bluuebunny/crossref_metadata_2025 huggingface dataset:
Lack of Association between Poor Glycemic Control in T2DM and Subclinical Hypothyroidism
Authors: Sharma Pragya , Sinha Rashmi , Prasad Anupa , Mitra J. K.
Published: September 2020

Background. Hypothyroidism is a highly prevalent and multifactorial disorder and has been implicated in the causation of dyslipidemia, dermatological diseases, atherosclerosis, and myocardial dysfunction, as well as endothelial dysfunction. The relationship between subclinical hypothyroidism and type 2 diabetes mellitus is not well established. In the present study, we attempt to find out the prevalence of subclinical hypothyroidism in type 2 diabetes mellitus and its association with glycemic control. Materials and Methods. This was an observational study in which 205 consecutive patients of T2DM visiting the outpatient department of medicine were recruited. Serum TSH, free thyroxine, free triiodothyronine, and lipid profile, as well as HbA1c assays, were done in the study participants, and they were categorized into three groups by HbA1c: <7%, 7–9%, and >9%. Results. There is a high prevalence of subclinical hypothyroidism in type 2 DM patients. Mean HbA1c in diabetics without SCH was 7.89%, whereas it was 8.33% in diabetics with SCH. This difference was statistically not significant. TSH was not found to be significantly associated with HbA1c. Conclusion. High prevalence of SCH in T2DM patients suggests that there is a need for regular follow-up to check the progression of SCH to overt hypothyroidism. High serum TSH is not a predictor of poor glycemic control.
Research on Evaluation Index and Application of Rockburst Risk in Deep Strip Mining
Authors: Jiang Bangyou , Ji Hongguang , Fu Long , Gu Shitan , Zou Tong , Lu Jiaxin
Published: September 2020

The practice shows that deep strip mining induces rockburst disaster easily. Accurately evaluating rockburst risk of the strip coal pillar is of great significance for ensuring the safety of deep strip mining. In this paper, the catastrophe mechanics model was used to analyze the abrupt instability condition of strip coal pillar. And the three indicators that are the medium stiffness ratio (k) of the elastic and plastic zone in the coal pillar, the plastic zone width ratio (aY), and the elastic deformation index (Uq) of core zone were put forward with considering the geometry size of coal pillar. Based on the 3202 panel of Gucheng Coal Mine, the evolution characteristics of rockburst risk of coal pillar under different mining widths and coal pillar widths were studied by numerical simulation. The evaluation result shows that the strip coal pillar of the 3202 panel is in danger of strong rockburst, which is more in line with the actual situation than the results of the traditional rockburst tendency identification test and comprehensive index method. These three indicators can be regarded as important indicators to evaluate the rockburst risk in the strip mining engineering field. Based on that, the design principle of strip mining in Gucheng Coal Mine was put forward, which is considered an important reference for similar cases.
Experimental Investigation of Dynamic Compression Mechanical Properties of Frozen Fine Sandstone
Authors: Wu Jiehao , Wang Haibo , Zong Qi , Xu Ying
Published: September 2020

Aiming at the dynamic mechanical properties of weakly cemented fine sandstone in the rich water‐bearing strata in western China under dynamic loading, a 50 mm rod diameter separation Hopkinson pressure bar (SHPB) test was used to study the Paleogene fine sandstone in a coal mine in Ningxia. The system carried out the impact compression tests of −15°C, −20°C, and −30°C and the average strain rate of 28 s−1–83 s−1 and obtained the dynamic compressive strength of the frozen fine sandstone specimens under different test conditions. The strain curve and the fracture morphology were analyzed for the relationship between dynamic peak stress, peak strain, dynamic strength growth coefficient (DIF), and fracture morphology and strain rate. The results show that the peak stress of frozen fine sandstone increases from the decrease of freezing temperature under the same average strain rate. The peak stress of the specimen increases from the increase in the average strain rate of the same freezing temperature. The failure modes of specimen are mainly divided into axial splitting tensile failure and compression crushing failure. To the splitting tensile failure and the compression crushing failure, the main factors determining the two failure modes are the strain rate, while the temperature affects the severity of the impact damage. In the load strain rate and temperature range, the DIF of the frozen fine sandstone is linearly correlated with the strain rate, and the lower the temperature, the slower the growth rate of the DIF.
YAP-Mediated Repression of HRK Regulates Tumor Growth, Therapy Response, and Survival Under Tumor Environmental Stress in Neuroblastoma
Authors: Shim Jenny , Lee Jasmine Y. , Jonus Hunter C. , Arnold Amanda , Schnepp Robert W. , Janssen Kaitlyn M. , Maximov Victor , Goldsmith Kelly C.
Published: September 2020

Following chemotherapy and relapse, high-risk neuroblastoma tumors harbor more genomic alterations than at diagnosis, including increased transcriptional activity of the Yes-associated protein (YAP), a key downstream component of the Hippo signaling network. Although YAP has been implicated in many cancer types, its functional role in the aggressive pediatric cancer neuroblastoma is not well-characterized. In this study, we performed genetic manipulation of YAP in human-derived neuroblastoma cell lines to investigate YAP function in key aspects of the malignant phenotype, including mesenchymal properties, tumor growth, chemotherapy response, and MEK inhibitor response. Standard cytotoxic therapy induced YAP expression and transcriptional activity in patient-derived xenografts treated in vivo, which may contribute to neuroblastoma recurrence. Moreover, YAP promoted a mesenchymal phenotype in high-risk neuroblastoma that modulated tumor growth and therapy resistance in vivo. Finally, the BH3-only protein, Harakiri (HRK), was identified as a novel target inhibited by YAP, which, when suppressed, prevented apoptosis in response to nutrient deprivation in vitro and promoted tumor aggression, chemotherapy resistance, and MEK inhibitor resistance in vivo. Collectively, these findings suggest that YAP inhibition may improve chemotherapy response in patients with neuroblastoma via its regulation of HRK, thus providing a critical strategic complement to MEK inhibitor therapy.

