bluuebunny/crossref_metadata_2025_split huggingface dataset:
The DIVE/DPV registries: evolution of empagliflozin use in clinical practice in Germany
Authors: Bramlage Peter , Tittel Sascha R , Wagner Christian , König Kerstin , Raddatz Dirk , Weber-Lauffer Rosmarie , Erath Diether , Hilgenberg Jost , Spies Carsten , Danne Thomas , Gabler Maximilian , Foersch Johannes , Ley Ludwin , Seufert Jochen 
Published: July 2020

IntroductionEmpagliflozin reduced morbidity and mortality in patients with type 2 diabetes mellitus (T2DM) in clinical trials. A registry study was undertaken to describe evolution of patient characteristics and assess the real-world effectiveness/safety of empagliflozin.Research design and methodsData from the Diabetes Patienten Verlaufsdokumentation (DPV)/Diabetes Versorgungsevaluation (DIVE) registries on 9571 adults with T2DM (registered in 2014–2019) receiving empagliflozin were used. Patients were grouped according to the following: early users (group 1; n=505) received empagliflozin before the EMPA-REG OUTCOME study publication (mid-September 2015); intermediate users (group 2; n=2961) started empagliflozin after the EMPA-REG OUTCOME publication but before the European Medicines Agency label change (from mid-September 2015 to mid-January 2017); and late users (group 3; n=6105) started empagliflozin after mid-January 2017. Data on clinical and treatment characteristics were collected.ResultsOver time, the proportion of recipients aged <65 years decreased (71.1% vs 54.4% among early and late adopters), male patients increased (from 50.9% to 66.5%), body mass index (mean±SD) decreased (from 35.5±6.7 to 32.7±6.6 kg/m2), proportion with cardiovascular morbidities increased (from 20.4% to 26.4%), and mean estimated glomerular filtration rate decreased (from 83.2±19.5 to 78.5±21.1 mL/min/1.73 m2) (all p<0.001). Patients increasingly received empagliflozin in combination with metformin (60.8% vs 68.6% of early and late adopters; p<0.001), glucagon-like peptide-1 (GLP-1) agonists (11.0 vs 14.1%; p<0.001) or insulin (34.3% vs 49.9%; p<0.001). Empagliflozin was generally added to existing antidiabetic regimens. Six months after empagliflozin initiation, the mean glycated hemoglobin (HbA1c) decreased by 0.4%, the proportion of patients with HbA1c <6.5% increased (19.2% vs 12.8%), and the mean fasting plasma glucose decreased (155.8±49.7 vs 168.0±55.1 mg/dL) (all p<0.001). No significant changes in rates of severe hypoglycemia and no cases of diabetic ketoacidosis were seen.ConclusionsOver time, empagliflozin is being prescribed to a broader patient range in routine practice, is usually added to existing antidiabetic regimens, and is increasingly used in combination with metformin, GLP-1 agonists and/or insulin. Empagliflozin had a beneficial effect on glycemic control, with no increase in hypoglycemia.
“Caring About Me": a pilot framework to understand patient-centered care experience in integrated care - a qualitative study
Authors: Youssef Alaa , Wiljer David , Mylopoulos Maria , Maunder Robert , Sockalingam Sanjeev 
Published: July 2020

ObjectiveThe aim of this study is to examine patients’ experiences in integrated care (IC) settings.DesignQualitative study using semistructured interviews.SettingsTwo IC sites in Toronto, Canada: (1) a community-based primary healthcare centre, supporting patients with hepatitis C and comorbid mental health and substance use issues; and (2) an integrated bariatric surgery programme, an academic tertiary care centre.ParticipantsThe study included patients (n=12) with co-occurring mental and physical health conditions. Seven participants (58%) were female and five (42%) were male.MethodsTwelve indepth semistructured interviews were conducted with a purposeful sample of patients (n=12) with comorbid mental and physical conditions at two IC sites in Toronto between 2017 and 2018. Data were collected and analysed using grounded theory approach.ResultsFour themes emerged in our analysis reflecting patients’ perspectives on patient-centred care experience in IC: (1) caring about me; (2) collaborating with me; (3) helping me understand and self-manage my care; and (4) personalising care to address my needs. Patients’ experiences of care were primarily shaped by quality of relational interactions with IC team members. Positive interactions with IC team members led to enhanced patient access to care and fostered personalising care plans to address unique needs.ConclusionThis study adds to the literature on creating patient-centredness in IC settings by highlighting the importance of recognising patients’ unique needs and the context of care for the specific patient population.
Dual neutralisation of IL-17F and IL-17A with bimekizumab blocks inflammation-driven osteogenic differentiation of human periosteal cells
Authors: Shah Mittal , Maroof Asher , Gikas Panos , Mittal Gayatri , Keen Richard , Baeten Dominique , Shaw Stevan , Roberts Scott J 
Published: July 2020

