bluuebunny/crossref_metadata_2025 huggingface dataset:
Framework of treating Alzheimer’s dementia
Authors: Yang Yuan-Han , Liscic Rajka , Dominguez Jacqueline
Published: January 2020

Current treatment paradigm in Alzheimer’s disease (AD) involves multiple approaches combining pharmacological and nonpharmacological intervention to mitigate the clinical symptoms, slow the progressive loss of cognitive and functional abilities, or modify the disease course. So far, beyond anti-cholinesterase inhibitors (AChEIs), donepezil, rivastigmine, galantamine, and antagonist of N-methyl-D-aspartic acid (NMDA) receptor, there are no newly approved medicines to treat AD. Under pharmacological treatment, the personal characteristic and the intra-individual therapeutic evaluations to examine various cognitive domains, behavioral and psychological problems, and global function should be considered when choosing any of AChEIs. The use of optimal dosage referring to the expected clinical outcomes and currently reported deficits from patient with AD has become an important issue in clinical treatment. Establishing and maintaining a strong therapeutic alliance to physician, patient, and caregiver is crucial and central to the comprehensive care in AD.
Innovation Institution and Spatial Transfer of Energy Industry: The Case of Jiangsu Province, China
Authors: Gao Xing , Zhai Keyu , Qiu Yue , Cao Mengqiu , Wu Meiling
Published: January 2020

This study aims to explore the effect of innovation institution on spatial transfer of energy industry in Jiangsu, China. We focus on the disparity of innovation and energy industry, and analyze the spatial transfer difference in different types of energy industry, rather than view energy industry as a whole. The study demonstrates the spatial change of energy industry at regional level and maps the spatial pattern at city level. The study chooses intellectual property rights (IPRs) protection intensity, authorization patents and local research and development (R&D) investment as the proxy of innovation. Using official data and employing panel fixed-effect model at city-industry level, we conclude (a) innovation abilities significantly influence the spatial transfer of energy industry in Jiangsu. Especially, due to the different time, IPRs protection, patent counts, and R&D investment have different effects on different regions in Jiangsu; (b) 2010 is an important turning point for energy industry development in Jiangsu, and after 2010, the energy industry begins to shift to the middle and northern Jiangsu, whereas the spatial pattern of energy industry in coastal cities is basically unchanged; (c) there is a great difference between the regions in Jiangsu Province, and industrial upgrading has not been achieved in northern Jiangsu.
Sport and the Quest for Unity: How the Logic of Consensus Undermines Democratic Culture
Authors: Butterworth Michael L.
Published: January 2020

In response to the political protest of National Football League (NFL) player Colin Kaepernick and subsequent controversial comments from President Donald Trump, New England Patriots owner Robert Kraft declared, “There is no greater unifier in this country than sports and, unfortunately, nothing more divisive than politics.” Such a sentiment is commonplace in sport, whether it is about race, political affiliations, or responses to tragic events, and it quickly became an organizing theme for NFL owners as they sought to defuse the issue. Meanwhile, sports media and others echoed the call for unity and largely dropped discussion of the commitment to social justice that had originally animated Kaepernick’s protest. This essay argues that claims to unity are rooted in the logic of consensus, a value in democratic theory that offers an illusion of peaceful cooperation while denying important conflicts and differences. As understood through the rhetorical tradition and theories of agonistic democracy, athletic activism in the NFL has been important precisely because it disrupts the illusion of unity on which the national anthem ritual rests. In short, contesting unity and consensus seeks to identify communicative resources that facilitate social justice in and through sport.
Not quite quiet, not quite encroachment: Interrogating the political nature of urban subaltern community engagement in Medellín, Colombia
Authors: Hayes-Conroy Allison , Saenz Montoya Alexis , Croog Rebecca , Muñoz Felipe
Published: January 2020