Significance:

This study identifies HRK as a novel tumor suppressor in neuroblastoma and suggests dual MEK and YAP inhibition as a potential therapeutic strategy in RAS-hyperactivated neuroblastomas.
CSPG4-Specific CAR.CIK Lymphocytes as a Novel Therapy for the Treatment of Multiple Soft-Tissue Sarcoma Histotypes
Authors: Leuci Valeria , Donini Chiara , Grignani Giovanni , Rotolo Ramona , Mesiano Giulia , Fiorino Erika , Gammaitoni Loretta , D'Ambrosio Lorenzo , Merlini Alessandra , Landoni Elisa , Medico Enzo , Capellero Sonia , Giraudo Lidia , Cattaneo Giulia , Iaia Ilenia , Pignochino Ymera , Basiricò Marco , Vigna Elisa , Pisacane Alberto , Fagioli Franca , Ferrone Soldano , Aglietta Massimo , Dotti Gianpietro , Sangiolo Dario
Published: September 2020

Purpose:

No effective therapy is available for unresectable soft-tissue sarcomas (STS). This unmet clinical need prompted us to test whether chondroitin sulfate proteoglycan 4 (CSPG4)-specific chimeric antigen receptor (CAR)-redirected cytokine-induced killer lymphocytes (CAR.CIK) are effective in eliminating tumor cells derived from multiple STS histotypes in vitro and in immunodeficient mice.

Experimental Design:

The experimental platform included patient-derived CAR.CIK and cell lines established from multiple STS histotypes. CAR.CIK were transduced with a retroviral vector encoding second-generation CSPG4-specific CAR (CSPG4-CAR) with 4-1BB costimulation. The functional activity of CSPG4-CAR.CIK was explored in vitro, in two- and three-dimensional STS cultures, and in three in vivo STS xenograft models.

Results:

CSPG4-CAR.CIK were efficiently generated from patients with STS. CSPG4 was highly expressed in multiple STS histotypes by in silico analysis and on all 16 STS cell lines tested by flow cytometry. CSPG4-CAR.CIK displayed superior in vitro cytolytic activity against multiple STS histotypes as compared with paired unmodified control CIK. CSPG4-CAR.CIK also showed strong antitumor activity against STS spheroids; this effect was associated with tumor recruitment, infiltration, and matrix penetration. CSPG4-CAR.CIK significantly delayed or reversed tumor growth in vivo in three STS xenograft models (leiomyosarcoma, undifferentiated pleomorphic sarcoma, and fibrosarcoma). Tumor growth inhibition persisted for up to 2 weeks following the last administration of CSPG4-CAR.CIK.

Conclusions:

This study has shown that CSPG4-CAR.CIK effectively targets multiple STS histotypes in vitro and in immunodeficient mice. These results provide a strong rationale to translate the novel strategy we have developed into a clinical setting.
Cardioversion Safety – Are We Doing Enough?
Authors: Khatami Mohsen , Pope Marita Knudsen , Le Page Sophie , Radic Petra , Schirripa Valentina , Grundvold Irene , Atar Dan
Published: September 2020

There is a considerable periprocedural risk of thromboembolic events in atrial fibrillation patients undergoing cardioversion, and treatment with anticoagulants is therefore a hallmark of cardioversion safety. Based on retrospective subgroup analyses and prospective studies, non-vitamin K anticoagulants are at least as efficient as vitamin K-antagonists in preventing thromboembolic complications after cardioversion. The risk of thromboembolic complications after cardioversion very much depends on the comorbidities in a given patient, and especially heart failure, diabetes, and age >75 years carry a markedly increased risk. Cardioversion has been considered safe within a 48-h time window after onset of atrial fibrillation without prior treatment with anticoagulants, but recent studies have set this practice into question based on e.g. erratic debut assessment of atrial fibrillation. Therefore, a simple and more practical approach is here suggested, where early cardioversion is performed only in hemodynamically unstable patients.
Hip Arthroscopy in a Baseball Catcher without the Use of a Perineal Post: A Crossover Case Report
Authors: Hagerty Michael P. , Skelley Nathan W.
Published: September 2020

A 17-year-old Caucasian male high school baseball catcher presented with bilateral hip and groin pain of insidious onset over a 4-year period. Following appropriate physical exam and radiographic testing, bilateral labral tears secondary to cam type femoroacetabular impingement was diagnosed. Arthroscopic corrective surgeries were performed 4 months apart by a single specialized sports medicine orthopedic surgeon. One hip arthroscopic procedure utilized a well-padded perineal traction post and was associated with neuropraxic complications during recovery. The second hip arthroscopic procedure was performed with the table in 15° of Trendelenburg for traction without a perineal traction post and no neuropraxia was noted during recovery. The patient reported that outcomes and postoperative radiographic studies were similar bilaterally; however, perineal nerve neuralgias with the second hip arthroscopy were not reported. While other studies have described the use of post-less traction for mitigation of perineal nerve compression during hip arthroscopic procedures, this crossover observational report is the first to the authors’ knowledge demonstrating both neuropraxia and lack of neuropraxia in a single patient undergoing the same procedure bilaterally where the only difference is the usage of perineal traction posts.
Psychosocial Risk and Its Association With Outcomes in Continuous-Flow Left Ventricular Assist Device Patients
Authors: DeFilippis Ersilia M. , Breathett Khadijah , Donald Elena M. , Nakagawa Shunichi , Takeda Koji , Takayama Hiroo , Truby Lauren K. , Sayer Gabriel , Colombo Paolo C. , Yuzefpolskaya Melana , Uriel Nir , Farr Maryjane A. , Topkara Veli K.
Published: September 2020

