental component summary scores (PCS and MCS) of the Short Form 12v2 Health Survey in the Lebanese population. We assessed the differences in the mean PCS and MCS scores among asymptomatic individuals with no stroke/transient ischemic attack (TIA) history (n = 1167), symptomatic individuals with no stroke/TIA history (n = 125) and those with stroke/TIA history (n = 46). Psychometric properties of the Lebanese version of the SF- 12v2 were evaluated using principal component analysis . Results Symptomatic individuals had an average PCS scores of 2.31 (95%CI: 0.75–3.88) points lower and those with stroke/TIA history had 3.26 (95%CI: 1.01–5.51) points lower when compared with asymptomatic individuals with no stroke/TIA history. Similarly, MCS scores for symptomatic individuals were 2.58 (95%CI: 1.02–4.13) points lower and those with stroke/TIA history had 3.28 (95%CI: 1.06–5.50) points lower than asymptomatic individuals. Conclusion Physical and mental health functioning declined among symptomatic individuals and those with stroke/TIA history. Thus, frequent monitoring for the early detection of stroke symptoms may be recommended.

Objective: Surgical resection of hilar cholangiocarcinoma carries significant morbidity and mortality, particularly if postoperative bile leak occurs. Prognostic factors and scoring tools have been described for overall morbidity and mortality but none are specific for postoperative bile leak. In this study, we investigate the prognostic utility of various factors in predicting overall morbidity, mortality and risk of biliary leak in Bismuth Type III tumors with the hopes of developing a scoring tool in future research. Materials and Methods: A retrospective sample of 23 patients with Bismuth Type III tumors exclusively who underwent surgery between 2010 and 2017 were selected for this study. Demographic, surgical, pathologic and biochemical data were collected from the patients’ medical records. Results: 11 patients underwent a right hepatectomy for type IIIa tumors and 10 patients underwent a left hepatectomy for type IIIb tumors. 2 patients were lost to follow up and were excluded. R0 resection was achieved in 20 patients. Overall survival at 1, 3 and 5 years was 78.3%, 61.9% and 38.1%, respectively. A BMI >24kg/m2 was associated with a worse prognosis, increased overall morbidity and decreased survival at 1, 3 and 5 years (p0.74 was associated with decreased 5-year survival (p24kg/m2 and a preoperative creatinine >0.74 are associated with a poor prognosis in Bismuth Type III Klatskin tumors. Furthermore, Age, sex, preoperative hemoglobin, tumor size, use of CUSA and type IIIb tumors demonstrate a borderline significant association with the occurrence of postoperative bile leak.

BACKGROUND Refractory chronic rhinosinusitis (CRS) remains a significant burden for patients, often leaving them with few therapeutic options that provide low-morbidity, long-term, and meaningful symptomatologic and endoscopic disease improvement. Macrolides have long been thought to offer both an immunomodulatory and antimicrobial effect. Our objective was to evaluate the efficacy of low-dose, long-term azithromycin in a carefully selected high-risk population failing appropriate medical therapy of budesonide nasal irrigations (BNIs) and endoscopic sinus surgery (ESS). METHODS A double-blind, randomized, placebo-controlled trial was completed in a single tertiary-care center assessing the addition of 250 mg azithromycin, 3 times per week for 16 weeks, in adults failing ESS and high-volume BNIs. Associated comorbidities, as well as symptomatologic, microbiologic, and serologic values, were systematically collected. RESULTS A total of 128 patients were enrolled and underwent ESS followed by BNI. At the 4-month post-ESS visit, 48 patients showed disease persistence and were randomized to azithromycin or placebo. Overall, azithromycin, when compared with placebo, did not show a statistically significant difference in disease clearance (54% vs 33%, respectively; p = 0.146), although patients with disease clearance who were on azithromycin showed significantly better 22-item Sino-Nasal Outcome Test score improvements than patients on placebo (18 vs -0.9, respectively; p = 0.046). In a subgroup analysis excluding aspirin-exacerbated respiratory disease (AERD) patients, azithromycin significantly improved disease clearance when compared with placebo (71% vs 35%, respectively; p = 0.031), with a number needed to treat of 3 (2.8). CONCLUSION Low-dose azithromycin is a therapeutic option with few side effects. Its use can show favorable clinical outcomes in this difficult-to-treat population, especially if patients are AERD-negative.

INTRODUCTION Organ dysfunction following traumatic brain injury (TBI) is common and has been associated with unpredictable outcomes. The aim of our study is to describe the incidence of non-neurological organ dysfunction (NNOD) and its impact on outcomes in patients with severe TBI admitted to our intensive care unit (ICU). METHODS We performed a 3-year (2015-2017) review of our Level 1 trauma center's prospectively maintained TBI database and included all adult (age ≥18y) patients with isolated severe TBI (head abbreviated injury severity (AIS) ≥3 and other AIS 48 hours. Organ dysfunction (OD) was measured by multiple organ dysfunction scores. Organ system failure was defined as a non-neurological component score of ≥3 on any day during the ICU stay. Outcomes measured were the incidence of NNOD and its effect on outcomes. Multivariate regression analysis was performed. RESULTS A total of 285 patients were included. The mean age was 48 ± 22 years, 72% were males, median [IQR] Glasgow Coma Scale (GCS) was 8[5-10], and median Injury Severity Score (ISS) was 17[10-26]. Epidural hematoma was the most common intracranial hemorrhage (49%) followed by subdural hematoma (46%). The overall incidence of NNOD was 33%, with the most common dysfunctional organ system being the respiratory (23%) followed by the cardiovascular (12%) and hepatic system (8%). The overall in-hospital mortality rate was 19% (NNOD:36% vs. No-NNOD:9%, p< 0.01). On regression analysis, NNOD was associated with higher in-hospital mortality (aOR: 2.0 [1.6-2.7]), discharge to skilled nursing facility (SNF) (aOR: 1.8 [1.4-2.2]), and Glasgow Outcome Scale-Extended (GOS-E) ≤4 (OR: 1.7 [1.3-2.3]) and p-values

BACKGROUND The sinonasal microbiome is believed to play an important role in the pathophysiology of refractory chronic rhinosinusitis (CRS). We evaluated changes in the microbiome following a 4-month course of low-dose azithromycin. Assessing microbiome alterations following such a treatment may help identify underlying mechanisms of this drug. METHODS A total of 48 adults with refractory CRS were enrolled in a double-blind, randomized, placebo-controlled trial. Patients were randomized to 250 mg of azithromycin or placebo 3 times weekly for 4 months. During this time, daily budesonide saline irrigations were continued. Sinonasal swabs were collected by endoscopically-assisted method prior to treatment initiation and at the end of it, and sent for 16S ribosomal RNA gene sequencing. High-resolution ANCHOR pipeline was used to infer and annotate putative species. The 2 patient groups were compared using DESeq2 differential abundance analysis. RESULTS From initiation to the end of azithromycin treatment, patients showed a significant difference in beta diversity analysis (p = 0.0004) along with a significant decrease in 71 different operational taxonomic units (OTUs) of Staphylococcus aureus (false discovery rate [FDR] < 0.05) obtained from the differential abundance analysis. This was not observed in placebo-treated patients. By the end of treatments, azithromycin-treated patients had a significant decrease in 29 different OTUs of S. aureus (FDR < 0.05) when compared to placebo. CONCLUSION A 4-month course of 250 mg of azithromycin 3 times weekly in patients with refractory CRS significantly decreases S. aureus abundance in the sinonasal microbiome. Considering the pathogenic role of S. aureus in the refractory CRS population, azithromycin may constitute an additional therapeutic option to help control this disease.