In Medellín, Colombia, hundreds of youth and community groups participate in activities aimed at transforming their lives and the interconnected lives of their neighbors. These activities are not necessarily conceived of as activism but they are also not politically passive; they are distinct from both survival strategies and “everyday resistance” but their relationships to the state and/or the rich and powerful are unstable. In this sense, these activities relate to but do not fit neatly within Asef Bayat’s framework of “quiet encroachment,” describing the “silent, protracted but pervasive advancement of the ordinary people on the propertied and powerful in order to survive and improve their lives”. Rather, they suggest a malleable kind of “quiet” action, one that moves both against and with state prerogatives. Building on the notion of quiet encroachment, and even more nuanced depictions coming out of Bayat’s later work, we describe the politics of recent activities accomplished by youth and community groups as a kind of “nonmovement” work, accomplished through spatial, affective, and organizational gains, that sits upon the more active political networking of previous eras.
Cardiorespiratory Events Associated With Ophthalmic Surgery: A Single-Center, Retrospective Records Review of 130 775 Patients, 1999–2015
Authors: Singh Vinodkumar , Bryant Ayesha S. , Hull Matthew , Skelley Jason , Walters Robin , Cross R. Clark , Rozner Marc A. , Boyd Gwendolyn L.
Published: January 2020

Purpose:

The most recent study of ophthalmic surgery morbidity and mortality was published in 1995, with a patient study population from 1977 to 1988. The present study reports surgical outcomes from a single-center, retrospective analysis of patient records from 1999 to 2015.

Methods:

Three International Classification of Diseases–9-CM codes for cardiorespiratory events were searched in the discharge diagnoses in an eye hospital over a 16-year period. The overall mortality and preoperative risk factors were analyzed, including the type of anesthetic, type of surgery, medical comorbidities, and bradycardia preceding the cardiac events.

Results:

Between February 1, 1999 and October 1, 2015, a total of 130 775 patients presented for ophthalmic surgery. Fifty-nine patients (0.45 per 1000) experienced a cardiorespiratory event. Of the 59 patients, 14 patients had a cardiorespiratory arrest, 9 of whom died during the perioperative period. Of the remaining 45 patients, 29 had significant adverse events needing some form of advanced monitoring, evaluation, and/or intervention. There was a significantly greater prevalence of diabetes among patients who had a cardiorespiratory event ( P < .001).

Conclusions:

The major risk factor associated with ophthalmic surgery morbidity and mortality was diabetes with its associated complications of autonomic neuropathy, nephropathy, and retinopathy. Of the 9 patients who died, 8 were diabetic with proliferative diabetic retinopathy and renal insufficiency/failure. The ninth mortality was secondary to a venous air embolism during ocular air infusion. The adage that “the eye is the window to our overall health” seems to be correct.
How I assess and manage the risk of bleeding in patients treated for venous thromboembolism
Authors: Klok Frederikus A. , Huisman Menno V.
Published: January 2020

For patients with venous thromboembolism (VTE), prediction of bleeding is relevant throughout the course of treatment, although the means and goal of this prediction differ between the subsequent stages of treatment: treatment initiation, hospital discharge, 3-month follow-up, and long-term follow-up. Even in the absence of fully established risk prediction schemes and outcome studies using a prediction scheme for treatment decisions, the present evidence supports screening for and targeting of modifiable risk factors for major bleeding, as well as the application of decision rules to identify patients at low risk of bleeding complications, in whom long-term anticoagulant treatment is likely safe. Moving forward, prediction tools need to be incorporated in well-designed randomized controlled trials aiming to establish optimal treatment duration in patients at high risk of recurrent VTE. Moreover, the benefit of their longitudinal assessment rather than application as stand-alone baseline assessments should be studied, because changes in bleeding risk over time likely constitute the best predictor of major bleeding. We provide the state-of-the-art of assessing and managing bleeding risk in patients with acute VTE and highlight a practical approach for daily practice illustrated by 2 case scenarios.
Targeting myeloid-cell specific integrin α9β1 inhibits arterial thrombosis in mice
Authors: Dhanesha Nirav , Nayak Manasa K. , Doddapattar Prakash , Jain Manish , Flora Gagan D. , Kon Shigeyuki , Chauhan Anil K.
Published: January 2020