Background:

Advanced heart failure therapies such as left ventricular assist device (LVAD) implantation require intricate follow-up and complex care. We sought to explore the burden of psychosocial risk factors among patients with LVAD and their impact on postimplant outcomes using the Interagency Registry for Mechanically Assisted Circulatory Support.

Methods:

Adult patients in the Interagency Registry for Mechanically Assisted Circulatory Support requiring durable LVAD between 2008 and 2017 were included. Individuals were determined to have psychosocial risk if they had one of the following: (1) limited social support; (2) limited cognition; (3) substance abuse (alcohol and drug); (4) severe psychiatric disease (including major depression and other major psychiatric diagnosis); and (5) repeated noncompliance. Univariate and multivariate Cox proportional hazard regression models were used to analyze predictors of survival and complications.

Results:

A total of 15 403 continuous-flow LVAD recipients were included. A total of 3163 (20.5%) had one or more psychosocial risk factors. The most prevalent psychosocial risk factor was substance abuse in 1941 (12.6%) recipients. Patients with psychosocial risk factors were significantly younger at LVAD implant, less likely to be White, and less likely to be female compared with those without psychosocial risk,
P
<0.001 for all. Patients with psychosocial risk were significantly more likely to receive an LVAD as destination therapy,
P
<0.001. In adjusted models, patients with psychosocial risk were at increased hazards for device-related infection, gastrointestinal bleeding, pump thrombosis, and readmission and reduced hazards for cardiac transplantation (
P
<0.05 for all). There was no statistically significant difference in survival on pump support or stroke.

Conclusions:

Psychosocial risk is an important component of patient selection for advanced heart failure therapies. Addressing these specific components may help improve access to advanced therapies and post-LVAD outcomes.
Comparison of Ultrathin, Bioresorbable-Polymer Sirolimus-Eluting Stents and Thin, Durable-Polymer Everolimus-Eluting Stents in Calcified or Small Vessel Lesions
Authors: Dan Kazuhiro , Garcia-Garcia Hector M. , Kolm Paul , Windecker Stephan , Saito Shigeru , Kandzari David E. , Waksman Ron
Published: September 2020

Background:

The ultrathin-strut bioresorbable-polymer sirolimus-eluting stent (BP-SES) demonstrated comparable performance to durable-polymer everolimus-eluting stent (DP-EES) in randomized controlled trials. The purpose of this study was to evaluate the performance of a BP-SES compared with a DP-EES in calcified or small vessel lesions, which represent higher risk of restenosis.

Methods:

From the pooled BIOFLOW (BIOFLOW-II, IV, and V; BIOTRONIK - A Prospective Randomized Multicenter Study to Assess the Safety and Effectiveness of the Orsiro Sirolimus Eluting Coronary Stent System in the Treatment of Subjects With up to Three De Novo or Restenotic Coronary Artery Lesions ) randomized controlled trials, a total of 1553 BP-SES and 784 DP-EES patients with valid 1-year follow-up data were available. Coronary lesions were assessed for the presence of moderate-to-severe calcification or small vessels (reference vessel diameter, ≤2.75 mm) by core laboratory analysis. One-year clinical outcomes were assessed with or without the lesion subsets between BP-SES and DP-EES.

Results:

Baseline characteristics were similar between the groups. Among patients with small vessel disease, target lesion failure (8.0% versus 12.4%;
P
<0.01) and target vessel myocardial infarction (4.2% versus 7.6%;
P
<0.01) were significantly lower in BP-SES than in DP-EES. No difference in the outcome between the stents was shown in patients with non-small vessel lesions. In patients with calcified lesions, target lesion failure (12.2% versus 6.9%;
P
=0.056), and cardiac death (1.9% versus 0.3%;
P
=0.081) were numerically higher in DP-EES than in BP-SES. In the noncalcified lesion analysis, target vessel myocardial infarction in DP-EES was significantly higher than in BP-SES. Stent thrombosis was similar between the stents in both lesion groups.

Conclusions:

Among patients with more complex disease representing a higher risk of target lesion failure, the effectiveness of an ultrathin-strut BP-SES compared with a thin-strut DP-EES was maintained through 1 year.

Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifiers: NCT01356888, NCT01939249, NCT02389946.
Overexpression of Central ACE2 (Angiotensin-Converting Enzyme 2) Attenuates the Pressor Response to Chronic Central Infusion of Ang II (Angiotensin II)
Authors: Ma Anyun , Gao Lie , Wafi Ahmed M. , Yu Li , Rudebush Tara , Zhou Wenxian , Zucker Irving H.
Published: September 2020