BackgroundNitric oxide synthase (NOS) activity, an enzyme potentially involved in the major depressive episodes (MDE), could be indirectly measured by the L-Citrulline/L-Arginine ratio (L-Cit/L-Arg). The aim of this study was: (1) to compare the NOS activity of patients with a MDE to that of healthy controls (HC); (2) to assess its change after antidepressant treatment.MethodsA total of 460 patients with a current MDE in a context of major depressive disorder (MDD) were compared to 895 HC for NOS activity (L-Cit/L-Arg plasma ratio). L-Arg and L-Cit plasma levels were measured using a MS-based liquid chromatography method. Depressed patients were assessed at baseline, and after 3 and 6 months of antidepressant treatment for depression severity and clinical response.ResultsDepressed patients had a lower NOS activity than HC at baseline [0.31 ± 0.09 v. 0.38 ± 0.12; 95% confidence interval (CI) −0.084 to −0.062, p < 0.0001]. Lower NOS activity at baseline predicted a higher response rate [odds ratio (OR) = 29.20; 95% CI 1.58–536.37; p = 0.023]. NOS activity in depressed patients increased significantly up to 0.34 ± 0.08 after antidepressant treatment (Est = 0.0034; 95% CI 0.0002–0.0067; p = 0.03).ConclusionsDepressed patients have a decreased NOS activity that improves after antidepressant treatment and predicts drug response. NOS activity may be a promising biomarker for MDE in a context of MDD.

Background Liquid packed red blood cells (LPRBCs) have a limited shelf life and worsening quality with age. Cryopreserved packed red blood cells (CPRBCs) can be stored up to 10 years with no quality deterioration. The effect of CPRBCs on outcomes in civilian trauma is less explored. This study aims to evaluate the safety and efficacy of CPRBCs in civilian trauma patients. Methods We analyzed the (2015-2016) Trauma Quality Improvement Program, including adult (age, ≥18 years) patients who received a RBC transfusion within 4 hours of admission. Patients were stratified, those who received LPRBC and those who received CPRBC. Primary outcomes were 24-hour and in-hospital mortality. Secondary outcomes were major complications. Propensity matching was performed adjusting for demographics, vitals, blood components, injury parameters, comorbidities, and center parameters. Results A total of 39,975 patients were identified, and a matched cohort of 483 was obtained. A total of 161 received CPRBC (CPRBC, 2 [2-4]; plasma, 2 [0-5]; platelets, 1 [0-2]) and 322 received LPRBC (LPRBC, 3 [2-6]; plasma, 3 [0-6]; platelets, 1 [0-2]). The mean age was 43 ± 22 years, 62% were men, Injury Severity Score was 18 (12-27), and 65% had a blunt injury. Patients who received CPRBC had similar 24-hour mortality (1.8% vs. 2.3%; p = 0.82) and in-hospital mortality (4.9% vs. 5.2%; p = 0.88). No difference was found in terms of complications (15.3% vs. 17.2%; p = 0.21) between the two groups. Conclusion Transfusion of CPRBCs may be as safe and effective as transfusion of LPRBCs in moderately injured trauma patients. Cryopreservation has the potential to expand our transfusion armamentarium in diverse settings, such as periods of increased usage, disaster scenarios, and rural areas. Level of evidence Therapeutic study, level III.

Objectives This study aims to assess the incidence of incidental activity in the gallbladder and the factors that may contribute to it in a large cohort of patients undergoing 18F-fluorodeoxyglucose-PET/CT for cancer evaluation. Methods 8096 PET/CTs were retrospectively reviewed. Data pertaining to patient demographics and PET/CT parameters were collected. Patients' records were reviewed for gallbladder disorders for up to 3 years after the exam. The presence/absence of gallbladder uptake was visually assessed. Findings were classified as focal, diffuse increased and diffuse increased wall uptake, or no uptake. Volumetric measurements of the gallbladder and SUVmax of the gallbladder, liver and blood pool were measured. Chi-square and Student's t-test were used for statistical analysis. Results 54 cases (0.67%) of incidental gallbladder uptake were detected (uptake group). 162 exams without uptake were selected as control (no uptake group). The injection-to-scan interval, SUVmax of the liver and blood pool, and the gallbladder volume did not differ significantly between both groups. Higher blood glucose levels were observed in the uptake (109.9 ± 32.5) vs. no uptake group (97.4 ± 18) (p = 0.01), with levels >150 mg/dL more common in the uptake group (p = 0.004). The incidence of gallbladder disease within 3 years after imaging was higher for the uptake group (12/36) compared to the no uptake group (15/115) (p = 0.02). Diffuse increased wall uptake was more likely in the group who later developed a pathology (4/12) (p = 0.03). Conclusion Incidental gallbladder uptake in patients is independent of the injected FDG dose, injection-to-scan interval or gallbladder volume, but may be related to blood glucose level. There's a higher incidence of gallbladder pathology three years after the exam particularly in cases of diffuse increased wall uptake.