ObjectivesInterleukin (IL)-17 signalling has been shown to be a key regulator of disease in ankylosing spondylitis (AS) with several IL-17 blockers currently clinically approved. Despite this, the role of IL-17 in bone pathology is poorly understood. This study aimed to investigate IL-17 signalling in the context of pathological bone formation.MethodsA biomimetic human periosteum-derived cell (hPDC) model of osteogenic differentiation was used in combination with recombinant IL-17 cytokines, T-cell supernatants or serum from patients with AS. IL-17A, IL-17F and bimekizumab monoclonal antibodies were used to block IL-17 cytokine action.ResultsRecombinant IL-17A and IL-17F are pro-osteogenic with respect to hPDC differentiation. T helper 17 or γδ-T cell supernatants also potently stimulated in vitro bone formation, which was blocked deeper by dual inhibition of IL-17A and IL-17F than by neutralisation of IL-17A or IL-17F individually. Osteogenic blockade may be due to an increase in expression of the Wnt antagonistDKK1. Interestingly, osteocommitment was also induced by serum obtained from patients with AS, which was also abrogated by dual neutralisation of IL-17A and IL-17F.ConclusionsThese data show for the first time that IL-17A and IL-17F enhance in vitro osteogenic differentiation and bone formation from hPDCs, inhibition of which may offer an attractive therapeutic strategy to prevent pathological bone formation.
Safety and Clinical Activity of Atezolizumab Plus Bevacizumab in Patients with Ovarian Cancer: A Phase Ib Study
Authors: Moroney John W. , Powderly John , Lieu Christopher H. , Bendell Johanna C. , Eckhardt S. Gail , Chang Ching-Wei , Molinero Luciana , Spahn Jessica , Williams Patrick , Lin Yvonne G. , Hodi F. Stephen 
Published: July 2020

Abstract

Purpose:
Atezolizumab has shown antitumor activity in patients with ovarian cancer. Dual blockade of programmed death-ligand 1 (PD-L1) and VEGF enhances anticancer immunity and augments antitumor activity in several cancers. The safety and efficacy of atezolizumab plus bevacizumab were evaluated in patients with ovarian cancer.

Patients and Methods:
In this open-label, multicenter phase Ib study, patients with platinum-resistant ovarian cancer received intravenous atezolizumab (1,200 mg) and bevacizumab (15 mg/kg) once every 3 weeks. The primary endpoint was safety; secondary endpoints included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Exploratory biomarkers were also evaluated.

Results:
Twenty patients received treatment. Treatment-related adverse events occurred in 19 patients (95%); seven (35%) had grade 3/4 events. No grade 5 events occurred. The safety profile of atezolizumab plus bevacizumab was consistent with those of the individual agents. Two patients (10%) discontinued treatment because of pneumonitis and small bowel obstruction. Three patients had partial responses of 11.3–18.9 months' duration; the ORR was 15%. Eight patients (40%) had stable disease, hence the disease control rate was 55%. The median DOR was not reached (95% confidence interval, 11.3–not reached). Median PFS was 4.9 months (range, 1.2–20.2); median OS was 10.2 months (range, 1.2–26.6). No association was seen between treatment response and PD-L1 expression, tumor histology, or number of prior therapies.

Conclusions:
Atezolizumab plus bevacizumab led to durable responses and/or disease stabilization in some patients with platinum-resistant ovarian cancer; the safety profiles were consistent with those of each agent.
Association of the Novel Inflammatory Marker GlycA and Incident Heart Failure and Its Subtypes of Preserved and Reduced Ejection Fraction
Authors: Jang Sunyoung , Ogunmoroti Oluseye , Ndumele Chiadi E. , Zhao Di , Rao Vishal N. , Fashanu Oluwaseun E. , Tibuakuu Martin , Otvos James D. , Benson Eve-Marie , Ouyang Pamela , Michos Erin D. 
Published: July 2020

Background:
GlycA, a nuclear magnetic resonance composite marker of systemic inflammation, reflects serum concentration and glycosylation state of main acute phase reactants. Prior studies have shown plasma GlycA levels were associated with cardiovascular disease even after adjusting for other inflammatory markers. However, little is known about the association of GlycA with the heart failure (HF) subtypes: heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction. We examined the association of GlycA with incident HF and its subtypes in a multiethnic cohort.

