bluuebunny/crossref_metadata_2025 huggingface dataset:
40 Years of Hydrogen–Deuterium Exchange Adjacent to Heteroatoms: A Survey
Authors: Roche Maxime , Michelotti Alessia
Published: January 2019

Deuteration of bioactive molecules is gaining more and more attention, especially after the approval of the first deuterated drug (Austedo™) by the US Food and Drug Administration (FDA). Not only is deuteration important for drug development, the amount of deuterium in a molecule is critical for the production of standards in mass spectrometry and the selectivity of the deuteration is mandatory for NMR applications. Very frequently, the molecules involved in these applications contain several heteroatoms. It has been demonstrated that oxygen-, nitrogen-, and more recently, sulfur-containing molecules can be easily deuterated at the α position leading to high deuterium incorporation. In this review we will focus our attention on the historical background and the recent progress made on heteroatom-directed deuteration, with particular attention on the catalysts and the mechanisms that drive such transformations.

1 Introduction

2 Oxygen-Directed Deuteration

3 Nitrogen-Directed Deuteration

4 Sulfur-Directed Deuteration

5 Conclusion
Morpholin-2-one Derivatives via Intramolecular Acid-Catalyzed Hydroamination
Authors: Knight David , Wirth Thomas , Hadi Aldmairi Abdul
Published: January 2019

Substituted morpholin-2-one derivatives were readily obtained in two steps starting from commercially available N-protected amino acids. In a metal-free and practical method, a catalytic amount of trifluoromethanesulfonic acid was sufficient to generate morpholinones under mild reaction conditions in an intramolecular hydroamination reaction in good to excellent yields.
Oxidative Dearomatization and Sigmatropic 1,3-Acyl Shift in Excited State: Aromatics to Embellished cis-Hydrindanes
Authors: Singh Vishwakarma , Sahu Raghaba
Published: January 2019

A stereoselective synthetic route to embellished cis-hydrindanes from simple aromatic precursors is described. Oxidative dearomatization, ring expansion, and photochemical 1,3-acyl shift are the key features of our approach. Oxidative dearomatization of o-(hydroxymethyl)phenols followed by π4s + π2s cycloaddition furnishes bicyclo[2.2.2]octanes with contiguous keto epoxide groups, which upon ring expansion lead to bicyclo[3.2.2]nonanes endowed with a β,γ-enone chromophore. Unbridging of bicyclo[3.2.2]nonanes upon singlet excitation furnishes embellished cis-hydrindanes.
Synthesis of Bullvalenes: Classical Approaches and Recent Developments
Authors: Ferrer Sofia , Echavarren Antonio
Published: January 2019

The goal of this short review is to provide an overview of the different synthetic methodologies applied along the years for the synthesis of bullvalenes, prototypical fluxional molecules that were key in the understanding of valence tautomerism phenomena. Some interesting applications of these unique shapeshifting compounds are also presented.

1 Introduction

2 Classical Syntheses of Bullvalenes

3 Recent Developments in the Synthesis of Bullvalenes

4 Applications of Bullvalenes

5 Conclusion
Engineered Cytochrome c-Catalyzed Lactone-Carbene B–H Insertion
Authors: Chen Kai , Huang Xiongyi , Zhang Shuo-Qing , Zhou Andrew , Kan S. B. Jennifer , Hong Xin , Arnold Frances
Published: January 2019

Previous work has demonstrated that variants of a heme protein, Rhodothermus marinus cytochrome c (Rma cyt c), catalyze abiological carbene boron–hydrogen (B–H) bond insertion with high efficiency and selectivity. Here we investigated this carbon–boron bond-forming chemistry with cyclic, lactone-based carbenes. Using directed evolution, we obtained a Rma cyt c variant BORLAC
that shows high selectivity and efficiency for B–H insertion of 5- and 6-membered lactone carbenes (up to 24,500 total turnovers and 97.1:2.9 enantiomeric ratio). The enzyme shows low activity with a 7-membered lactone carbene. Computational studies revealed a highly twisted geometry of the 7-membered lactone carbene intermediate relative to 5- and 6-membered ones. Directed evolution of cytochrome c together with computational characterization of key iron-carbene intermediates has allowed us to expand the scope of enzymatic carbene B–H insertion to produce new lactone-based organoborons.
Stereocontrol in the Synthesis of β-Lactams Arising from the Interlocked Structure of Benzylfumaramide-Based Hydrogen-Bonded [2]Rotaxanes
Authors: Martinez-Cuezva Alberto , Lopez-Leonardo Carmen , Alajarin Mateo , Berna Jose
Published: January 2019

β-Lactams are highly valuable compounds due to their antibiotic activity. Among the number of well-established methodologies for building this privileged scaffold, our research group has settled on a novel synthetic approach for their preparation. This Account focuses on our latest progress in the synthesis of these compounds through a novel base-promoted intramolecular cyclization of benzylfumaramide-based rotaxanes. The mechanical bond plays a significant role in the process by activating the cyclization inside the macrocycle void, avoiding the formation of byproducts and fully controlling the diastereoselectivity. Further investigations on this transformation led to the formation of ­enantioenriched 2-azetidinones. The cyclization of enantiopure interlocked α-methylbenzylfumaramides allows the formation of two new stereogenic centers in the lactamic four-membered ring, one of them a quaternary carbon, keeping the initial configuration of the chiral group of the starting material.