Evidence suggests that neutrophils contribute to thrombosis via several mechanisms, including neutrophil extracellular traps (NETs) formation. Integrin α9β1 is highly expressed on neutrophils when compared with monocytes. It undergoes affinity upregulation on neutrophil activation, and stabilizes adhesion to the activated endothelium. The role of integrin α9 in arterial thrombosis remains unexplored. We generated novel myeloid cell-specific integrin α9−/− mice (α9fl/flLysMCre+) to study the role of integrin α9 in arterial thrombosis. α9fl/fl littermates were used as controls. We report that α9fl/flLysMCre+ mice were less susceptible to arterial thrombosis in ferric chloride (FeCl3) and laser injury-induced thrombosis models with unaltered hemostasis. Neutrophil elastase-positive cells were significantly reduced in α9fl/flLysMCre+ mice concomitant with reduction in neutrophil count, myeloperoxidase levels, and red blood cells in the FeCl3 injury-induced carotid thrombus. The percentage of cells releasing NETs was significantly reduced in α9fl/flLysMCre+ mouse neutrophils stimulated with thrombin-activated platelets. Furthermore, we found a significant decrease in neutrophil-mediated platelet aggregation and cathepsin-G secretion in α9fl/flLysMCre+ mice. Transfusion of α9fl/fl neutrophils in α9fl/flLysMCre+ mice restored thrombosis similar to α9fl/fl mice. Treatment of wild-type mice with anti-integrin α9 antibody inhibited arterial thrombosis. This study identifies the potential role of integrin α9 in modulating arterial thrombosis.
NADPH oxidase controls pulmonary neutrophil infiltration in the response to fungal cell walls by limiting LTB4
Authors: Song Zhimin , Huang Guangming , Chiquetto Paracatu Luana , Grimes Derayvia , Gu Jiwei , Luke Cliff J. , Clemens Regina A. , Dinauer Mary C.
Published: January 2020

Leukocyte reduced NADP (NADPH) oxidase plays a key role in host defense and immune regulation. Genetic defects in NADPH oxidase result in chronic granulomatous disease (CGD), characterized by recurrent bacterial and fungal infections and aberrant inflammation. Key drivers of hyperinflammation induced by fungal cell walls in CGD are still incompletely defined. In this study, we found that CGD (CYBB−) neutrophils produced higher amounts of leukotriene B4 (LTB4) in vitro after activation with zymosan or immune complexes, compared with wild-type (WT) neutrophils. This finding correlated with increased calcium influx in CGD neutrophils, which was restrained in WT neutrophils by the electrogenic activity of NADPH oxidase. Increased LTB4 generation by CGD neutrophils was also augmented by paracrine cross talk with the LTB4 receptor BLT1. CGD neutrophils formed more numerous and larger clusters in the presence of zymosan in vitro compared with WT cells, and the effect was also LTB4- and BLT1-dependent. In zymosan-induced lung inflammation, focal neutrophil infiltrates were increased in CGD compared with WT mice and associated with higher LTB4 levels. Inhibiting LTB4 synthesis or antagonizing the BLT1 receptor after zymosan challenge reduced lung neutrophil recruitment in CGD to WT levels. Thus, LTB4 was the major driver of excessive neutrophilic lung inflammation in CGD mice in the early response to fungal cell walls, likely by a dysregulated feed-forward loop involving amplified neutrophil production of LTB4. This study identifies neutrophil LTB4 generation as a target of NADPH oxidase regulation, which could potentially be exploited therapeutically to reduce excessive inflammation in CGD.
Gestational and lactational exposure to gossypol alters the testis transcriptome
Authors: Louvandini Helder , Corrêa Patricia S. , Amorín Rocío , Liu Lihe , Ieda Egon H. , Jimenez Carolina R. , Tsai Siu M. , McManus Concepta M. , Peñagaricano Francisco
Published: January 2020

Background

Reproductive capacity can be altered by challenges experienced during critical periods of development, including fetal development and early neonatal life. Gossypol is a polyphenolic compound, commonly found in cotton seeds, that impairs male reproduction. Here, we investigated whether the exposure to gossypol in utero and during lactation alters male reproductive function in sheep. From conception until 60 days postpartum, ewes were randomly assigned to a control diet or a gossypol-rich diet based on cottonseed. Lamb testicles were removed at 60 days of age and subjected to RNA-sequencing.