We investigated the mechanism by which ACE2 (angiotensin-converting enzyme 2) overexpression alters neurohumoral outflow and central oxidative stress. Nrf2 (nuclear factor [erythroid-derived 2]-like 2) is a master antioxidant transcription factor that regulates cytoprotective and antioxidant genes. We hypothesized that upregulation of central ACE2 inhibits the pressor response to Ang II (angiotensin II) by reducing reactive oxygen species through a Nrf2/antioxidant enzyme–mediated mechanism in the rostral ventrolateral medulla. Synapsin human Angiotensin Converting Enzyme 2 positive (SynhACE2
+/+
) mice and their littermate controls synhACE2
−/−
were used to evaluate the consequence of intracerebroventricular infusion of Ang II. In control mice, Ang II infusion evoked a significant increase in blood pressure and norepinephrine excretion, along with polydipsia and polyuria. The pressor effect of central Ang II was completely blocked in synhACE2
+/+
mice. Polydipsia, norepinephrine excretion, and markers of oxidative stress in response to central Ang II were also reduced in synhACE2
+/+
mice. The MasR (Mas receptor) agonist Ang 1–7 and blocker A779 had no effects on blood pressure. synhACE2
+/+
mice showed enhanced expression of Nrf2 in the rostral ventrolateral medulla which was blunted following Ang II infusion. Ang II evoked nuclear translocation of Nrf2 in cultured Neuro 2A (N2A) cells. In synhACE2
−/−
mice, the central Ang II pressor response was attenuated by simultaneous intracerebroventricular infusion of the Nrf2 activator sulforaphane; blood pressure was enhanced by knockdown of Nrf2 in the rostral ventrolateral medulla in Nrf2 floxed (Nrf2
f/f
) mice. These data suggest that the hypertensive effects of intracerebroventricular Ang II are attenuated by selective overexpression of brain synhACE2 and may be mediated by Nrf2-upregulated antioxidant enzymes in the rostral ventrolateral medulla.
Premature Parental Cardiovascular Disease and Subclinical Disease Burden in the Offspring
Authors: Lieb Wolfgang , Song Rebecca J. , Vasan Ramachandran S. , Xanthakis Vanessa
Published: September 2020

Background

Offspring of parents with premature cardiovascular disease (CVD) have an increased risk of developing subclinical and clinical CVD. It is unclear whether this association differs by vascular beds in the offspring or by the age cut points used to define premature parental CVD.

Methods and Results

Using 3 generations of Framingham Heart Study participants, we assessed prevalent coronary artery calcification, the progression of coronary artery calcification over 6.1 years (median), carotid intima media thickness and the ankle‐brachial index in 1046 offspring of parents with premature CVD before age 70 years, in 1618 offspring with both parents free of CVD and in 923 offspring with parents with CVD after age 70 years. We used different age cut points (55, 60, 65, and 70 years) to define premature parental CVD. In multivariable‐adjusted models, offspring of parents with premature CVD (onset before age 65 years) displayed greater odds for prevalent coronary artery calcification (odds ratio [OR], 1.81; 95% CI, 1.35–2.43), higher carotid intima media thickness (OR, 1.50; 95% CI, 0.92–2.44) and lower ankle‐brachial index (OR, 1.89; 95% CI, 1.00–3.58). These associations were generally consistent across different age cut points used to define premature parental CVD. The association with the progression of coronary artery calcification was less consistent.

Conclusions

Parental premature CVD is associated with increased subclinical CVD burden in the offspring, with consistent relations across different vascular beds and for different age cut points used to define premature parental CVD. Future studies should evaluate whether screening for subclinical CVD traits is warranted in offspring with premature parental CVD.
Neural Substrates of Working Memory Updating
Authors: Nir-Cohen Gal , Kessler Yoav , Egner Tobias
Published: September 2020

Working memory (WM) needs to protect current content from interference and simultaneously be amenable to rapid updating with newly relevant information. An influential model suggests these opposing requirements are met via a BG–thalamus gating mechanism that allows for selective updating of PFC WM representations. A large neuroimaging literature supports the general involvement of PFC, BG, and thalamus, as well as posterior parietal cortex, in WM. However, the specific functional contributions of these regions to key subprocesses of WM updating, namely, gate opening, content substitution, and gate closing, are still unknown, as common WM tasks conflate these processes. We therefore combined fMRI with the reference-back task, specifically designed to tease apart these subprocesses. Participants compared externally presented face stimuli to a reference face held in WM, while alternating between updating and maintaining this reference, resulting in opening versus closing the gate to WM. Gate opening and substitution processes were associated with strong BG, thalamic, and frontoparietal activation, but intriguingly, the same activity profile was observed for sensory cortex supporting task stimulus processing (i.e., the fusiform face area). In contrast, gate closing was not reliably associated with any of these regions. These findings provide new support for the involvement of the BG in gate opening, as suggested by the gating model, but qualify the model's assumptions by demonstrating that gate closing does not seem to depend on the BG and that gate opening also involves task-relevant sensory cortex.
Sortition, its advocates and its critics: An empirical analysis of citizens’ and MPs’ support for random selection as a democratic reform proposal
Authors: Jacquet Vincent , Niessen Christoph , Reuchamps Min
Published: September 2020

This article explores the prospects of an increasingly debated democratic reform: assigning political offices by lot. While this idea is advocated by political theorists and politicians in favour of participatory and deliberative democracy, the article investigates the extent to which citizens and MPs actually endorse different variants of ‘sortition’. We test for differences among respondents’ social status, disaffection with elections and political ideology. Our findings suggest that MPs are largely opposed to sortitioning political offices when their decision-making power is more than consultative, although leftist MPs tend to be in favour of mixed assemblies (involving elected and sortitioned members). Among citizens, random selection seems to appeal above all to disaffected individuals with a lower social status. The article ends with a discussion of the political prospects of sortition being introduced as a democratic reform.
Tensor Veli Palatinopexy as a Novel Treatment for Eustachian Tube Dysfunction: A Cadaveric Feasibility Study
Authors: Eisen Eric A. , Wu Xiaotian , Rees Christiaan A. , Pastel David A. , Paydarfar Joseph A. , Saunders James E.
Published: September 2020

Objective

To demonstrate the feasibility of a novel procedure whereby a suture is placed transorally in the tensor veli palatini muscle to tighten it, thereby dilating the cartilaginous portion of the eustachian tube (ET).