1 Introduction

1.1 Mechanically Interlocked Molecules and Applications

1.2 Chemical Stabilization of the Mechanical Bond

2 Literature Methods for 4-exo-trig Ring Closures of Fumaramides for the Synthesis of β-Lactams

3 Our First Encounter with Interlocked β-Lactams

3.1 An Unexpected Result in Our Laboratory

3.2 Finding the Optimal Reaction Conditions

3.3 Elucidating the Effects of the Mechanical Bond

4 Diastereoselective Synthesis of Interlocked and Non-Interlocked β-Lactams

5 Asymmetric Cyclization of Enantiopure Interlocked Fumaramides

6 Conclusions
Stereoselective Synthesis of Maresin-Like Lipid Mediators
Authors: Hong Song , Lu Yan , Morita Masao , Saito Shun , Kobayashi Yuichi , Jun Bokkyoo , Bazan Nicolas , Xu Xiaoming , Wang Yapin
Published: January 2019

14S,22-Dihydroxy-docosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid (maresin-L1) and 14R,22-dihydroxy-docosa-4Z,7Z,10Z, 12E,16Z,19Z-hexaenoic acid (maresin-L2) were chemically synthesized. They were identical to activated macrophage-produced counterparts and their total synthesis was highly stereoselective, as revealed by chiral LC-UV-MS/MS analysis. The synthesis involved the following steps: (1) kinetic resolution of a racemic allylic alcohol by the asymmetric epoxidation; (2) transformation of the epoxy alcohol to γ-hydroxyenal derivative; and (3) the Wittig reaction to furnish the Z-olefin.
Use of the Rochester Epidemiology Project for Clinical Research in Colon and Rectal Surgery
Authors: Cima Robert , Lightner Amy
Published: January 2019

The Rochester Epidemiology Project (REP), a longitudinal population-based database, is the largest epidemiologic database in the world. Originally established at Mayo Clinic in Rochester, Minnesota, the REP has been instrumental in defining the natural history of disease states and the impact of treatment in a well-defined population. In the United States, the REP has made important contributions to the colon and rectal literature, largely because healthcare is fragmented with no unique identifier to longitudinally follow-up with a patient throughout the system over his or her lifespan. Investigation with the REP has provided insight to the economic burden associated with inflammatory bowel disease, the benefit of screening for colorectal cancer, and the natural history of Mekel's and diverticular disease. In addition to practice changing research, the REP can be used as a model for future linkage systems in the United States.
Clinical Research Using the National Inpatient Sample: A Brief Review of Colorectal Studies Utilizing the NIS Database
Authors: Kelley Katherine , Tsikitis V.
Published: January 2019

The National Inpatient Sample (NIS) is the largest collection of longitudinal hospital care data in the United States and is sponsored by the Agency for Healthcare Research and Quality. The data are collected from state organizations, hospital associations, private organizations, and the federal government. This database has been used in more than 400 disease-focused studies to examine health care utilization, access, charges, quality, and outcomes of care. The database has been maintained since 1988, making it one of the oldest on hospital data. The focus of this review is to explore and discuss the use of NIS database in colorectal surgery research and to formulate a simplified guide of the data captured for future researchers.
Safety and Efficacy of Perampanel as Adjunctive Therapy in Patients with Refractory Focal Epilepsy Over 12 Months: Clinical Experience in a Real-World Setting
Authors: Rinaldi Fabrizio , De Maria Giovanni
Published: January 2019

Background The main purpose of this study is to assess efficacy and tolerability of perampanel (PER), a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonist, as an add-on treatment in adult patients with refractory focal-onset seizures.

Patients and Methods A prospective, open label, observational study was conducted in patients with refractory focal-onset seizures treated with PER at our Epilepsy Unit, from May 2015 to February 2016. Patients were followed up for 1 year. Frequency of seizure and tolerability was assessed every 3 months. Patients were under a polytherapy, and the mean number of concomitant antiepileptic drugs (AEDs) at PER initiation was 2.9.

Results We consecutively enrolled 52 patients (M/F = 18/34). Three were lost on follow-up. Mean age was 38.7 years, with a mean duration of disease of 28.1 years. After 1 year of treatment, 57.14% reported a 50% or greater reduction in seizure frequency; five (10.21%) were seizure free. Six (12.25%) patients reported a reduction lower than 50%. Mean dosage of PER was 7.57 mg. Thirty-one patients were taking enzyme-inducing AEDs (carbamazepine, oxcarbazepine, phenytoin). In this subgroup, the responder rate was 45.2%. Twenty-one patients reported side-effects, most frequently somnolence (11), vertigo/ataxia (6), and aggressiveness (5). Eleven (22.4%) patients reduced or discontinued at least one concomitant AED, while the electroencephalography improved in four (8.16%). Sixteen (32.65%) patients withdrew PER, after a mean duration of 163 days, the mean dosage being 6.4 mg (range 4–12).

Conclusions Adjunctive PER can achieve clinically meaningful improvement, or even seizure freedom, in almost two-thirds of patients suffering from refractory focal-onset epilepsies. It seems similarly safe and well-tolerated. Enzyme-inducing AEDs may limit the efficacy of PER.
Smart Medication
™, an Electronic Diary for Surveillance of Haemophilia Home Care and Optimization of Resource Distribution
Authors: Mondorf Wolfgang , Eichler Hermann , Fischer Ronald , Holstein Katharina , Klamroth Robert , Nimtz-Talaska Antje , Wermes Cornelia , Richter Heinrich , Severin Kai
Published: January 2019