Results

Lambs derived from the maternal cottonseed diet showed significantly lower growth and lower testis weight as a proportion of the total body weight, and reduced testosterone levels. In addition, the testis transcriptome was significantly altered by the maternal cottonseed diet. Most of the altered genes are directly implicated in testis development and sperm biology, cell communication, iron ion metabolism, calcium homeostasis and signaling, among other functions. Interestingly, network analysis revealed that exposure to gossypol significantly disturbed coexpression patterns among spermatogenesis-related genes, suggesting a disruption in coregulation mechanisms.

Conclusions

Our findings provide evidence that maternal exposure to gossypol alters male reproductive function in the offspring, with potential lasting or lifelong negative consequences.
miR32-5p promoted vascular smooth muscle cell calcification by upregulating TNFα in the microenvironment
Authors: Cao Jingsong , Chen Ling , Zhong Xiaoling , Shen Yingying , Gao Yan , Chen Qian , Zu Xuyu , Liu Jianghua
Published: January 2020

Background

Vascular calcification is often associated with chronic inflammation and is a risk factor for brain arterial stiffness. Our previous results showed that miR32-5p was positively correlated with vascular smooth muscle cells (VSMC) calcification, but it is unclear whether miR32-5p promoted VSMC calcification by regulating inflammatory factor production.

Results

In this study, bioinformatics analysis was used to select tumour necrosis factor α (TNFα) as a candidate inflammatory factor associated with calcification. Moreover, alizarin red staining and qRT-PCR analysis revealed that TNFα produced by BV2 cells was the key promoting factor of VSMC calcification. Interestingly, the expression of TNFα was significantly increased at the mRNA and protein levels after miR32-5p mimic treatment but significantly decreased after miR32-5p antagomir treatment. To explore the mechanism of the regulation of TNFα expression by miR32-5p, bioinformatics analysis indicated that PIKfyve was a candidate target gene of miR32-5p, and luciferase assays verified that the expression of PIKfyve was significantly repressed by miR32-5p mimics. Importantly, rescue experiments showed that the expression of TNFα in BV2 cells treated with miR32-5p antagomir and the PIKfyve inhibitor YM201636 was significantly increased.

Conclusions

The production of TNFα in microglia could be affected by miR32-5p targeting PIKfyve, and these results will be beneficial to reveal the mechanism of brain arterial calcification.
Leriche syndrome in a patient with acute pulmonary embolism and acute myocardial infarction: a case report and review of literature
Authors: An Xuanqi , Fu Rui , Zhao Zhihui , Ni Xinhai , Xiong Changming , Cheng Xiansheng , Liu Zhihong
Published: January 2020

Background

Both acute myocardial infarction and acute pulmonary embolism are distinct medical urgencies while they may conincide. Leriche’s syndrome is a relatively rare aortoiliac occlusive disease characterized by claudication, decreased femoral pulses, and impotence. We present the first case of concomitant acute pulmonary embolism, acute myocardial infarction, and Leriche syndrome.