BACKGROUND Blunt cerebrovascular injury (BCVI) is associated with cerebrovascular accidents (CVA). Early therapy with antiplatelet agents or anticoagulants is recommended. There are limited data comparing the effectiveness of these treatments. The aim of our study was to compare outcomes between BCVI patients who received anticoagulants versus those who received antiplatelet agents. METHODS We performed an (2011-2015) analysis of the Nationwide Readmission Database and included all adult trauma patients 18 years or older who had an isolated BCVI (other body regions Abbreviated Injury Scale [AIS] < 3). Head injury patients or those who developed a CVA during the index admission were excluded. Patients were stratified into anticoagulants and antiplatelet agents. Propensity score matching was performed (1:1 ratio) to control for demographics, comorbidities, BCVI grade, distribution, and severity of injuries. Outcomes were readmission with CVA and mortality within 6 months. RESULTS A total of 725 BCVI patients were identified. A matched cohort of 370 patients (antiplatelet agents, 185; anticoagulants, 185) was obtained. Mean age was 50 ± 15 years, neck AIS was 3 (3,4), and Injury Severity Score was 12 (9-17). The majority of the patients (69%) had high-grade BCVI (AIS ≥ 3). Overall, 3.7% were readmitted with CVA and 3% died within 6 months. Patients who received anticoagulants had a lower rate of readmission with CVA (1.8% vs. 5.72%; p = 0.03), and a lower rate of 6-month mortality (1.3% vs. 4.9%; p = 0.03). There was no significant difference between the two groups reading the median time to stroke (9 days vs. 6 days; p = 0.12). CONCLUSION The BCVI patients on CVA prophylaxis for BCVI have a 3.7% rate of stroke after discharge. Compared with antiplatelet agents, anticoagulants are associated with lower rates of CVA in the first 6-month postdischarge. Further studies are required to identify the optimal agent to prevent CVA in this high-risk subset of trauma patients. LEVEL OF EVIDENCE Therapeutic, level IV.

Introduction Major depression is associated with metabolic syndrome and cardiovascular risk. We have previously shown that severe insomnia, a core symptom of major depression episode (MDE), is associated with hypertriglyceridemia, a component of metabolic syndrome, in women but not in men with major depression. Since insomnia is related to cardiovascular morbidity in the general population and major depression also, our objective was to assess the link between insomnia and metabolic syndrome, a marker syndrome of cardiovascular risk, during MDE, in women and in men. Methods In 624 patients with a current MDE cohort, both insomnia and metabolic syndrome were assessed in women and men. Insomnia was rated from 0 to 6 based on the HDRS corresponding items, severe insomnia being defined by a total insomnia score ≥4. Results severe insomnia was associated with metabolic syndrome in women but not in men. In multivariate logistic regressions, these results in women were independent from age, educational level, major depressive disorder duration and current smoking. These results were only significant in women aged ≥50 years, a cut-off age for menopausal status but not in women under 50 years. Conclusion Women aged ≥50 years with a severe insomnia during MDE have an increased risk of metabolic syndrome. Severe insomnia may be a clinical marker of metabolic risk in this population. They should be particularly monitored for metabolic syndrome and may benefit from sleep recommendations and cardiovascular prevention.

Purpose: To report a primary objective clinical outcome of ipsilateral breast recurrence following accelerated partial breast irradiation (APBI) in cautionary (as described in 2017 revised ASTRO APBI guidelines) and high-risk women (age Methods and Material: Between March 2004 and April 2016 patients were enrolled in two APBI breast protocols (Phase II NCT01185145 and Phase III NCT01185132). Patients were treated with 38.5 Gy IMRT or 3D-CRT APBI w/ 3.85 Gy fraction/BID fractionation for 10 fractions. Patients who were ER/PR negative, ER negative, PR negative, HER2 positive, ≥2 cm primary tumors, or triple negative were compared to a total of 543 patients who were enrolled in the Phase II and Phase III trials. High risk patients were defined as those who possess one or more high risk criteria: triple negative (n=30), ER-/PR- (n=40), tumor size ≥2 cm Results: Median follow up was 4.0 years for all patients. No significant difference was found for this cautionary/high risk cohort at 5 years for ipsilateral breast, or regional recurrences. However, axillary recurrence was significantly adversely impacted by triple negative status, as well as both ER- and combined ER/PR- status (p=0.01, p=0.04, p=0.03, respectively). On multivariate analysis, the only significant correlations were between triple negative type and axillary recurrence (p=0.03). Overall survival for all patients was unaffected by any of the high-risk categories. Estimated Recurrence-free and Overall Survival at 5 years VariableIpsilateral breast recurrencepAxillary recurrencepRegional recurrencepAll Patients OSpHER-2/neupositive100%0.45100%0.64100%0.3895.3%0.88negative98%99.5%97.4%95.8%Size Triple negativeyes100%0.3496.7%0.0196.7%0.9384.3%0.16no98%99.7%97.6%95.9%HistologyIDCA98%0.4599.7%0.0797.7%0.7595.8%0.14ILCA100%97.5%97.5%88.9%Age> 5098%0.2899.5%0.4597.8%0.5595.2%0.10≤ 5097%100%97%96.6%ERpositive97.9%0.399.7%0.0497.6%0.9496%0.29negative100%97.5%97.5%87.5% Conclusion: There were no statistically significant differences in clinical local ipsilateral breast or regional recurrence outcomes at 5 years for patients currently considered to be cautionary/high risk. Axillary recurrence, however, was adversely impacted by triple negative, ER-, and combined negative ER/PR status. ER- and ER/PR- status similarly affected axillary recurrence. In light of these differences, however, the actual increase in axillary recurrence ranges from 2.4%-3% and are of questionable clinical significance. These data suggest that women possessing cautionary/high risk features are at no more risk for ipsilateral breast recurrence than other patients considered to be acceptable for APBI treatment. Citation Format: Anabel Goulding, Charles Leonard, Shannon Tole, Lora Barke, Jodi Widner, Lina Asmar, Yunfei Wang. Outcomes after accelerated partial breast irradiation in “high risk” and women categorized as cautionary in the ASTRO guidelines [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-13-05.

Given the recent successes of anti-PD-1 immunotherapy, many clinical trials have sought to assess the safety and efficacy of this treatment modality in the neoadjuvant setting. This systematic review provides a comprehensive summary of findings from neoadjuvant head and neck cancer immunotherapy clinical trials with a focus on PD-1/PD-L1 axis blockade. Pubmed, Embase, Cochrane Library, Web of Science, Google Scholar, and clinicaltrials.gov were systematically searched for all eligible neoadjuvant head and neck cancer immunotherapy clinical trials. Eight clinical trials met the inclusion criteria comprising a total of 260 patients. Study drugs included nivolumab, pembrolizumab, ipilimumab, durvalumab, and tremelimumab. The overall mean objective response rate (ORR) was 45.9 ± 5.7% with a 41.5 ± 5.6% single agent mean ORR. There were no deaths due to immune-related toxicities. Neoadjuvant immunotherapy for mucosal head and neck squamous cell cancer has demonstrated favorable response rates with no unexpected immune-related toxicities in phase I/II clinical trials.