Im Folgenden wird das elektronische Substitutionstagebuch smart medication
™ vorgestellt, sowie eine Analyse der damit erhobenen Echtzeitdaten. Seit 2012 wurde smart medication
™ von 663 Patienten in 30 Deutschen Hämophilie Zentren (HZ) genutzt. Daten aus 9 HZ wurden für die nachfolgende Analyse zusammengeführt. Entsprechend der Mittelwerte des jährlichen Faktorenverbrauchs und der Anzahl von Gelenkblutungen wurden vier Gruppen gebildet. Die größte Gruppe (A, 42%) war die mit unterdurchschnittlichem Faktorenverbrauch und weniger als 2,25 Gelenkblutungen pro Jahr. Die zweitgrößte Gruppe (B, 32%) zeigte ähnlich niedrige Blutungsraten bei überdurchschnittlichem Faktorenverbrauch. Eine Reduktion des Faktorenverbrauchs bei einigen dieser Patienten wäre ggf. möglich. Hingegen könnten andere Patienten mit häufigen Gelenkblutungen bei gleichzeitig niedrigem Faktorenverbrauch (D, 13%), von einer Erhöhung der Dosis profitieren. Patienten mit häufigen Gelenkblutungen trotz überdurchschnittlichem Faktorenverbrauch (C, 13%) benötigen eine intensivierte Behandlung jenseits einer Dosisanpassung, wie pharmakokinetisch adaptierte Dosisanpassungen oder orthopädische Maßnahmen. Mit Hilfe von smart medication
™ können Patienten, die eine Änderung ihrer laufenden Behandlung benötigen, lange vor der nächsten Vorstellung im HZ identifiziert werden. Der ständig wachsende Datenpool erlaubt zudem eine kontinuierliche Analyse von Echtzeitdaten und damit eine Optimierung der zur Verfügung stehenden Ressourcen.
The Neuroanatomy of Reproduction: Seeing Is Believing
Authors: Vlasak Alexander L. , Schaub Amelia , Barry Margaret E. Robin , Rhoton-Vlasak Alice S.
Published: January 2019

The brain is the central controller of reproduction and the menstrual cycle. Reproductive endocrinologists spend their days treating patients with perturbations in reproduction as a result of pituitary diseases and manipulate pituitary hormones to enhance fertility and quality of life. Microscopic neuroanatomical images will allow a better understanding of how a tumor in the pituitary might affect vision, or a mass in the brain might cause amenorrhea. Clinical correlations that are taught every day become much clearer once the anatomical relationships are explored. The objective of this pictorial tour is to elucidate anatomical and clinical relationships while showcasing the neuroanatomy of reproduction.
Outcomes Measures in Hip Arthroscopy
Authors: Trofa David , Westermann Robert , Hagen Mia , Rosneck James , Lynch T. , Sonnenfeld Julian
Published: January 2019

As techniques in hip arthroscopy are rapidly advancing, patient-reported outcome (PRO) measures are becoming an integral part of measuring treatment effectiveness. The movement toward developing valid and reproducible outcome measurement tools has shifted from the traditional physician-derived data to patient-centered scores. As a result, the current standard for measuring the effectiveness of any surgical treatment is to use an outcome that reflects the patient's perspective. This review highlights the quality of the questionnaire properties and their application to the patient undergoing hip arthroscopy. Although the Modified Harris Hip Score (mHHS) has historically been used as the traditional outcome measure for hip surgery, new PRO tools in the field have been developed. The Nonarthritic Hip Score (NAHS) was intended for the younger, active patient to assess hip pain and function without radiographic findings. The Copenhagen Hip and Groing Outcome Score (HAGOS) and Hip Disability and Osteoarthritis Outcome Score (HOOS) both incorporated hip related quality of life measures. The Hip Outcome Score (HOS) was developed to assess the treatment outcomes of hip arthroscopy in young-to-middle-aged individuals. Finally, the International Hip Outcome Tool-33 (iHOT-33) addresses the outcomes of treatment in young active patients with hip disorders, in conjuction with the multicenter arthroscopy of the hip outcomes research network. Among the available literature comparing PROs in this patient population, the iHOT-33, HOS, and HOOS remain reliable, valid, and consistent available PRO tools for hip arthroscopy surgery.
Concussions: Activity Avoidance and Rest Recommendation
Authors: Salvatore Anthony , Banks Russell
Published: January 2019

Research surrounding rest recommendations for the concussed population is discussed. Rest is compared with activity avoidance, which is common in several chronic disease and traumatic injury types. The case is made for rest recommendations tailored to each head-injured individual. Research is presented which suggests that activity in the initial stages of concussion recovery may be beneficial in reducing postconcussion symptom duration and severity. Furthermore, a gradual increase in activity may potentially aid in returning to normal daily activity sooner than those who avoid both physical and cognitive activity during the acute stage of a traumatic brain injury. Finally, the current state of rest recommendations is reviewed and anticipated future directions are discussed.
Malignant Pleural Effusions: Management Options
Authors: Porcel Jose , Rahman Najib , McCracken David
Published: January 2019

Malignant pleural effusion (MPE) represents advanced metastatic malignancy and is associated with poor median survival. Incidence remains high and continues to rise, in part due to changing population demographics. This therefore represents a significant health care burden. Management is predominantly palliative in nature and multiple interventions are available within conventional treatment paradigms, all of which are proven to result in statistically significant patient benefit. This article further explores the methods available in the management of MPE along with the pitfalls, complications, and alternatives. Recent advances within the field are discussed with an exploration of likely future directions, including the role of ultrasound as a prospective predictor and the role of intrapleural fibrinolytic therapy.
Sticky Platelet Syndrome: 35 Years of Growing Evidence
Authors: Holly Pavol , Stasko Jan , Kubisz Peter
Published: January 2019