Case presentation

A 56-year-old male with a history of intermittent claudication was admitted for evaluating the sudden onset of chest pain. Elevated serum troponin level, sustained high D-dimer level, ST-T wave changes on electrocardiogram, and segmental wall motion abnormality of the left ventricle on transthoracic echocardiography were noted. Pulmonary Computed Tomography Angiogram revealed multiple acute emboli. Aortic Computed Tomography Angiogram spotted complete obstructions of the subrenal aorta and bilateral common iliac arteries with collateral circulation, maintaining the vascularization of internal and external iliac arteries. We stated the diagnosis of acute pulmonary embolism and Leriche syndrome and initiated oral anticoagulation. However, Q waves on electrocardiogram and wall motion abnormality on echocardiography persisted after embolus dissolved successfully. Coronary computed tomography angiogram found coronary arterial plaques while myocardial Positron Emission Tomography detected decreased viable myocardium of the left ventricle. We subsequently ratified the diagnosis of concurrent acute pulmonary embolism, acute myocardial infarction, and Leriche syndrome. The patient was discharged and has been followed up at our center.

Conclusion

We described the first concurrence of acute pulmonary embolism, acute myocardial infarction, and Leriche syndrome.
Complication during transportation and 30 days mortality of patients with acute coronary syndrome
Authors: Czapla Michał , Zyśko Dorota , Quinn Tom , Karniej Piotr
Published: January 2020

Background

Patients with acute coronary syndrome (ACS) who present to hospitals without interventional facilities frequently require transfer to another hospital equipped with a cardiac catheterization laboratory. This retrospective cohort study evaluates the association of the type of medical transport with patient outcomes.

Methods

A retrospective analysis of medical records of patients with ACS transported by basic (BT) and specialist transfer (ST) by emergency medical teams (EMTs). We analyzed age, gender, hemodynamic parameters, type of the emergency medical team, and complications during transport as well as patient survival to hospital admission, survival time and the 30-day mortality rate.

Results

Of 500 patients who underwent transfer, ST transported 368 (73.6%) and BT 132 (26.4%) patients (p < 0.001). Complications during transportation occurred in 3 (1%) in the ST group and 2 (1.5%) in and BT group. Cardiac arrest during transfer occurred in no (0%) patients in the ST group, and 2 (1.5%) in the BT group (p = 0.118). Survival to admission was recorded in all patients in the ST group and 131/132 (0.8%) patients in the BT group (p = 0.592). 40 (12%) of patients in the ST group and 13 (11%) patients in the BT group (p = 0.731) died within 30 days of transfer.

Conclusions

Complications during medical transport of ACS patients from hospitals without a cardiac catheter lab to hospitals equipped with such a lab were rare and their incidence was not associated with the type of transporting EMT. The type of EMT was not associated with 30-day patient mortality.
Comparison of sequential, delayed and simultaneous resection strategies for synchronous colorectal liver metastases
Authors: Wang Li-Jun , Wang Hong-Wei , Jin Ke-Min , Li Juan , Xing Bao-Cai
Published: January 2020

Background

The present study aimed to compare the perioperative safety and long-term survival of patients with synchronous colorectal liver metastases undergoing sequential resection (SeR), delayed resection (DeR) and simultaneous resection (SiR).

Methods

From January 2007 to December 2016, data from patients undergoing surgery at Peking University Cancer Hospital for synchronous colorectal liver metastases were retrospectively collected. The above three different surgical strategies were compared.

Results

A total of 233 cases were included, with 49 in the SeR group, 98 in the DeR group and 86 in the SiR group. The incidence of severe complications was 26.7% in the SiR group, higher than that in the DeR group (11.2%, P = 0.007) and the SeR group (16.3%, P = 0.166). The overall survival at 1 and 3 years in the SeR group (93.9 and 50.1%) was lower than that in the DeR group (94.9 and 64.8%, P = 0.019), but not significantly different from that in the SiR group (93.0 and 55.2%, P = 0.378). Recurrence-free survival at 1 and 3 years in the SeR group (22.4 and 18.4%) was lower than that in the DeR group (43.9 and 24.2%, P = 0.033) but not significantly different from that in the SiR group (31.4 and 19.6%, P = 0.275). Cox multivariate analysis indicated that T4, lymph node-positive primary tumour, liver metastases > 30 mm and SiR (compared with DeR) were correlated with poor prognosis.