Human studies have demonstrated that physiologically relevant changes in circulating glucagon‐like peptide‐1 (GLP‐1) elicit a rapid increase in renal sodium excretion when combined with expansion of the extracellular fluid volume. Other studies support the involvement of various gastrointestinal hormones, e.g., gastrin and cholecystokinin (CCK) in a gut‐kidney axis, responsible for a rapid‐acting feed‐forward natriuretic mechanism. This study was designed to investigate the hypothesis that the postprandial GLP‐1 plasma concentration is sensitive to the sodium content in the meal. Under fixed sodium intake for 4 days prior to each experimental day, 10 lean healthy male participants were examined twice in random order after a 12‐hr fasting period. Arterial blood samples were collected at 10–20‐min intervals for 140 min after 75 grams of oral glucose + 6 grams of oral sodium chloride (NaCl) load versus 75 grams of glucose alone. Twenty‐four‐hour baseline urinary sodium excretions were similar between study days. Arterial GLP‐1 levels increased during both oral glucose loads and were significantly higher at the 40–80 min period during glucose + NaCl compared to glucose alone. The postprandial arterial responses of CCK, gastrin, and glucose‐dependent insulinotropic polypeptide as well as glucose, insulin, and C‐peptide did not differ between the two study days. Arterial renin, aldosterone, and natriuretic peptides levels did not change within subjects or between study days. Angiotensin II levels were significantly lower at the time GLP‐1 was higher (60–80 min) during glucose + NaCl. Sodium intake in addition to a glucose load selectively amplifies the postprandial GLP‐1 plasma concentration. Thus, GLP‐1 may be part of an acute feed‐forward mechanism for natriuresis., This study demonstrates that postprandial glucose‐driven glucagon‐like peptide‐1 (GLP‐1) secretion is sensitive to dietary sodium chloride intake and that this is associated with significantly lower angiotensin II (ANG II) but not aldosterone concentrations. In perspective, this feed‐forward Na+‐driven GLP‐1/ANGII response could have an impact on renal Na+‐handling.

We have recently demonstrated that renal extraction of GLP-1 is ∼45% and that extracellular fluid volume expansion in healthy participants uncovered a natriuretic action of GLP-1 probably via a tubular mechanism secondary to suppression of angiotensin II (ANG II) and independent of changes in renal hemodynamics. It is not known whether the high extraction is due to receptor binding. The present study was designed to test the hypotheses that the renal extraction and natriuretic effect of GLP-1 are mediated via GLP-1 receptor. Under fixed sodium intake for 4 days before each study day, 6 healthy male participants were recruited from our recent study1 and examined during a 3-h infusion of GLP-1 (1.5 pmol/kg/min) together with a 3.5-h infusion of the GLP-1 receptor antagonist, exendin 9-39 (Ex 9-39) (900 pmol/kg/min), initiated 30 minutes before start of GLP-1 infusion. Timed urine collections were conducted throughout the experiments. Renal plasma flow (RPF), glomerular filtration rate (GFR), and renal extraction of GLP-1 were measured via Fick’s principle after catheterization of a renal vein. Renal extraction of GLP-1 was ∼45% during infusion of GLP-1 alone and decreased significantly to ∼25% during co-infusion of GLP-1 and Ex 9-39. Urinary sodium and osmolar excretions remained at baseline levels during co-infusion of GLP-1 and Ex 9-39 compared to a mean 2-fold natriuretic effect during GLP-1 infusion alone. Arterial plasma ANG II levels were unaffected during the co-infusions, whereas ANG II decreased significantly during GLP-1 alone. Arterial plasma renin levels decreased similarly on the two study days, and arterial aldosterone levels remained unchanged on both days. RPF and GFR remained unchanged on both days. In conclusion, renal extraction of GLP-1 is partially and natriuresis is fully dependent on GLP-1 receptor activation, probably via GLP-1-mediated ANG II suppression. 1Asmar A et al. J Clin Endocrinol Metab. 2019 Jul 1;104(7):2509-2519. Disclosure A. Asmar: None. P.K. Cramon: None. M. Asmar: None. L. Simonsen: None. S. Madsbad: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. C.M. Sorensen: None. B. Hartmann: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. P. Hovind: None. B.L. Jensen: None. J. Bülow: None.

Purpose The natriuretic effect of glucagon-like peptide-1 (GLP-1) in humans is independent of changes in renal plasma flow (RPF) and glomerular filtration rate (GFR) but may involve suppression of angiotensin II (ANG II) and a significant (~45%) renal extraction of GLP-1. The current study was designed to investigate the consequences for the renal extraction and the natriuretic effect of blocking GLP-1 receptors with the specific GLP-1 receptor antagonist, Exendin 9–39 (Ex 9–39). Methods Under fixed sodium intake for 4 days before each study day, 6 healthy male participants were recruited from our recent study where GLP-1 or vehicle was infused (1). In the present new experiments, participants were examined during a 3-hour infusion of GLP-1 (1.5 pmol/kg/min) together with a 3.5-hour infusion of Ex 9–39 (900 pmol/kg/min). Timed urine collections were conducted throughout the experiments. Renal extraction of GLP-1 as well as RPF and GFR were measured via Fick’s principle after catheterization of a renal vein. Arterial plasma renin, ANG II, and aldosterone concentrations were measured. Results Co-infusion of Ex 9–39 significantly reduced renal extraction of GLP-1 to ~25% compared with GLP-1 infusion alone (~45%). Urinary sodium excretions remained at baseline levels during co-infusion of Ex 9–39 as well as vehicle. By contrast, GLP-1 infusion alone resulted in a 2-fold increase in natriuresis. Ex 9–39 abolished the GLP-1-induced decrease in arterial ANG II concentrations. RPF and GFR remained unchanged during all experiments. Conclusions Renal extraction of GLP-1 and its effect on natriuresis are both dependent on GLP-1 receptor activation in healthy humans.

Background Electronic devices for blood pressure (BP) measurements need to go through independent clinical validation as recommended by different authorities, both in general and in special populations such as pregnancy. Objective To evaluate the accuracy of the Omron Evolv® (HEM-7600T-E) and the Omron M3 Comfort® (HEM-7134-E) devices in pregnancy and pre-eclampsia according to the Universal Standard Validation Protocol. Methods Both devices, the Evolv and the M3 Comfort, measure BP at the brachial level using the oscillometric method. The study was performed according to the recently published protocol, the so-called "modified Advancement of Medical Instrumentation (AAMI)/British Hypertension Society (BHS)/European Society of Hypertension (ESH) protocol" or the "Universal Standard Protocol." Validation of each device included 45 pregnant women in the second and third gestational trimester of whom 15 had pre-eclampsia, 15 had gestational hypertension and 15 were normotensives. BP differences between the observer and the device BP values were classified into three categories (≤5, ≤10, and ≤15 mmHg) and the mean BP differences (test vs reference) and its SD were calculated. Results Both devices, the Evolv and the M3 Comfort, achieved a grade A/A in both pregnancy and pre-eclampsia. The mean difference (SD) between the mercury standard and the device BP values in pregnancy were: 1) for the Evolv of -0.7±2.3 mmHg for systolic blood pressure (SBP) and -0.1±1.8 mmHg for diastolic blood pressure (DBP); 2) for the M3 Comfort of -1.6±2.8 mmHg for SBP and -0.1±2.3 mmHg for DBP. Conclusion Both devices, the Evolv and the M3 Comfort, achieved a grade A/A for both SBP and DBP and fulfill the validation protocol criteria in pregnancy and pre-eclampsia. Consequently, these two devices can be recommended for home BP measurements in this specific population.