Since the identification of antithrombin deficiency by Egeberg in 1956, ongoing research in prothrombotic defects continues to progress. Interestingly, past research has predominantly focused on coagulation factors and not on other components of the hemostatic system. The possible role of platelet function defects in the development of thrombotic events was suggested for the first time in the late 1970s, when an increased platelet adhesiveness and aggregation after epinephrine (EPI) and adenosine diphosphate (ADP) was found in a group of patients with unexplained transient ischemic attack. Clinical evidence for other types of thrombotic events (e. g. myocardial infarction, ischemic stroke, optic neuropathy, and pregnancy-related complications) with similar laboratory findings was provided by several authors in the 1980s and 1990s, with Drs. Mammen and Bick undertaking key research. The familial occurrence was noted as well, and the term sticky platelet syndrome was introduced by Holliday in 1983 to describe the defect. The term in our present understanding describes a thrombophilic qualitative platelet disorder characterized by increased in vitro platelet aggregation after the addition of very low concentrations of ADP and/or EPI and an increased risk of thromboembolic (predominantly arterial) events. Although now recognized for 35 years, significant issues, namely its etiology, inheritance, epidemiology, and diagnostics, remain a matter of vigorous debate. The aim of this review is to summarize the history, key works, and present understanding of the syndrome and to outline present-day diagnostic and clinical problems and controversies.
Management of Asymptomatic Popliteal Artery Aneurysms
Authors: Kim Tanner , Sumpio Bauer
Published: January 2019

Popliteal artery aneurysms (PAAs) are the most common peripheral artery aneurysms. They are frequently symptomatic and are associated with high rates of morbidity and limb loss. PAA can be treated by open or endovascular means, although there are no specified recommendations guiding treatment choice. This article delineates many of the differences between open and endovascular repair of asymptomatic PAA, and highlights several key articles comparing open and endovascular repair to guide decision making. Proper diagnosis and choice of repair can lead to good outcomes in the treatment of asymptomatic PAA.
Influence of Amlodipine on Haemostatic Measurements during Clopidogrel Treatment in Patients with Coronary Artery Disease
Authors: Koh Jin-Sin , Park Yongwhi , Ahn Jong-Hwa , Kang Min Gyu , Kim Kye-Hwan , Bae Jae Seok , Park Hyun Woong , Jang Jeong Yoon , Park Jeong Rang , Hwang Seok-Jae , Kwak Choong Hwan , Hwang Jin-Yong , Tantry Udaya , Gurbel Paul , Jeong Young-Hoon
Published: January 2019

Amlodipine has a potential to reduce clopidogrel bioactivation through the cytochrome P450 3A4 enzyme in vivo, but the clinical impact of this interaction remains controversial. This randomized, open-label, two-period, crossover study was performed to evaluate the influence of amlodipine on the haemostatic profiles of high-risk patients during clopidogrel treatment. We recruited 40 Asian patients (Male/Female: n = 36/4) receiving clopidogrel (75 mg/day), aspirin (100 mg/day) and rosuvastatin for at least 6 months following percutaneous coronary intervention. Patients were randomly assigned to receive either 5 mg daily amlodipine or not for 2 weeks, and then were crossed over to the other treatment for 2 weeks. Haemostatic measurements were conducted with the VerifyNow assay and thromboelastography (TEG). Primary endpoint was P2Y12 Reaction Units (PRU) during on- versus off-amlodipine treatment. The on-amlodipine strategy showed higher level of PRU compared with the off-amlodipine strategy (176.8 ± 75.4 vs. 150.7 ± 65.5 PRU; ∆mean: 26.1 PRU; ∆95% confidence interval [CI]: 4.5–47.7 PRU; p = 0.019). Platelet-fibrin clot strength measured by TEG was lower during on- versus off-amlodipine treatment (7,712 ± 1,889 vs. 8,559 ± 2,174 dyne/cm2; ∆mean: –847 dyne/cm2; ∆95% CI: –1,632 to –62 dyne/cm2; p = 0.035). After amlodipine discontinuation, 27 patients (67.5%) showed a decrease in PRU, which was associated with ‘PRU ≥ 160 on-amlodipine’ in multivariate analysis (odds ratio: 62.014; 95% CI: 2.302–1670.328; p = 0.014). In conclusion, amlodipine increases platelet reactivity and decreases platelet-fibrin clot strength during clopidogrel treatment. In addition, the effect of amlodipine discontinuation on clopidogrel responsiveness is associated with on-amlodipine platelet reactivity.
The Reach and Feasibility of an Interactive Lung Cancer Screening Decision Aid Delivered by Patient Portal
Authors: Dharod Ajay , Bellinger Christina , Foley Kristie , Case L. Doug , Miller David
Published: January 2019

Objective Health systems could adopt population-level approaches to screening by identifying potential screening candidates from the electronic health record and reaching out to them via the patient portal. However, whether patients would read or act on sent information is unknown. We examined the feasibility of this digital health outreach strategy.

Methods We conducted a single-arm pragmatic trial in a large academic health system. An electronic health record algorithm identified primary care patients who were potentially eligible for lung cancer screening (LCS). Identified patients were sent a patient portal invitation to visit a LCS interactive Web site which assessed screening eligibility and included a decision aid. The primary outcome was screening completion. Secondary outcomes included the proportion of patients who read the invitation, visited the interactive Web site, and completed the interactive Web site.

Results We sent portal invitations to 1,000 patients. Almost all patients (86%, 862/1,000) read the invitation, 404 (40%) patients visited the interactive Web site, and 349 patients (35%) completed it. Of the 99 patients who were confirmed screening eligible by the Web site, 81 made a screening decision (30% wanted screening, 44% unsure, 26% declined screening), and 22 patients had a chest computed tomography completed.