Study Design

The study design was a prospective cadaveric experiment to examine the feasibility of a novel treatment for ET dysfunction.

Setting

Academic medical center in a research‐oriented operating room with intraoperative computed tomography (CT) capabilities.

Methods

Seven fresh‐frozen cadaver heads were obtained, each of which was thawed for 36 hours prior to use. The preprocedural volumes of the cartilaginous ET were measured by filling the ET with an iodine‐containing radiocontrast agent via the nasopharynx and then obtaining CT images. Submucosal flaps in the soft palate were raised, and sutures were placed in the tensor veli palatini bilaterally to increase tension. After completion of the procedure, contrast placement and CT imaging were repeated. Three‐dimensional models of the ETs were created, and the volumes were measured and compared.

Results

Of the 14 ETs evaluated, 13 showed an increase in postprocedure volume. On average, postprocedure volumes showed a 57% increase from preprocedure volumes (mean relative change, 57.1%; P =. 013).

Conclusion

Placement of a tension‐holding suture in the tensor veli palatini muscle can reliably dilate the cartilaginous portion of the ET. Such a procedure may be useful in the treatment of ET dysfunction.
Political Theology and Historical Materialism: Reading Benjamin against Agamben
Authors: List Lotte
Published: September 2020

Giorgio Agamben’s work on the power of sovereignty has been greatly influential in recent political thought. However, it has also overshadowed the independently original contributions of his two primary theoretical sources, Carl Schmitt and Walter Benjamin. In this article, I argue that Agamben’s political defeatism can be traced back to a double misconception in his reception of these two authors: first a formalistic reduction of Schmitt, and second a Schmittian reduction of Benjamin. Through this reduction to juridical formalism, the radicality of Benjamin’s historical materialist critique is replaced by a messianic nihilism, leading to the colonization of society by the logic of the concentration camp. Though Agamben’s theory of sovereignty and its implications for a positive political project have been contested, this origin of the decline of radical philosophy has not previously undergone a systematic critique.
(Re)Playing (with) Video game History: Moving beyond Retrogaming
Authors: Redhead Ahm Kristian
Published: September 2020

This article will argue that the current literature on retrogaming as a practice and the retrogamer as a subject has been lacking in fully describing the variety of practices and subjects that engage with old games. Based on data collected by interviewing nine self-described Danish retrogamers, three motivations for engaging with old games, besides nostalgia, are identified. These motivations are typologized into three player types: amateur archaeologists, amateur art historians, and techno-historians. Following the analysis, it will be argued that retrogaming might be an imprecise term to encompass the many different ways that individuals engage with old games. The concepts historical play and nostalgic play are presented to alleviate this.
Massive blood loss protocol ‘Code Red’ at Papworth Hospital: A closed loop audit
Authors: Tennyson M , Redlaff J , Biosse-Duplan G , Lewin M , Jones N , Layard Horsfall H
Published: September 2020

Aim

To investigate if the massive blood loss protocol ‘Code Red’ at a specialist cardiothoracic hospital was activated according to local and national guidelines by a closed loop audit.

Methods

Electronic and paper patient care systems were searched in 2015 and 2018 to access records for the ‘Code Red’ activations. Activation of the massive blood loss protocol was compared against the national standards set by The British Committee for Standards in Haematology. The percentage of cases meeting each of the ten standards in the specialist cardiac unit’s Protocol for the Management of Massive Blood Loss in Adults (adapted from the national standards) were evaluated.

Results

‘Code Red’ protocol was activated on 18 occasions in 2015 and nine occasions in 2018, representing just 0.83 and 0.26% of emergency surgeries, respectively. Between 2015 and 2018, there was a 6% increase of ‘Code Red’ cases being appropriately activated, a 26% increase in the prompt notification of the haematology department upon activation, alongside a 30% increase in the timely delivery of blood products, and a 25% decrease in the average amount of blood transferred prior to ‘Code Red’ activation.

Conclusion

There has been an improvement in the standards of care and management of massive blood loss this specialist cardiac centre despite the target timeframe being reduced from 30 to 15min between 2015 and 2018. Preparation for and anticipation of massive blood loss has likely decreased the number of incidences requiring ‘Code Red’ activation, permitting delivery of safe patient care.
How I treat anticoagulant-refractory thrombotic antiphospholipid syndrome
Authors: Cohen Hannah , Isenberg David A.
Published: September 2020