Methods:
We studied 6507 Multi-Ethnic Study of Atherosclerosis participants aged 45 to 84 without baseline cardiovascular disease or HF who had data on GlycA and incident hospitalized HF. We used multivariable-adjusted Cox hazards models to evaluate the association of GlycA with incident total HF, HFpEF, and heart failure with reduced ejection fraction. Models were adjusted for sociodemographics, cardiovascular disease risk factors, and inflammatory biomarkers.

Results:
The mean (SD) for age was 62 (10) years and for GlycA was 375 (82) μmol/L; 53% women. Over a median follow-up of 14.0 years, participants in the highest quartile of GlycA, compared with the lowest, experienced increased risk of developing any HF (hazard ratio, 1.48 [95% CI, 1.01–2.18]) in fully adjusted models. However, this increased risk was only seen for HFpEF (2.18 [1.15–4.13]) and not heart failure with reduced ejection fraction [1.06 (0.63–1.79)]. There was no significant interaction by sex, age, or race/ethnicity.

Conclusions:
GlycA was associated with an increased risk of any HF, and in particular, HFpEF. Future studies should examine mechanisms that might explain differential association of GlycA with HF subtypes, and whether therapeutic lowering of GlycA can prevent HFpEF development.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT00005487.
MDM2-Mediated Ubiquitination of Angiotensin-Converting Enzyme 2 Contributes to the Development of Pulmonary Arterial Hypertension
Authors: Shen Hui , Zhang Jiao , Wang Chen , Jain Pritesh P. , Xiong Mingmei , Shi Xinxing , Lei Yuyang , Chen Shanshan , Yin Qian , Thistlethwaite Patricia A. , Wang Jian , Gong Kaizheng , Yuan Zu-Yi , Yuan Jason X.-J. , Shyy John Y.-J. 
Published: July 2020

Background:
Angiotensin-converting enzyme 2 (ACE2) converts angiotensin II, a potent vasoconstrictor, to angiotensin-(1–7) and is also a membrane protein that enables coronavirus disease 2019 (COVID-19) infectivity. AMP-activated protein kinase (AMPK) phosphorylation of ACE2 enhances ACE2 stability. This mode of posttranslational modification of ACE2 in vascular endothelial cells is causative of a pulmonary hypertension (PH)–protective phenotype. The oncoprotein MDM2 (murine double minute 2) is an E3 ligase that ubiquitinates its substrates to cause their degradation. In this study, we investigated whether MDM2 is involved in the posttranslational modification of ACE2 through its ubiquitination of ACE2, and whether an AMPK and MDM2 crosstalk regulates the pathogenesis of PH.

Methods:
Bioinformatic analyses were used to explore E3 ligase that ubiquitinates ACE2. Cultured endothelial cells, mouse models, and specimens from patients with idiopathic pulmonary arterial hypertension were used to investigate the crosstalk between AMPK and MDM2 in regulating ACE2 phosphorylation and ubiquitination in the context of PH.

Results:
Levels of MDM2 were increased and those of ACE2 decreased in lung tissues or pulmonary arterial endothelial cells from patients with idiopathic pulmonary arterial hypertension and rodent models of experimental PH. MDM2 inhibition by JNJ-165 reversed the SU5416/hypoxia-induced PH in C57BL/6 mice. ACE2-S680L mice (dephosphorylation at S680) showed PH susceptibility, and ectopic expression of ACE2-S680L/K788R (deubiquitination at K788) reduced experimental PH. Moreover, ACE2-K788R overexpression in mice with endothelial cell–specific AMPKα2 knockout mitigated PH.