Conclusion The digital outreach strategy reached the majority of patient portal users. While the study focused on LCS, this digital outreach approach could be generalized to other health needs. Given the broad reach and potential low cost of this digital strategy, future research should investigate best practices for implementing the system.
Limitations in the Assessment of Prosthesis-Patient Mismatch
Authors: Amorim Paulo A. , Diab Mahmoud , Walther Mario , Färber Gloria , Hagendorff Andreas , Bonow Robert O. , Doenst Torsten
Published: January 2019

Background Prosthesis-patient mismatch (PPM) after aortic valve replacement (AVR) may affect survival but data are conflicting. It is assessed by relating effective orifice area (EOA) to body surface area (EOAi). EOA is patient-specific as the result of flow-velocity times area at the individual patient's outflow tract levels (LVOTA) divided by trans-prosthetic flow velocity. However, some studies use projected EOAs (i.e., valve size associated EOAs from other patient populations) to assess how PPM affects outcome.

Methods We analyzed 76 studies addressing hemodynamic outcome and/or mortality after bioprosthetic AVR.

Results In 48 studies, projected or measured EOA for calculation of EOAi and PPM assessment was used (of which 25 demonstrated an effect on survival). We identified 28 additional studies providing measured EOA values and the corresponding Bernoulli's pressure gradients after AVR. Despite EOA being a patient-specific parameter, 77% of studies assessing a PPM impact on survival used projected EOAs. The 28 studies are providing measured EOA values and the corresponding Bernoulli's pressure gradients in patients after AVR showed a highly significant, linear relationship between EOA and Bernoulli's gradient. Considering this relationship, it is surprising that relating EOA to body surface area (BSA) (EOAi) is standard but relating pressure gradients to BSA is not.

Conclusion We conclude that the majority of studies assessing PPM have used false assumptions because EOA is a patient-specific parameter and cannot be transferred to other patients. In addition, the use of EOAi to assess PPM may not be appropriate and could explain the inconsistent relation between PPM and survival in previous studies.
Clinical Characteristics and Neuroimaging Findings in Internal Jugular Venous Outflow Disturbance
Authors: Zhou Da , Ding Jiayue , Asmaro Karam , Pan Liqun , Ya Jingyuan , Yang Qi , Fan Chunqiu , Ding Yuchuan , Ji Xunming , Meng Ran
Published: January 2019

Recently, internal jugular vein stenosis (IJVS) is gaining increasing attention from clinical researchers due to a series of confounding symptoms that impair the quality of life in affected individuals but cannot be explained by other well-established causes. In this study, we aimed to elucidate the clinical features, neuroimaging characteristics and pathogenesis of IJVS, and explore their possible correlations, in attempt to provide useful clues for clinical diagnosis and treatment. Forty-three eligible patients with unilateral or bilateral IJVS confirmed by contrast-enhanced magnetic resonance venography of the brain and neck were enrolled in this study. Magnetic resonance imaging along with magnetic resonance angiography or computed tomography angiography was applied to identify the radiological pattern of parenchymal or arterial lesions. Cerebral perfusion and metabolism were evaluated by single-photon emission computed tomography (SPECT). Of the 43 patients (46.0 ± 16.0 years old; 30 female), 14 (32.6%) had bilateral and 29 had unilateral IJVS. The common clinical symptoms at admission were tinnitus (60.5%), tinnitus cerebri (67.6%), headache (48.8%), dizziness (32.6%), visual disorders (39.5%), hearing impairment (39.5%), neck discomfort (39.5%), sleep disturbance (60.5%), anxiety or depression (37.5%) and subjective memory decline (30.2%). The presence of bilateral demyelination changes with cloudy-like appearance in the periventricular area and/or centrum semiovale was found in 95.3% (41/43) patients. SPECT findings showed that 92.3% (24/26) patients displayed cerebral perfusion and metabolism mismatch, depicted by bilaterally and symmetrically reduced cerebral perfusion and increased cerebral glucose consumption. IJVS may contribute to alterations in cerebral blood flow and metabolism, as well as white matter lesion formation, all of which may account for its clinical manifestations.
Antiplatelet Therapy versus Anticoagulation after Surgical Bioprosthetic Aortic Valve Replacement: A Systematic Review and Meta-Analysis
Authors: An Kevin , Belley-Cote Emilie , Um Kevin , Gupta Saurabh , McClure Graham , Jaffer Iqbal , Pandey Arjun , Spence Jessica , Van der Wall Sake , Eikelboom John , Whitlock Richard
Published: January 2019

Background The optimal antithrombotic therapy after surgical bioprosthetic aortic valve replacement (BAVR) is uncertain. We conducted a systematic review and meta-analysis of observational studies and randomized controlled trials (RCTs) comparing antiplatelet therapy and anticoagulation in patients with surgical BAVR.

Methods We searched Cochrane CENTRAL, MEDLINE and EMBASE from inception to 3 November 2017 for studies evaluating antiplatelet therapy versus anticoagulation early after surgical BAVR. We performed title and abstract screening, full-text review, risk of bias evaluation and data collection independently and in duplicate. We evaluated overall quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework, and pooled data using a random effects model.

Results We identified 2 RCTs (n = 397) and 5 observational studies (n = 2,012) meeting our eligibility criteria. The mean follow-up for all outcomes was 3 months in RCTs, and 10 months for observational studies. Antiplatelet compared with anticoagulant therapy demonstrated a trend towards fewer major bleeds in RCTs (relative risk [RR], 0.34; 95% confidence interval [CI], 0.11–1.04, p = 0.06, I
2 = 0%, low quality evidence), and significantly fewer major bleeds in observational studies (RR, 0.34; 95% CI, 0.20–0.58, p ≤ 0.0001, I
2 = 0%, very low quality evidence), but stroke, thromboembolism and mortality did not show a significant difference in either RCTs or observational studies.