Introduction: The European Society of Hypertension (ESH) International Protocol (ESH-IP) for the validation of blood pressure (BP) measuring devices was published in 2002, with the main objective of simplifying the validation procedures, so that more BP monitors would be subjected to independent validation. This article provides an overview of the international impact of the ESH-IP and of the lessons learned from its use, to be able to justify further developments in validation protocols. Methods: A review of published (PubMed) validation studies from 2002 to 2017 was performed. Results: One hundred and seventy-seven validation studies using the ESH-IP, 59 using the British Hypertension Society protocol, 46 using the Association for the Advancement of Medical Instrumentation (AAMI) standard and 23 using the International Organization for Standardization (ISO) standard were identified. Lists of validated office-clinic, home and ambulatory BP monitors are provided. Of the ESH-IP studies, 93% tested oscillometric devices, 80% upper arm, 71% home, 25% office and 7% ambulatory monitors (some had more than one function). Conclusion: The original goal of the ESH-IP has been fulfilled in that in the last decade the number of published validation studies has more than doubled. It is now recognized that the provision of accurate devices would be best served by having a universal protocol. An international initiative has been put in place by AAMI, ESH and ISO experts aiming to reach consensus for a universal validation protocol to be accepted worldwide, which will allow a more thorough evaluation of the accuracy and performance of future BP monitors.

The approval of the interleukin (IL)-17A inhibitor secukinumab (Cosentyx; Novartis International, King of Prussia, PA) was a major advance in psoriasis treatment, with most patients experiencing a 75% reduction in severity.1 Known side effects include an increase in minor infections, but no major infectious adverse events and no nervous system involvement,1-4 leading to broad use and an increase in clinical trials targeting the IL-17 pathway. Here, we describe a patient administered with secukinumab who presented with severe neurologic deficits due to multifocal brain lesions. These were found to be disseminated streptococcal infection and resolved after antibiotic treatment.

Introduction/Background* Digestive tract resection is a common procedure performed in bulky advanced-stage ovarian cancer (AOC) to achieve complete cytoreductive surgery (CRS). Very few data are available on the incidence and the prognostic impact of mesenteric lymph node (MLN) involvement. The aim of this study is to determine the incidence of MLN involvement in patients undergoing a digestive tract resection at the time of CRS for AOC and to analyze its prognostic impact. Methodology A retrospective study including patients who underwent CRS for AOC between 2006 and 2017. Patient’s clinico-pathological characteristics were collected, incidence of various LN basin involvement were analyzed focusing on MLN. Overall survival (OS) and disease free survival (DFS) were calculated with the KM method. Result(s)* During the study period 72 of 176 (40.9%) patients with stage III-IVa AOC had a digestive tract resection during CRS with the recto-sigmoid resection being the most frequent (52 patients). There was an involvement of the serosa in 38 (52.8%), sub-serosa in 10 (13.9%), muscularis propria in 10 (13.9%), and mucosa in 5 cases (6.9%), respectively. MLN were found in 37 out of 72 (51.4%) patients with digestive tract resection. 25 patients (67.5%) had MLN involvement with a median of 5 involved nodes (range, 1 to 45). There was a trend in worse 5-year OS (45.8% vs 63.6%, p=0.064) for patients with MLN involvement. Conclusion* Patients with AOC involving the digestive tract is associated with a high incidence of MLN metastasis. Resection of the associated lymphatic tributaries of affected bowel segment and correct pathological examination of the MLN should be performed regularly to improve staging and better evaluate their prognostic impact in case of LN involvement.

BackgroundIt is unclear whether olfactory deficits improve after remission in depressed patients. Therefore, we aimed to assess in drug-free patients the olfactory performance of patients with major depressive episodes (MDE) and its change after antidepressant treatment.MethodsIn the DEP-ARREST-CLIN study, 69 drug-free patients with a current MDE in the context of major depressive disorder (MDD) were assessed for their olfactory performances and depression severity, before and after 1 (M1) and 3 (M3) months of venlafaxine antidepressant treatment. They were compared to 32 age- and sex-matched healthy controls (HCs). Olfaction was assessed with a psychophysical test, the Sniffin’ Sticks test (Threshold: T score; Discrimination: D score; Identification: I score; total score: T + D + I = TDI score) and Pleasantness (pleasantness score: p score; neutral score: N score; unpleasantness score: U score).ResultsAs compared to HCs, depressed patients had lower TDI olfactory scores [mean (s.d.) 30.0(4.5) v. 33.3(4.2), p < 0.001], T scores [5.6(2.6) v. 7.4(2.6), p < 0.01], p scores [7.5(3.0) v. 9.8(2.8), p < 0.001)] and higher N scores [3.5(2.6) v. 2.1(1.8), p < 0.01]. T, p and N scores at baseline were independent from depression and anhedonia severity. After venlafaxine treatment, significant increases of T scores [M1: 7.0(2.6) and M3: 6.8(3.1), p < 0.01] and p scores [M1: 8.1(3.0) and M3: 8.4(3.3), p < 0.05] were evidenced, in remitters only (T: p < 0.01; P: p < 0.01). Olfaction improvement was mediated by depression improvement.ConclusionsThe olfactory signature of MDE is restored after venlafaxine treatment. This olfaction improvement is mediated by depression improvement.

To characterize the use of olodaterol and indacaterol in clinical practice and to quantify the off-label use in asthma. Drug utilization study of new users of olodaterol or indacaterol between 2014 and 2017 in the PHARMO Database Network in the Netherlands, the Danish population registers, and the IMS Real-World Evidence Longitudinal Patient Database panels in France. On-label use was defined as use among adults with a recorded diagnosis of COPD. Off-label use was defined as use among adults with a recorded diagnosis of asthma without a recorded diagnosis of COPD or as use among patients aged ≤18 years. Potential off-label use was defined as no recorded diagnosis of either COPD or asthma. The study included 4,158 new users of olodaterol and 9,966 new users of indacaterol. Prevalence of off-label use ranged from 3.5% for both drugs to 12.4% for olodaterol and 11.9% for indacaterol. Prevalence of on-label use ranged from 47.8% to 77.7% for olodaterol and from 28.7% to 70.1% for indacaterol. The remaining new users of olodaterol and indacaterol were classified as potential off-label users, with prevalence ranging from 17.3% to 48.6% for olodaterol and from 20.5% to 66.6% for indacaterol. This study provides no evidence of a major concern in Europe for olodaterol or indacaterol for off-label use in asthma or for pediatric use.