The standard treatment of thrombotic antiphospholipid syndrome (APS) is lifelong oral anticoagulation with a vitamin K antagonist (VKA), generally warfarin. A minority of patients with APS rethrombose despite seemingly adequate anticoagulation. These patients are deemed anticoagulant refractory. The management of anticoagulant-refractory APS is largely empirical and extrapolated from other clinically similar situations. Further options include increased VKA anticoagulation intensity or alternative antithrombotic strategies, including low-molecular-weight heparin, fondaparinux, the addition of antiplatelet therapy, and consideration of vascular options. Patients with anticoagulant-refractory thrombotic APS may have APS-associated thrombocytopenia, which necessitates balancing the risk of recurrent thrombosis vs bleeding to achieve adequate anticoagulation. The multiple mechanisms involved in the generation of the thrombotic phenotype in APS suggest that anticoagulation alone may not control thrombosis. Thus, other modalities, including adjunctive treatment (hydroxychloroquine, statins, and vitamin D) for APS-related thrombosis, merit consideration, as do immunomodulatory therapy and complement inhibition. Patients with APS may have coexistent systemic lupus erythematosus, which adds to the complexity of managing their thromboembolic disease. However, with attention to detail and judicious application of the limited data, it is possible to minimize the morbidity resulting from anticoagulant-refractory thrombotic APS. Multicenter studies are required to guide the sequence of interventions and their comparative efficacy in patients with anticoagulant-refractory thrombotic APS.
Chromosome 20 loss is characteristic of breast implant–associated anaplastic large cell lymphoma
Authors: Los-de Vries G. Tjitske , de Boer Mintsje , van Dijk Erik , Stathi Phylicia , Hijmering Nathalie J. , Roemer Margaretha G. M. , Mendeville Matias , Miedema Daniel M. , de Boer Jan Paul , Rakhorst Hinne A. , van Leeuwen Flora E. , van der Hulst René R. W. J. , Ylstra Bauke , de Jong Daphne
Published: September 2020

Breast implant–associated anaplastic large cell lymphoma (BIA-ALCL) is a very rare type of T-cell lymphoma that is uniquely caused by a single environmental stimulus. Here, we present a comprehensive genetic analysis of a relatively large series of BIA-ALCL (n = 29), for which genome-wide chromosomal copy number aberrations (CNAs) and mutational profiles for a subset (n = 7) were determined. For comparison, CNAs for anaplastic lymphoma kinase (ALK)− nodal anaplastic large cell lymphomas (ALCLs; n = 24) were obtained. CNAs were detected in 94% of BIA-ALCLs, with losses at chromosome 20q13.13 in 66% of the samples. Loss of 20q13.13 is characteristic of BIA-ALCL compared with other classes of ALCL, such as primary cutaneous ALCL and systemic type ALK+ and ALK− ALCL. Mutational patterns confirm that the interleukin-6–JAK1–STAT3 pathway is deregulated. Although this is commonly observed across various types of T-cell lymphomas, the extent of deregulation is significantly higher in BIA-ALCL, as indicated by phosphorylated STAT3 immunohistochemistry. The characteristic loss of chromosome 20 in BIA-ALCL provides further justification to recognize BIA-ALCL as a separate disease entity. Moreover, CNA analysis may serve as a parameter for future diagnostic assays for women with breast implants to distinguish seroma caused by BIA-ALCL from other causes of seroma accumulation, such as infection or trauma.
Recipient-specific T-cell repertoire reconstitution in the gut following murine hematopoietic cell transplant
Authors: Zheng Pingping , Tamaresis John , Thangavelu Govindarajan , Xu Liwen , You Xiaoqing , Blazar Bruce R. , Negrin Robert S. , Zehnder James L. , Iliopoulou Bettina P. , Meyer Everett H.
Published: September 2020

Graft-versus-host disease (GVHD) is a complication of hematopoietic cell transplantation (HCT) caused by alloreactive T cells. Murine models of HCT are used to understand GVHD and T-cell reconstitution in GVHD target organs, most notably the gastrointestinal (GI) tract where the disease contributes most to patient mortality. T-cell receptor (TCR) repertoire sequencing was used to measure T-cell reconstitution from the same donor graft (C57BL/6 H-2b) in the GI tract of different recipients across a spectrum of matching, from syngeneic (C57BL/6), to minor histocompatibility (MHC) antigen mismatch BALB.B (H-2b), to major MHC mismatched B10.BR (H-2k) and BALB/c (H-2d). Although the donor T-cell pools had highly similar TCR, the TCR repertoire after HCT was very specific to recipients in each experiment independent of geography. A single invariant natural killer T clone was identifiable in every recipient group and was enriched in syngeneic recipients according to clonal count and confirmatory flow cytometry. Using a novel cluster analysis of the TCR repertoire, we could classify recipient groups based only on their CDR3 size distribution or TCR repertoire relatedness. Using a method for evaluating the contribution of common TCR motifs to relatedness, we found that reproducible sets of clones were associated with specific recipient groups within each experiment and that relatedness did not necessarily depend on the most common clones in allogeneic recipients. This finding suggests that TCR reconstitution is highly stochastic and likely does not depend on the evaluation of the most expanded TCR clones in any individual recipient but instead depends on a complex polyclonal architecture.
Pharmacometric modeling to explore 4F-PCC dosing strategies for VKA reversal in patients with INR below 2
Authors: Sarode Ravi , Fukutake Katsuyuki , Yasaka Masahiro , Tortorici Michael A. , Mangione Antoinette , Pfister Marc , Cuker Adam
Published: September 2020