Conclusion Antiplatelet therapy demonstrated reduced bleeding risk with no negative effects on stroke, thromboembolism or mortality compared with anticoagulation therapy after surgical BAVR. Our confidence in the results is reduced by the low quality of the available evidence.
Automatic Detection of Front-Line Clinician Hospital Shifts: A Novel Use of Electronic Health Record Timestamp Data
Authors: Dziorny Adam , Orenstein Evan , Lindell Robert , Hames Nicole , Washington Nicole , Desai Bimal
Published: January 2019

Objective Excess physician work hours contribute to burnout and medical errors. Self-report of work hours is burdensome and often inaccurate. We aimed to validate a method that automatically determines provider shift duration based on electronic health record (EHR) timestamps across multiple inpatient settings within a single institution.

Methods We developed an algorithm to calculate shift start and end times for inpatient providers based on EHR timestamps. We validated the algorithm based on overlap between calculated shifts and scheduled shifts. We then demonstrated a use case by calculating shifts for pediatric residents on inpatient rotations from July 1, 2015 through June 30, 2016, comparing hours worked and number of shifts by rotation and role.

Results We collected 6.3 × 107 EHR timestamps for 144 residents on 771 inpatient rotations, yielding 14,678 EHR-calculated shifts. Validation on a subset of shifts demonstrated 100% shift match and 87.9 ± 0.3% overlap (mean ± standard error [SE]) with scheduled shifts. Senior residents functioning as front-line clinicians worked more hours per 4-week block (mean ± SE: 273.5 ± 1.7) than senior residents in supervisory roles (253 ± 2.3) and junior residents (241 ± 2.5). Junior residents worked more shifts per block (21 ± 0.1) than senior residents (18 ± 0.1).

Conclusion Automatic calculation of inpatient provider work hours is feasible using EHR timestamps. An algorithm to assess provider work hours demonstrated criterion validity via comparison with scheduled shifts. Differences between junior and senior residents in calculated mean hours worked and number of shifts per 4-week block were also consistent with differences in scheduled shifts and duty-hour restrictions.
Exercise Training Improved Longitudinal Intrinsic Left Ventricle Function in Heart Failure with Preserved Ejection Fraction
Authors: Purwowiyoto Sidhi , Purwowiyoto Budhi , Soesanto Amiliana , Santoso Anwar
Published: January 2019

Exercise improves morbidity, fatality rate, and quality of life in heart failure with low ejection fraction, but fewer data available in heart failure with preserved ejection fraction (HFPEF).

The purpose of this study is to test the hypothesis that exercise training might improve the longitudinal intrinsic left ventricular (LV) function in HFPEF patients.

This quasi-experimental study had recruited 30 patients with HFPEF. Exercise training program had been performed for a month with a total of 20 times exercise sessions and evaluated every 2 weeks. Echocardiography was performed before sessions, second week and fourth week of exercise training. Six-minute walk tests (6MWTs) and quality-of-life variables using Minnesota living with HF scoring and the 5-item World Health Organization Well-Being Index scoring were measured before and after exercise as well.

Left ventricular filling pressure, represented by the ratio of early diastolic mitral flow velocity/early diastolic annular velocity and left atrial volume index, improved during exercise. The longitudinal intrinsic LV function, represented by four-chamber longitudinal strain, augmented during exercise (p < 0.001). Aerobic capacity, measured by 6MWT, increased significantly (p = 0.001). Quality of life improved significantly during exercise (p < 0.001).

Exercise training was suggested to improve the longitudinal intrinsic LV function and quality of life in HFPEF. Clinical Trial Registration: ACTRN12614001042639.
Third Head of the Biceps Brachii Muscle and a Communication between the Musculocutaneous and Median Nerves: A Case Report
Authors: Dussin Caroline , Moyses Lucas , Siqueira Sávio
Published: January 2019

Many authors have reported and classified several anatomical variations between the musculocutaneous (Mc) and median (Me) nerves, regarding their origin, number, and proximity with the coracobrachialis muscle. There also are, in the scientific community, records classifying the origin of supernumerary heads of the biceps brachii muscle. However, the occurrence of both aforementioned variations in the same arm is very uncommon. During a routine dissection of the right upper limb of a male cadaver, a third head of the biceps brachii was found originating from the fibers of the brachialis muscle, as well as a communicating branch between the Mc and the Me nerves, in the same limb. The objective of the present case report is to describe these multiple variations found, relating them and discussing their relevant clinical implications.
PCSK9 in Haemostasis and Thrombosis: Possible Pleiotropic Effects of PCSK9 Inhibitors in Cardiovascular Prevention
Authors: Paciullo Francesco , Momi Stefania , Gresele Paolo
Published: January 2019