Autologous hematopoietic cell transplantation (AHCT) is standard therapy for patients with chemosensitive, relapsed, diffuse large B cell lymphoma (DLBCL). We performed a retrospective cohort study to delineate subsequent (conditional) and relative survival in 371 adult patients with DLBCL who underwent AHCT between 2000 and 2014 and had survived for 1, 2, 3, or 5 years after transplant. The probability of overall survival at 10 years after AHCT was 62%, 71%, 77%, and 86%, respectively, for the 4 cohorts, whereas that of progression-free survival (PFS) was 55%, 65%, 72%, and 81%, respectively. The respective cumulative incidence of nonrelapse mortality (NRM) at 10 years after transplantation was 13%, 12%, 11%, and 8%, respectively. In multivariable analysis, older age was associated with greater mortality risk among all but 5-year survivors; relapse within the landmark time was associated with greater mortality risk in all groups. Older age and relapse within the landmark time were associated with worse PFS in all groups. Standardized mortality ratio (SMR) was significantly higher than an age-, gender-, and race-matched general population, with the magnitude of SMR decreasing as the landmark time increased (4.0 for 1-year, 3.0 for 2-year, 2.4 for 3-year, and 1.8 for 5-year survivors). Our study provides information on long-term survival and prognosis that will assist in counseling patients with DLBCL who have received AHCT. Survival improves with longer time in remission post-transplant, although patients continue to remain at risk for NRM, underscoring the need for continued vigilance and prevention of late complications.

Background: Randomized and controlled trials of glucagon-like peptide-1 (GLP-1) derived drugs have shown that the most frequent adverse symptoms are gastrointestinal. Some of the side effects such as dyspepsia, nausea and upper abdominal pain may well be of gastric origin. Since the antral hormone gastrin regulates gastric secretion of acid and enzymes and contributes to the regulation of gastric motility, we examined the effect of GLP-1 on the secretion of gastrin in normal subjects and diabetes patients. Method: Plasma was sampled from ten healthy subjects and ten patients with diabetes mellitus type 1 with glucose clamped between 6 and 9 mM. GLP-1 or saline were infused for 4 h during and after a meal. Plasma concentrations of gastrin and GLP-1 were measured using specific radioimmunoassays. Results: Basal plasma concentrations of gastrin were similar in controls and patients. After the meal, the gastrin concentrations rose significantly during saline infusion, whereas the GLP-1 infusion suppressed the secretion of gastrin significantly, most pronounced in the diabetes patients. Conclusions: The results show that GLP-1 infusion suppresses the postprandial secretion of gastrin in normal subjects and even more so in the diabetes patients. The results may therefore shed further light on the upper gastrointestinal side effects of GLP-1-derived drugs in diabetic patients.

The non-receptor tyrosine kinase Src activation plays a role in the malignant progression of breast cancer, including development of endocrine therapy resistance and survival of bone metastases. This study investigated whether adding Src kinase inhibitor dasatinib to aromatase inhibitor (AI) therapy improved outcomes in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer (MBC). Postmenopausal patients with ER-positive, HER2-negative MBC (0–1 prior chemotherapies and no prior AI for MBC) were eligible for this non-comparative, parallel group, phase-II study. Patients were randomized to letrozole (2.5 mg/day PO) alone or with dasatinib (100 mg/day PO). Patients with disease progression on letrozole alone could crossover to dasatinib plus continued letrozole. The primary endpoint was clinical-benefit-rate (CBR; complete response + partial response + stable disease ≥6 months). A total of 120 patients were randomized. The CBR of 71% (95% CI 58–83%) was observed with letrozole + dasatinib versus the projected CBR of the combination of 56%. The CBR of 66% (95% CI 52–77%) with letrozole alone also exceeded the projected CBR of 39% with letrozole alone. The CBR was 23% in the crossover arm of letrozole plus dasatinib in patients progressing on letrozole alone. Median progression-free survival with the combination was 20.1 months and 9.9 months with letrozole alone. Letrozole plus dasatinib was well tolerated, although 26% of patients required dasatinib dose reductions. In this non-comparative phase-II trial, the CBR of 71% and the median PFS of 20.1 months with letrozole + dasatinib are encouraging and suggest that dasatinib may inhibit the emergence of acquired resistance to AI therapy.

Malignant phyllodes tumors (MPT) have always been a great deal of controversy among fibroepithelial tumors of the breast. Genetics, histopathology, and tumor behavior on the cellular scale shape their extent of aggressiveness. Diagnosis is based on radiological and pathological findings. Cure is surgical excision. This article reveals the most common clinical indices, which should raise the surgeon's concerns on a benign-looking tumor to further investigate its nature, and the importance of an adequate surgical intervention, preferably done by an oncoplastic breast surgeon, in order to accomplish the ideal outcome for the patient.

Background Electronic devices for blood pressure (BP) measurements need to go through independent clinical validation as recommended by different authorities, both in general and special populations. Reproducibility of such validation protocols is unknown. Objective The aim of this study was to assess the inter-centre reproducibility of the European Society of Hypertension-International protocol (ESH-IP) in patients with large arm circumference at least 32 cm or obesity. Methods Two independent validation studies were performed in parallel according to the ESH-IP protocol in two centres (Serbia and Armenia). The two studies were performed blindly and independently. The ESH-IP criteria were applied for the analysis. The OMRON RS7 wrist oscillometric devices were used in both studies. Results The distribution of the mean differences values of 5 or less, 10 or less and 15 mmHg or less between the observers and the device were for the Serbia team: 74, 95 and 98 for SBP and 78, 95 and 99 for DBP; and for the Armenia team: 86, 95 and 99 for SBP and 90, 99 and 99 for DBP. The mean differences (SD) of BP values between the observers and the device were for the Serbia team of 1.7 ± 4.8 mmHg for SBP and 1.2 ± 4.6 mmHg for DBP and for the Armenia team of -1.1 ± 4.2 mmHg for SBP and -0.3 ± 3.5 mmHg for DBP. Conclusion This study showed that the ESH-IP validation protocol presents a good inter-centre reproducibility. The OMRON RS7 device showed similar results, fulfilling the validation criteria in two independent studies in patients with arm circumference at least 32 cm.