The indicated dose of 4-factor prothrombin complex concentrate (4F-PCC) for urgent vitamin K antagonist (VKA) reversal in patients with an international normalized ratio (INR) of 2 to 4 is 25 IU/kg, but there is no indicated dose for INR <2. We explored 4F-PCC dosing strategies for baseline INR <2. Clinical trial data were used to develop pharmacometric models for Factor X (FX) and FII, accounting for covariates including baseline INR. FX and FII levels over time were simulated for mean baseline INR levels of the clinical trial participants plus baseline INRs 3.1, 1.9, and 1.6. For each INR, 200 virtual male patients were simulated to evaluate 4F-PCC doses of 35, 25, 20, 15, 12.5, and 10 IU/kg. Given an elevated bleeding risk with VKA therapy in Japanese vs Western populations, results were stratified by Japanese and non-Japanese patients. Target levels of FX and FII were ≥50% activity at 30 minutes after dosing in ≥80% of patients. FX- and FII-time models were developed with 1088 FX observations from 193 patients and 1074 FII observations from 192 patients. Model-based simulations indicated that at baseline INR 3.1, ≥80% of patients achieved ≥50% FX and FII activity with 25 IU/kg and 20 IU/kg 4F-PCC, respectively; at baseline INR 1.9, corresponding doses were 20 IU/kg and 15 IU/kg 4F-PCC, and at baseline INR 1.6, corresponding doses were 15 IU/kg, and 10 IU/kg 4F-PCC. Trends in Japanese and non-Japanese patients were similar. In conclusion, low 4F-PCC doses (15-20 IU/kg) may be sufficient to achieve hemostatic levels of FX and FII in Japanese and non-Japanese patients with baseline INR <2.
Charge-altering releasable transporters enable phenotypic manipulation of natural killer cells for cancer immunotherapy
Authors: Wilk Aaron J. , Weidenbacher Nancy Lynn-Benner , Vergara Rosemary , Haabeth Ole A. W. , Levy Ronald , Waymouth Robert M. , Wender Paul A. , Blish Catherine A.
Published: September 2020

Chimeric antigen receptor (CAR) natural killer (NK) cells are an emerging cell therapy with promising results in oncology trials. However, primary human NK cells are difficult to transfect, hampering both mechanistic studies and clinical applications of NK cells. Currently, NK cell CAR modification relies on viral vectors or cell activation. The former raises cost and tolerability issues, while the latter alters NK cell biology. Here, we report that readily synthesized and inexpensive nonviral charge-altering releasable transporters (CARTs) efficiently transfect primary human NK cells with messenger RNA without relying on NK cell activation. Compared with electroporation, CARTs transfect NK cells more efficiently, better preserve cell viability, and cause minimal reconfiguration of NK cell phenotype and function. We use CARTs to generate cytotoxic primary anti-CD19 CAR NK cells, demonstrating this technology can drive clinical applications of NK cells. To our knowledge, CARTs represent the first efficacious transfection technique for resting primary human NK cells that preserves NK cell phenotype and can enable new biological discoveries and therapeutic applications of this understudied lymphocyte subset.
Two C-terminal sequence variations determine differential neurotoxicity between human and mouse α-synuclein
Authors: Landeck Natalie , Strathearn Katherine E. , Ysselstein Daniel , Buck Kerstin , Dutta Sayan , Banerjee Siddhartha , Lv Zhengjian , Hulleman John D. , Hindupur Jagadish , Lin Li-Kai , Padalkar Sonal , Stanciu Lia A. , Lyubchenko Yuri L. , Kirik Deniz , Rochet Jean-Christophe
Published: September 2020

Background

α-Synuclein (aSyn) aggregation is thought to play a central role in neurodegenerative disorders termed synucleinopathies, including Parkinson’s disease (PD). Mouse aSyn contains a threonine residue at position 53 that mimics the human familial PD substitution A53T, yet in contrast to A53T patients, mice show no evidence of aSyn neuropathology even after aging. Here, we studied the neurotoxicity of human A53T, mouse aSyn, and various human-mouse chimeras in cellular and in vivo models, as well as their biochemical properties relevant to aSyn pathobiology.

Methods

Primary midbrain cultures transduced with aSyn-encoding adenoviruses were analyzed immunocytochemically to determine relative dopaminergic neuron viability. Brain sections prepared from rats injected intranigrally with aSyn-encoding adeno-associated viruses were analyzed immunohistochemically to determine nigral dopaminergic neuron viability and striatal dopaminergic terminal density. Recombinant aSyn variants were characterized in terms of fibrillization rates by measuring thioflavin T fluorescence, fibril morphologies via electron microscopy and atomic force microscopy, and protein-lipid interactions by monitoring membrane-induced aSyn aggregation and aSyn-mediated vesicle disruption. Statistical tests consisted of ANOVA followed by Tukey’s multiple comparisons post hoc test and the Kruskal-Wallis test followed by a Dunn’s multiple comparisons test or a two-tailed Mann-Whitney test.

Results

Mouse aSyn was less neurotoxic than human aSyn A53T in cell culture and in rat midbrain, and data obtained for the chimeric variants indicated that the human-to-mouse substitutions D121G and N122S were at least partially responsible for this decrease in neurotoxicity. Human aSyn A53T and a chimeric variant with the human residues D and N at positions 121 and 122 (respectively) showed a greater propensity to undergo membrane-induced aggregation and to elicit vesicle disruption. Differences in neurotoxicity among the human, mouse, and chimeric aSyn variants correlated weakly with differences in fibrillization rate or fibril morphology.

Conclusions

Mouse aSyn is less neurotoxic than the human A53T variant as a result of inhibitory effects of two C-terminal amino acid substitutions on membrane-induced aSyn aggregation and aSyn-mediated vesicle permeabilization. Our findings highlight the importance of membrane-induced self-assembly in aSyn neurotoxicity and suggest that inhibiting this process by targeting the C-terminal domain could slow neurodegeneration in PD and other synucleinopathy disorders.
Arbuscular mycorrhiza improved drought tolerance of maize seedlings by altering photosystem II efficiency and the levels of key metabolites
Authors: Hu Yanbo , Xie Wei , Chen Baodong
Published: September 2020

Background

Water shortage can limit plant growth, which can be ameliorated by arbuscular mycorrhizal (AM) symbiosis through physiological and metabolic regulations. Deciphering which physiological and metabolic processes are central for AM-mediated regulations is essential for applications of mycorrhizal biotechnology in dryland agriculture.