Conclusions:
Maladapted posttranslational modification (phosphorylation and ubiquitination) of ACE2 at Ser-680 and Lys-788 is involved in the pathogenesis of pulmonary arterial hypertension and experimental PH. Thus, a combined intervention of AMPK and MDM2 in the pulmonary endothelium might be therapeutically effective in PH treatment.
Immunothrombotic Dysregulation in COVID-19 Pneumonia Is Associated With Respiratory Failure and Coagulopathy
Authors: Nicolai Leo , Leunig Alexander , Brambs Sophia , Kaiser Rainer , Weinberger Tobias , Weigand Michael , Muenchhoff Maximilian , Hellmuth Johannes C. , Ledderose Stephan , Schulz Heiko , Scherer Clemens , Rudelius Martina , Zoller Michael , Höchter Dominik , Keppler Oliver , Teupser Daniel , Zwißler Bernhard , von Bergwelt-Baildon Michael , Kääb Stefan , Massberg Steffen , Pekayvaz Kami , Stark Konstantin 
Published: July 2020

Background:
Severe acute respiratory syndrome corona virus 2 infection causes severe pneumonia (coronavirus disease 2019 [COVID-19]), but the mechanisms of subsequent respiratory failure and complicating renal and myocardial involvement are poorly understood. In addition, a systemic prothrombotic phenotype has been reported in patients with COVID-19.

Methods:
A total of 62 subjects were included in our study (n=38 patients with reverse transcriptase polymerase chain reaction–confirmed COVID-19 and n=24 non–COVID-19 controls). We performed histopathologic assessment of autopsy cases, surface marker–based phenotyping of neutrophils and platelets, and functional assays for platelet, neutrophil functions, and coagulation tests, as well.

Results:
We provide evidence that organ involvement and prothrombotic features in COVID-19 are linked by immunothrombosis. We show that, in COVID-19, inflammatory microvascular thrombi are present in the lung, kidney, and heart, containing neutrophil extracellular traps associated with platelets and fibrin. Patients with COVID-19 also present with neutrophil-platelet aggregates and a distinct neutrophil and platelet activation pattern in blood, which changes with disease severity. Whereas cases of intermediate severity show an exhausted platelet and hyporeactive neutrophil phenotype, patients severely affected with COVID-19 are characterized by excessive platelet and neutrophil activation in comparison with healthy controls and non–COVID-19 pneumonia. Dysregulated immunothrombosis in severe acute respiratory syndrome corona virus 2 pneumonia is linked to both acute respiratory distress syndrome and systemic hypercoagulability.

Conclusions:
Taken together, our data point to immunothrombotic dysregulation as a key marker of disease severity in COVID-19. Further work is necessary to determine the role of immunothrombosis in COVID-19.
Presenting the past in Middle Indic
Authors: Hoose Anahita 
Published: July 2020

Abstract
Up to three verbal categories are available for encoding past tense in Middle Indic: inherited finite pasts (lost in younger languages), old past passive participles, and morphological presents. I explore aspectual factors governing the choice of one verb form in preference to another in four texts in Pāli and Jaina-Māhārāṣṭrī, showing that finite pasts (where present) are compatible with multiple aspectual readings, participles almost always have perfective or anterior aspect, and presents have an association with imperfective aspect (exceptionless in Pāli but not in Jaina-Māhārāṣṭrī).
The Transcendental Subaltern
Authors: Taylor Byron 
Published: July 2020

Abstract
Was Immanuel Kant Russian? More striking than the fact itself is the length of time it was overlooked: following historian Alexander Etkind’s research on the topic, this paper details Königsberg’s occupation by the Russian Empire, considering the possibilities of reinstating Kant’s thought in the postcolonial tradition, more specifically that of the subaltern (as framed by Gayatri Chakravorty Spivak). Taking this colonial context into account via a range of historical records and correspondences, I argue for a postcolonial reinterpretation and re-evaluation of the philosopher’s work, beginning with his famous essay on the topic of enlightenment. In what ways does this pertain to the enlightenment, as Kant sees it, and the way he distinguishes between the public and private spheres? Furthermore, how does Spivak’s reading of Kant overlook the subaltern status that she herself defines?
Savi Scout Radar Localization Versus Wire Localization for Breast Biopsy Regarding Positive Margin, Complication, and Reoperation Rates
Authors: Tingen Joseph S. , McKinley Brian P. , Rinkliff John M. , Cornett Wendy R. , Lucas Claiborne 
Published: July 2020