Background: Metabolic syndrome is a multiorgan disease and it could aggravate other diseases. Its effect on chronic obstructive pulmonary disease needs to be addressed. Aim of the work: to examine if metabolic syndrome increases the frequency, duration and severity of acute exacerbations of chronic obstructive pulmonary disease. Patients and methods: 60 patients who admitted with COPD exacerbation were included and were divided into two groups: Group 1 (COPD without metabolic syndrome). Group 2 (COPD with metabolic syndrome). All submitted to full history taking, clinical examination, laboratory and radiological examination. Results: COPD severity was GOLD class II in 25.0%, class III in 51.7% and class IV in 23.3%; and disease severity was significantly higher in patients with metabolic syndrome. The frequency of COPD exacerbations showed significant increase in group 2 when compared to group 1 (2.17±0.65 vs 1.43±0.57 respectively). In addition, the duration of hospital stay increased significantly in group 2 when compared to group 1 (4.33±0.80 vs 3.37±0.61). Conclusion: metabolic syndrome could play a role in pathogenesis- or may be a consequence of- COPD. Thus, metabolic syndrome had a harmful effect on the outcome of COPD exacerbations.

A fructose-enriched diet has been shown to be associated with an increase in fatty infiltration of liver, kidney, and pancreas. Our objective was to determine the concentration threshold at which a fructose-enriched diet induces damage in these organs. We hypothesized that a 20% fructose-enriched diet will induce steatosis or histopathological changes in the kidneys or pancreas. In this study, 40 Wistar male rats were randomly divided into 4 groups of 10, and each group was assigned a diet of equal quantity (15 g/rat) but of varying fructose amount. The first group (control group) was fed a standardized diet. The second and third groups were fed 10% and 20% fructose-enriched diets, respectively, whereas the fourth group was fed a high-fructose diet (30% fructose). At week 16, the 30% fructose group had the highest percentage of fat-enriched cells (10%) and a significant decrease in adiponectin as compared with week 1 (P .05). Twenty percent of this group developed interstitial fibrosis, but none presented changes in the pancreatic islet structure or fibrosis. The 10% fructose group showed the absence of perisinusoidal and interstitial fibrosis, whereas these were present in the 20% fructose group, but neither group showed significant steatosis (5%) or pancreatic damage. The results suggest that a 20% fructose-enriched diet could be considered as the threshold for inducing kidney and liver damage in the rat. Nutritional interventions to reduce fructose to less than 20% of the total energy intake should be considered to prevent metabolic risks and organ damage.

Hepatic epithelioid hemangioendothelioma (HEH) is a rare tumor that can affect multiple organs. Little is known about the pathophysiology, clinical course and management of this disease. The aim of this study is to determine survival rates and elucidate the role of various prognostic factors and therapeutic modalities as compared to surgery on patients with HEH. A retrospective analysis on patients diagnosed with HEH between 2004 and 2016 was performed utilizing the SEER database. Kaplan–Meier curves were constructed to determine overall and cancer-specific survival, and the log-rank test was used to compare between groups. To explore prognostic factors and treatment outcomes, univariable and multivariable Cox proportional hazard models were developed. A total of 353 patients with HEH (median age: 50.4 years) were identified. The most common surgery performed was liver resection (90.8%). One-year OS in the surgical group and non-surgical group was 86.6% and 61.0%, respectively, while 5-year OS was 75.2% and 37.4%, respectively. On multivariable analysis, surgery emerged as a favorable prognostic factor [HR (95%CI): 0.404 (0.215–0.758) p value = 0.005]. Age > 65 years [HR (95%CI): 2.548 (1.442–4.506) p value = 0.001] and tumor size > 10 cm [HR (95%CI): 2.401 (1.319–4.37) p value = 0.004] were shown to be poor survival prognostic factors. HEH is a rare disease that is poorly understood. Surgical intervention is associated with improved survival rates. Multicenter prospective collaborations are needed to improve our limited knowledge about this neoplasm and determine the optimal treatment strategy.

Background: Candida bloodstream infection (BSI) remains one of the leading causes of BSI in critically ill and immunosuppressed cancer patients. In light of the changing epidemiology and rising resistant species, duration of treatment and appropriate timing of stepdown therapy from intravenous (IV) to oral antifungal agents are crucial for utmost disease control and overall survival. Method: We performed a multicenter retrospective study, with 119 non-neutropenic patients enrolled from four different medical institutions in Brazil, Lebanon ,Spain and the United States, to assess the duration of IV therapy and appropriate time to step down to oral therapy in adult patients, 14 years of age and older, with documented candidemia. The analysis was done using the statistical program R and SAS v9.4. Descriptive statistics are presented as frequencies and tables and the Fisher exact test was used to test the association between the categorical variables: organism, cancer, country, antifungal drug and duration of therapy, and time of step-down. Results: Candida albicans contributed to 45% bloodstream infection versus 55% infection caused Candida non-albicans. The three most common Candida non-albicans are: Candida glabrata 24%, Candida parapsilosis 13% and Candida tropicalis 8%. Most (57%) of the patients were admitted to ICU whereas 52% had underlying malignancy. Multivariate analysis showed that a stay at ICU or an underlying cancer requiring chemotherapy were independently associated with failure and death (p 5 days of treatment (24% mortality - p = 0.75). Conclusion: Our data support the IDSA guidelines in that the total duration of treatment for candidemia should be at least 14 days after a negative blood culture. However, in non-neutropenic cancer patients with candidemia, a step down to oral azole therapy can safely take place early (within 4 days of initiating IV therapy) as long as the patient had clinical and microbiologic resolution of the bloodstream infections.

BACKGROUND Primary care management of hypertension under new guidelines incorporates assessment of cardiovascular disease risk and commonly requires review of electronic health record (EHR) data. Visual analytics can streamline the review of complex data and may lessen the burden clinicians face using the EHR. This study sought to assess the utility of a visual analytics dashboard in addition to EHR in managing hypertension in a primary care setting. METHODS Primary care physicians within an urban, academic internal medicine clinic were tasked with performing 2 simulated patient encounters for hypertension management: the first using standard EHR, and the second using EHR paired with a visual dashboard. The dashboard included graphical blood pressure trends with guideline-directed targets, calculated atherosclerotic cardiovascular disease risk score, and relevant medications. Guideline-appropriate antihypertensive prescribing, correct target blood pressure goal, and total encounter time were assessed. RESULTS We evaluated 70 case simulations. Use of the dashboard with the EHR compared with use of the EHR alone was associated with greater adherence to prescribing guidelines (95% vs. 62%, P < 0.001) and more correct identification of blood pressure target (95% vs. 57%, P < 0.01). Total encounter time fell an average of 121 seconds (95% confidence interval 69–157 seconds, P < 0.001) in encounters that used the dashboard combined with the EHR. CONCLUSIONS The integration of a hypertension-specific visual analytics dashboard with EHR demonstrates the potential to reduce time and improve hypertension guideline implementation. Further widespread testing in clinical practice is warranted.