Methodology

In this study, the influence of AM symbiosis on growth performance, photosynthesis, and organ accumulation of key C and N metabolites were assessed by growing maize (Mo17, Lancaster Sure Crop) seedlings inoculated with or without AM fungus (Rhizophagus irregularis Schenck & Smith BGC AH01) under different water regimes in greenhouse.

Results

Drought stress reduced shoot growth, while AM symbiosis significantly improved growth performances, with significant changes of photochemical processes and organ concentration of the key metabolites. AM symbiosis increased root levels of the metabolites in ornithine cycle and unsaturation of fatty acids regardless of water conditions. Root putrescine (Put) concentration was higher in AM than non-inoculated (NM) plants under well-watered conditions; the conversion of Put via diamine oxidase to γ-aminobutyric acid (GABA) occurred in roots of AM plants under drought stress. Leaf concentration of Put, the tricarboxylic acids, and soluble sugars significantly increased in AM plants under drought stress, showing higher values compared to that of NM plants. Moreover, photosystem II efficiency and chlorophyll concentration were higher in AM than NM plants regardless of water status.

Conclusion

Fatty acid- and ornithine cycle-related metabolites along with soluble sugars, Put, and GABA were the key metabolites of AM-mediated regulations in response to drought stress.
From regional society to migrant society: a study on urban transformation in China
Authors: Zhou Daming
Published: September 2020

This paper considers the process of the change in Chinese society—in which its people went from being regional to being migrant in urban communities—and recognizes urban transformation as being based on and an expression of cultural transformation. The transformation of urban communities accompanied the “migration era,” and China’s urban communities, in fact, have been gradually changing from a relatively closed regional society to a diverse and civilized migrant one. The diversification of migrants has caused many problems for cities during their transition, affecting such aspects of social life as the equal enjoyment of public resources, the changes in family and kinship, regional discrimination, the complexity of interpersonal and ethnic relations, etc. The related topics are worthy of further discussion.
Association between vitamin D status and depression in children with chronic liver disease
Authors: Behairy Ola G. , Abo Amer Al Rawhaa A. , Mansour Amira I. , Mohamed Karim I.
Published: September 2020

Background

Deficiency of vitamin D and depression are commonly occurring in patients with chronic liver diseases. This study aimed to determine the association between 25-OH-vitamin D status and depressive symptoms among children with chronic liver diseases. Eighty children were enrolled and divided into 2 groups: the patients’ group (60 children with chronic hepatitis) and the control group (20 healthy children). All children have been analyzed for their clinical, biochemical features, histological profile, serum 25-OH-vitamin D levels, and assessment of childhood depression using Arabic form based on Kovacs Children’s Depression Inventory.

Results

Serum level of 25(OH) D was significantly lower in the hepatic group than the control group [17 (5–52) ng/ml, 45 (13–95) ng/ml,p= <0001 respectively]. Depression score was significantly higher in the hepatic group as 30% of the control group had mild depression, while 36.7% of the hepatic group had mild depression, 16.7% had moderate depression, and 10% had severe depression. There was a statistically significant difference between children with depressive symptoms and non-depressive symptoms as regards the level of serum vitamin D as it was lower in children with depressive symptoms [median (range) 17 (5–40) ng/ml, 27.5 (8–52) ng/ml,p= 0.04 respectively]. There were statistically significant differences between the serum level of 25(OH) D and depression as it decreases with increasing severity of depression.

Conclusion

Children with chronic liver disease who had depressive symptoms showed significantly lower levels of vitamin D when compared with those without depressive symptoms; also, vitamin D had an inverse correlation with depression scores in these children.
Trends in generalised anxiety disorders and symptoms in primary care: UK population-based cohort study
Authors: Slee April , Nazareth Irwin , Freemantle Nick , Horsfall Laura
Published: September 2020

Background

Generalised anxiety disorder and symptoms are associated with poor physical, emotional and social functioning and frequent primary and acute care visits. We investigated recent temporal trends in anxiety and related mental illness in UK general practice.

Aims

The aims of this analysis are to examine temporal changes in recording of generalised anxiety in primary care and initial pharmacologic treatments.

Method

Annual incidence rates of generalised anxiety diagnoses and symptoms were calculated from 795 UK general practices contributing to The Health Improvement Network (THIN) database between 1998 and 2018. Poisson mixed regression was used to account for age, gender and general practitioner practice. Subsequent pharmacologic treatment was examined.

Results

Generalised anxiety recording rates increased in both genders aged 18–24 between 2014 and 2018. For women, the increase was from 17.06 to 23.33/1000 person years at risk (PYAR); for men, 8.59 to 11.65/1000 PYAR. Increases persisted for a composite of anxiety and depression (49.74 to 57.81/1000 PYAR for women; 25.41 to 31.45/1000 PYAR for men). Smaller increases in anxiety were seen in both genders age 25–34 and 35–44. Anxiety rates among older patients remained stable, although a composite of anxiety and depression decreased for older women. About half of drug-naïve patients were prescribed anxiety drugs within 1 year following diagnosis. The most common choice was a selective serotonin reuptake inhibitor. Benzodiazepine prescription rate has fallen steadily.

Conclusions

We observed a substantial increase in general practitioner consulting for generalised anxiety and depression recently, concentrated within younger people and in particular women.