Since increased cholesterol levels are crucial in determining the development of atheroma, their reduction represents a mainstay in primary and secondary cardiovascular prevention. The most recent spectacular advancement in cholesterol-lowering therapy is represented by proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors. Although their benefit over currently available treatments has been ascribed primarily to their strong low-density lipoprotein (LDL)-cholesterol reducing action, several clues suggest that PCSK9 inhibitors may also influence platelet function and blood coagulation. PCSK9 knockout mice develop less venous and arterial thrombosis and show reduced in vivo platelet activation upon arterial injury. In patients with acute coronary syndromes (ACSs) treated with P2Y12 inhibitors, a direct association between PCSK9 serum levels and residual platelet reactivity was found. A direct correlation between urinary excretion of 11-dehydro-thromboxane-B2, a marker of in vivo platelet activation, and circulating PCSK9 levels was reported in patients with atrial fibrillation. Moreover, recombinant human PCSK9 added in vitro to human platelets potentiated activation induced by weak agonists. Finally, blood clotting factor VIII (FVIII), which is associated with stroke and ACS risk, is cleared from the circulation by members of the LDL receptor (LDLR) family. Given that PCSK9 degrades LDLR, it is conceivable that PCSK9 inhibitors by enhancing the expression of LDLR may slightly decrease circulating FVIII, in this way contributing to the prevention of cardiovascular events. This review aims to discuss the possible and hypothetical interactions between PCSK9 and the haemostatic system and to examine the possible pleiotropic effects of PCSK9 inhibitors in cardiovascular prevention.
Wideband Tympanometry
Authors: Dutta Nilotpal , Biswas Anirban
Published: January 2019

Traditional tympanometry done with 226 Hz probe tone frequency has some inherent defects and limitations due to which it does not give a very true picture of the middle ear status, and tympanometric findings are often very deceptive. It is not uncommon for otologists to find that on opening the middle ear, the pathology in the middle ear is very different from what they had expected from tympanometric findings. This is because the 226 or 220 Hz, that is used for the traditional single tone tympanometry is based on physical convenience, i.e., practicalities in carrying out the test rather than on test performance, i.e., the diagnostic efficacy of the test. The 226 Hz tympanometry is a poor predictor of middle ear effusions in babies and will be wrong in approximately 50% of cases and diagnosis of ossicular chain discontinuity by type A tympanogram is correct in only about 40% cases, if not lesser. In most cases of otosclerosis, though there is a middle ear stiffness, the tympanometric findings with traditional tympanometry show normal compliance, which is not expected in stiffness of the middle ear. Tympanometry is basically to identify common middle ear pathologies, such as middle ear effusion, ossicular chain discontinuity and otosclerosis. However, if in these very cases the diagnostic efficacy is so poor, then the objective of the test is lost. Traditional tympanometry has a lot of limitations and fallacies. These issues led scientists to sharpen the diagnostic efficacy of tympanometry and the final outcome of the research is wide band tympanometry (WBT). The special advantages of WBT, its difference from traditional single frequency tympanometry, and its clinical utility are presented in this article. Here, we review the concept of WBT, the basic mechanism, and its vast clinical applications. Most of the deficiencies of traditional tympanometry have been overcome by WBT. Not only that, the scope of tympanometry has been further widened by WBT and in addition to diagnosing middle ear pathologies with much more confidence, it can also be used for postoperative monitoring using non-pressurized wideband absorbance.
Visceral Artery Aneurysms: Decision Making and Treatment Options in the New Era of Minimally Invasive and Endovascular Surgery
Authors: Xu Jun , Sharafuddin Mel , Corson John , Hosn Maen
Published: January 2019

The abdominal viscera blood supply is derived from anterior branches of the abdominal aorta. Visceral artery aneurysms (VAAs) include aneurysms of the following arteries and their branches: the celiac artery, the hepatic artery, the splenic artery, the superior mesenteric artery, the inferior mesenteric artery, the pancreaticoduodenal artery, and the gastroduodenal artery. Overall VAAs comprise < 2% of all types of arterial aneurysms. Asymptomatic VAAs are now being encountered more frequently due to the widespread use of advanced diagnostic abdominal imaging. The incidental finding of a VAA frequently leaves clinicians with a dilemma as to the best course of management. The focus of this review is on current treatment options and management guidelines for both symptomatic and asymptomatic VAAs.
Sensing Glycans as Biochemical Messages by Tissue Lectins: The Sugar Code at Work in Vascular Biology
Authors: Kaltner Herbert , Gabius Hans-Joachim
Published: January 2019

Although a plethora of players has already been revealed to be engaged in the haemostatic system, a fundamental consideration of the molecular nature of information coding can give further explorations of the mechanisms of blood clotting, platelet functionality and vascular trafficking direction. By any measures, looking at ranges of occurrence and of potential for structural versatility, at strategic positioning to influence protein and cell sociology as well as at dynamics of processing and restructuring for phenotypic variability, using sugars as an alphabet of life for generating the glycan part of glycoconjugates is a success story. The handiwork by the complex system for glycan biosynthesis renders biochemical messages of exceptionally high coding capacity available. They are read and translated into cellular effects by receptors termed lectins. The different levels of regulation on both sides, that is, glycan and lectin, establish an intriguingly fine-tuned capacity for functional pairing. The emerging insights into the highly branched routes of glycosylation, into lectin structures up to complete characterization in solution and the shape of lectin networks, first obtained for the three selectins, now extended to considering many other C-type lectins, galectins and siglecs, as well as into intra- and inter-family cross-talk and cooperations are sure to push boundaries in our understanding of the molecular basis of haemostasis.
Transorbital Approach for Improved Access in the Management of Paranasal Sinus Mucoceles
Authors: Miller Craig , Berens Angelique , Patel Sapna A. , Humphreys Ian M. , Moe Kris S.
Published: January 2019

Introduction Paranasal sinus mucoceles result from obstruction of mucous glands resulting in a cystic fluid collection that expands and encroaches upon surrounding structures. Transnasal endoscopic marsupialization has largely replaced open resection. However, mucoceles located in the orbital region or the lateral frontal sinus continue to be difficult to approach via the transnasal approach alone and often require additional approaches, such as the frontal trephine. This study sought to investigate the feasibility of the transorbital technique as an adjunct to traditional transnasal approaches in the management of paranasal sinus mucoceles.