Background Breast cancer is the most commonly diagnosed noncutaneous malignancy and remains the second leading cause of cancer deaths in women. The Savi Scout (Cianna Medical, Merit Medical Systems, Inc. South Jordan, UT) is a wireless, nonradioactive, wave reflection implant system that enables surgeons to remove targeted breast lesions. Our study aims to be the largest comparison of wire and Savi Scout localization techniques for positive margin, complication, and reoperation rates. Methods Single-institution retrospective review of 512 patients that had Savi Scout Surgical Guidance System breast lesion biopsy or wire localized breast biopsy from May 2017 to December 2018. A RedCaps database was created and reviewed for outcomes. Results For 320 Savi scout patients, margins were positive or less than 1 mm in 18 cases (5.6%). 17 (5.3%) patients required reoperation. Surgical site occurrence was found in 7 (2.1%) patients, and 2 patients required intervention (0.6%). For 175 wire localization patients, margins were positive or less than 1 mm in 24 patients, and all required reoperation (13.7%). A surgical site occurrence was found in 13 (7.4%) patients and 5 patients required intervention (2.8%). Discussion In our series, the Savi Scout localization system resulted in a lower rate of positive margins, reoperation, and surgical site occurrence. These data suggest that Savi Scout localization is a reasonable replacement to wire localization for breast lesions and might produce superior results.
Pelvic Binder Utilization in Combat Casualties: Does It Matter?
Authors: Parker William J. , Despain Robert W. , Delgado Adam , Rodriguez Carlos J. , Baird Dean , Elster Eric A. , Bradley Matthew J. 
Published: July 2020

Introduction The purpose of this study was to evaluate the utilization of pelvic binders, the proper placement of binders, and to determine any differences in blood product transfusions between combat casualties with and without a pelvic binder identified on initial imaging immediately after the injury. Methods We conducted a retrospective review of all combat-injured patients who arrived at our military treatment hospital between 2010 and 2012 with a documented pelvic fracture. Initial imaging (X-ray or computed tomography) immediately after injury were evaluated by 2 independent radiologists. Young-Burgess (YB) classification, pelvic diastasis, correct binder placement over the greater trochanters, and the presence of a pelvic external fixator (ex-fix) was recorded. Injury severity score (ISS), whole blood, and blood component therapy administered within the first 24-hours after injury were compared between casualties with and without a pelvic binder. Results 39 casualties had overseas imaging to confirm and radiographically classify a YB pelvic ring injury. The most common fracture patterns were anteroposterior (53%) and lateral compression (28%). 49% (19/39) did not have a binder or ex-fix identified on initial imaging or in any documentation after injury. Ten patients had a binder, with 30% positioned incorrectly over the iliac crest. ISS (34 ± 1.6) was not statistically different between the binder and the no-binder group. Pubic symphysis diastasis was significantly lower in the binder group (1.4 ± 0.2 vs 3.7 ± 0.5, P < .001). There was a trend toward decreased 24-hour total blood products between the binder and no-binder groups (75 ± 11 vs 82 ± 13, P = .67). This was due to less cryoprecipitate in the binder group (6 ± 2 vs 19 ± 5, P = .01). Conclusions Pelvic binder placement in combat trauma may be inconsistent and an important area for continued training. While 24-hour total transfusions do not appear to be different, no-binder patients received significantly more cryoprecipitate.
A Comparison of Prehospital Nonphysician and Hospital Physician Placed Tube Thoracostomy
Authors: Harrell Kevin N. , Brooks Dylan E. , Palm Preston H. , Cowart Jonathan T. , Maxwell Robert , Barker Donald 
Published: July 2020

Background Prehospital chest decompression can be a lifesaving procedure in severe chest trauma. Studies investigating prehospital chest decompression are mostly European where physicians are assigned to prehospital care units. This report is one of the first to compare demographics and outcomes in patients undergoing prehospital chest decompression by trained aeromedical nonphysician personnel to hospital chest decompression by physicians. Methods Prehospital tube thoracostomy (PTT) patients were identified from January 2014 to January 2019 and were matched in a 1:2 ratio based on age, Injury Severity Score (ISS), and chest Abbreviated Injury Score (AIS) to patients who underwent hospital tube thoracostomy (HTT) within 24 hours of admission. Results Forty-nine PTT patients were matched to 98 HTT patients. PTT patients had lower admission Glasgow Coma Scale (GCS), a higher rate of pre-chest tube needle decompression, and higher level 1 trauma activation. PTT were placed sooner (21.9 vs 157.0 minutes, P < .001). Rates of tube malposition, organ injury, tube dislodgement, empyema, and hospital-acquired pneumonia over the course of hospital admission were not significantly different between the 2 groups. PTT patients had longer intensive care unit length of stay (LOS), but similar hospital LOS, and overall mortality. Discussion This report demonstrates that PTT is performed sooner than hospital placed tubes. Complication rates associated with tube thoracostomy and patient outcomes were not statistically different between PTT and HTT groups.