PurposeTo report a primary objective clinical outcome of ipsilateral breast recurrence following accelerated partial breast irradiation (APBI) in women with triple negative and other high risk breast cancer (as described in 2017 ASTRO guidelines) (i.e., age 40–49, size 2.1–3.0 cm, estrogen receptor negative and invasive lobular breast cancer). Secondary objectives of axillary and regional failure as well as overall survival are also reported.Methods and MaterialPatients from two clinical trials (NCT01185145, NCT01185132) were treated with 38.5 Gy IMRT or 3D-CRT APBI w/3.85 Gy fraction/BID fractionation for 10 fractions. Triple negative and other high risk patients (n=269) were compared to a total of 478 low risk patients which ASTRO defined as “suitable” for APBI. High risk patients, for the purpose of this study, were defined as those who possess one or more high risk criteria: triple negative (n=30), tumor size >2 cm ResultsMedian follow up was 4.0 years for all patients. No significant difference was found for this high-risk cohort at 5 years for ipsilateral breast, or regional recurrences. Axillary recurrence was significantly adversely impacted by triple negative and ER- statuses (p=0.01, p=0.04). There were significant correlations between triple negative type and axillary recurrence on multivariate analysis (p=0.03). Overall survival for all patients was unaffected by any of the high-risk categories.ConclusionThe data from this study suggests that women possessing high risk features are at no more meaningful risk for recurrence than other patients considered to be acceptable for APBI treatment. However, the finding of axillary recurrence in patients with triple negative breast cancer does warrant a degree of caution in proceeding with accelerated partial breast irradiation technique in this patient group.

Objective The aim of this study was to determine the accuracy of the PHILIPS DL8760, an oscillometric blood pressure (BP) measuring device designed for self-measurement in the general population according to the European Society of Hypertension International Protocol (ESH-IP) revision 2010. Participants and methods The PHILIPS DL8760 measures BP at the brachial level. The validation was performed in 33 subjects. The mean age of the participants was 55.8 ± 14 years. SBP 146.1 ± 26 mmHg (range: 103-193), DBP was 86.8 ± 17.0 mmHg (range: 47-123), and arm circumference was 28.3 ± 4.0 cm (range: 22-39). Results The PHILIPS DL8760 fulfilled the criteria of the ESH-IP by passing phases one and two for both SBP measurements and DBP measurements. The device overestimated SBP by 1.5 ± 5.0 mmHg and underestimated DBP by 0.7 ± 3.9 mmHg. Conclusion The PHILIPS DL8760 BP device, with its specially designed cuff covering a broad range of arm circumferences, fulfilled the requirements of the International Protocol Revision 2010.

INTRODUCTION Studies have proposed the use of antibiotics only in cases of acute uncomplicated appendicitis (AUA). However, there remains a paucity of data evaluating this nonoperative approach in the vulnerable frail geriatric population. The aim of this study was to examine long-term outcomes of frail geriatric patients with AUA treated with appendectomy compared with initial nonoperative management (NOP). METHODS We conducted a 1-year (2017) analysis of the Nationwide Readmissions Database and included all frail geriatric patients(age, ≥65 years) with a diagnosis of AUA. Frailty was assessed using the five-factor modified frailty index. Patients were stratified into those undergoing appendectomy at index admission (operative management) versus those receiving antibiotics only without operative intervention (NOP). Propensity score matching in a 1:1 ratio was performed adjusting for patient- and hospital-related factors. RESULTS A total of 5,562 frail geriatric patients with AUA were identified from which a matched cohort of 1,320 patients in each group was obtained. Patients in the NOP and operative management were comparable in terms of age (75.5 ± 7.7 vs. 75.5 ± 7.4 years; p = 0.882) and modified frailty index (0.4 [0.4-0.6] vs. 0.4 [0.4-0.6]; p = 0.526). Failure of NOP management was reported in 18% of patients, 95% of which eventually underwent appendectomy. Over the 6-month follow-up period, patients in the NOP group had significantly higher rates of Clostridium difficile enterocolitis (3% vs. 1%; p < 0.001), greater number of overall hospitalized days (5 [3-9] vs. 4 [2-7] days; p < 0.001), and higher overall costs (US $16,000 [12,000-25,000] vs. US $11,000 [8,000-19,000]; p < 0.001). Patients undergoing appendectomy after failed NOP had significantly higher rates of complications (20% vs. 11%; p < 0.001), mortality (4% vs. 2%; p = 0.019), and appendiceal neoplasm (3% vs. 1%; p = 0.027). CONCLUSION One in six patients failed NOP within 6 months and required appendectomy with subsequent more complications and higher mortality. Appendectomy may offer better outcomes in managing AUA in the frail geriatric population. LEVEL OF EVIDENCE Therapeutic, level IV.

INTRODUCTION Nonoperative management of acute calculous cholecystitis (ACC) in the frail geriatric population is underexplored. The aim of our study was to examine long-term outcomes of frail geriatric patients with ACC treated with cholecystectomy compared with initial nonoperative management. METHODS We conducted a 2017 analysis of the Nationwide Readmissions Database and included frail geriatric (≥65 years) patients with ACC. Frailty was assessed using the five-factor modified frailty index. Patients were stratified into those undergoing cholecystectomy at index admission (operative management [OP]) versus those managed with nonoperative intervention (nonoperative management [NOP]). The NOP group was further subdivided into those who received antibiotics only and those who received percutaneous drainage. Primary outcomes were procedure-related complications in the OP group and 6-month failure of NOP (readmission with cholecystitis). Secondary outcomes were mortality and overall hospital length of stay. RESULTS A total of 53,412 geriatric patients with ACC were identified, 51.0% of whom were frail: 16,791 (61.6%) in OP group and 10,472 (38.4%) in NOP group (3,256 had percutaneous drainage, 7,216 received antibiotics only). Patients were comparable in age (76 ± 7 vs. 77 ± 8 years; p = 0.082) and modified frailty index (0.47 vs. 0.48; p = 0.132). Procedure-related complications in the OP group were 9.3%, and 6-month failure of NOP was 18.9%. Median time to failure of NOP management was 36 days (range, 12-78 days). Mortality was higher in the frail NOP group (5.2 vs. 3.2%; p < 0.001). The NOP group had more days of hospitalization (8 [4-15] vs. 5 [3-10]; p < 0.001). Both receiving antibiotics only (odds ratio, 1.6 [1.3-2.0]; p < 0.001) and receiving percutaneous drainage (odds ratio, 1.9 [1.7-2.2]; p < 0.001) were independently associated with increased mortality. CONCLUSION One in five patients failed NOP and subsequently had complicated hospital stays. Nonoperative management of frail elderly ACC patients may be associated with significant morbidity and mortality. LEVEL OF EVIDENCE Therapeutic, level IV.