Methods A retrospective case series of paranasal sinus mucoceles approached with a transorbital technique from a tertiary care center.

Results From 2008 to 2016, 17 patients were treated with a transorbital approach for 20 mucoceles. Of note, 24% of the patients in our series had undergone previous surgical management of the mucocele (nontransorbital approach), representing revision cases. Most mucoceles involved the frontal sinus (82%). The total complication rate was 6%. We observed no new or worsened diplopia, ptosis, or permanent visual loss. Recurrence rate was 6%.

Conclusions The endoscopic transorbital approach is a feasible complement to transnasal approaches for treatment of mucoceles located in technically challenging locations. We have demonstrated that transorbital approaches can be performed with no resultant orbital damage, visual change, ptosis, or permanent diplopia. While most patients can be treated with a standard transnasal approach, the transorbital approach can be used as part of a multiportal strategy for those with difficult to access mucoceles. Future prospective studies are needed to further characterize patient selection and outcomes.
Migration of Umbilical Venous Catheters
Authors: Plooij-Lusthusz Anneloes M. , van Vreeswijk Nick , van Stuijvenberg Margriet , Bos Arend F. , Kooi Elisabeth M. W.
Published: January 2019

Objective Migration of umbilical venous catheters (UVCs) after initial correct position has been described. The aim of this study was to assess the incidence of malposition of the tip of the UVCs at 24 to 36 hours postinsertion.

Study Design Retrospective analysis of all neonates who had UVC placement in a 14-month period. The primary outcome was the rate of UVCs incorrectly positioned 24 to 36 hours after initial correct placement, defined as the UVC tip below or more than 5 mm above the level of the right diaphragm on a thoracoabdominal X-ray.

Results We included 86 neonates with a median (range) birth weight of 1,617 (535–5,000) grams, and gestational age of 31 (24–42) weeks. Of the 80 UVCs that were further analyzed, only in 38 (48%) of 80 patients, the tip of the UVC still had a correct position 24 to 36 hours after initial placement. In 22 (28%) of 80 patients, the UVCs had a position that was too high and in 20 (25%) that was too low.

Conclusion More than half of UVCs migrated at 24 to 36 hours postinsertion to positions known to have higher complication rates. We, therefore, recommend follow-up evaluation at 24 to 36 hours postinsertion, to prevent complications from malposition.
Highly Elevated Quantitative D-Dimer Assay Values Increase the Likelihood of Venous Thromboembolism
Authors: Francis Samuel , Limkakeng Alexander , Zheng Hui , Hollander Judd , Fermann Gregory , Parry Blair , Lovecchio Frank , Werner Nikos , Schellong Sebastian , Kabrhel Christopher
Published: January 2019

Objectives In patients with suspected venous thromboembolism (VTE), the D-dimer assay is commonly utilized as part of the workup. The assay is primarily used to determine whether to proceed with radiographic imaging. We compared D-dimer levels in patients suspected of having VTE. We hypothesized that higher D-dimer values predict a higher likelihood of subsequent VTE diagnosis.

Methods We conducted a secondary analysis of a multinational, prospective observational study of low- to intermediate-risk adult patients presenting to the emergency department with suspicion of VTE. Demographic and clinical data were collected in a structured manner. Advanced imaging including ultrasound, computed tomography (CT) pulmonary angiography, and ventilation/perfusion scanning was obtained at the discretion of the treating physicians. Imaging was evaluated by board-certified radiologists in real time. D-dimer values' bins were evaluated using a logistic regression model.

Results We evaluated 1,752 patients for suspected deep vein thrombosis (DVT), with 191 (10.4%) DVT positive. We evaluated 1,834 patients for suspected pulmonary embolism (PE), with 108 (5.9%) PE positive. Higher D-dimer values in both groups were associated with higher likelihood of subsequent VTE diagnosis, with D-dimer values > 3,999 ng/mL in both groups having the highest incidence of VTE. More than 50% of those patients were VTE positive.

Conclusions Increasing D-dimer values predict increased likelihood of being found VTE positive in this patient population. Among those in the highest D-dimer category, > 3,999 ng/mL, over half of patients were VTE positive. Further research could determine additional nuance in D-dimer as a tool to work up suspected VTE.
Persistence of Neonatal Brachial Plexus Palsy among Nulliparous Versus Parous Women
Authors: McLaren Rodney , Chang Kate , Ankumah Nana-Ama , Yang Lynda , Chauhan Suneet
Published: January 2019

Objective Our objective was to compare persistence of neonatal brachial plexus palsy (NBPP) at 1 and 2 years in children of nulliparous versus parous women.

Study Design We conducted a retrospective cohort study of children diagnosed with NBPP followed at the University of Michigan, Interdisciplinary Brachial Plexus Program (UM-BPP). Self-reported demographics, delivery history, including birth weight (BW) < versus ≥ 9 lbs, and presence of shoulder dystocia (SD) were recorded. Student's t-test and Chi-square test with odds ratio (OR) with 95% confidence intervals (CI) were calculated for comparisons of maternal, neonatal, and peripartum characteristics.

Results Of 337 children with NBPP, 43% (146) were of nulliparas and 57% (191) of multiparas. At 1 year, children with persistent NBPP were similar in both groups (87% vs. 88%, aOR 1.357, 95% CI: 0.297–6.208). Persistent NBPP was not significantly different among nulliparous and multiparous women at 2 years (97% vs. 92% respectively, aOR 0.079, 95% CI: 0.006–1.050).

Conclusion In one of the largest cohorts of NBPP, maternal parity did not influence the likelihood of NBPP persistence at 1 and 2 years.