Conclusion

Simultaneous resection has a relatively higher incidence of severe complications, and with a staged resection strategy, the prognosis of delayed resection was better than that of sequential resection.
Qualitative exploration of the acceptability of a postnatal pelvic floor muscle training intervention to prevent urinary incontinence
Authors: Grant Aileen , Currie Sinead
Published: January 2020

Background

Childbirth is a major risk factor for urinary incontinence (UI). As a result, pelvic floor muscle training (PFMT) is commonly recommended during and after pregnancy to prevent the onset of UI. PFMT is often classed as a physical activity (PA) behaviour, hence PA guidelines for postnatal women encourage PFMT alongside aerobic activities. However, postnatal lifestyle interventions tend to overlook PFMT which can be detrimental to women’s health and future health risks, including urinary incontinence. This study aimed to explore perceptions and acceptability of a postnatal physical activity and PFMT intervention with postnatal women in Scotland.

Methods

We recruited women who had given birth within the last 5 years by displaying posters in health centres and community centres in Stirling and through Facebook. Data was gathered via online and face-to-face focus groups, that were audio recorded and transcribed verbatim. Analytic themes were initially organised under related concepts derived from the topic guide and thematic analysis conducted. Subsequent analysis was by the Framework technique.

Results

A total of seven online and face-to-face focus group discussions with 31 women identified there was a clear intention behaviour gap for engagement in PA, with both psychological and logistical barriers identified such as motivation and childcare. This was distinct from PFMT where there was a feeling of helplessness around not knowing how to perform a correct PFMT contraction subsequently resulting in women not adhering to PFMT guidance. Women felt there was no accessible PFMT advice available through the NHS. Some participants had received PFMT advice after childbirth and spoke of the Squeezee app being useful in adhering to a PFMT regimen but they did require additional teaching on how to do correct contractions. There was need for clarity and practical support for PFMT in the postnatal period with an approved intervention incorporating an accessible app being suggested by participants.

Conclusions

Women would like to be trained on postnatal PFMT but face barriers to accessing adequate information and education on how to do a PFMT contraction. An intervention combining PFMT training and an app would be the most useful for their needs and circumstances.
Does insurance protect individuals from catastrophic payments for surgical care? An analysis of Ghana’s National Health Insurance Scheme at Korle-Bu teaching Hospital
Authors: Okoroh Juliet , Sarpong Doris Ottie-Boakye , Essoun Samuel , Riviello Robert , Harris Hobart , Weissman Joel S.
Published: January 2020

Background

According to the World Health Organization, essential surgery should be recognized as an essential component of universal health coverage. In Ghana, insurance is associated with a reduction in maternal mortality and improved access to essential medications, but whether it eliminates financial barriers to surgery is unknown. This study tested the hypothesis that insurance protects surgical patients against financial catastrophe.

Methods

We interviewed patients admitted to the general surgery wards of Korle-Bu Teaching Hospital (KBTH) between February 1, 2017 – October 1, 2017 to obtain demographic data, income, occupation, household expenditures, and insurance status. Surgical diagnoses and procedures, procedural fees, and anesthesia fees incurred were collected through chart review. The data were collected on a Qualtrics platform and analyzed in STATA version 14.1. Fisher exact and Student T-tests were used to compare the insured and uninsured groups. Threshold for financial catastrophe was defined as health costs that exceeded 10% of household expenditures, 40% of non-food expenditures, or 20% of the individual’s income.

Results

Among 196 enrolled patients, insured patients were slightly older [mean 49 years vs 40 years P < 0.05] and more of them were female [65% vs 41% p < 0.05]. Laparotomy (22.2%) was the most common surgical procedure for both groups. Depending on the definition, 58–87% of insured patients would face financial catastrophe, versus 83–98% of uninsured patients (all comparisons by definition were significant, p < .05).

Conclusion

This study—the first to evaluate the impact of insurance on financial risk protection for surgical patients in Ghana—found that although insured patients were less likely than uninsured to face financial catastrophe as a result of their surgery, more than half of insured surgical patients treated at KBTH were not protected from financial catastrophe under the Ghana’s national health insurance scheme due to out-of-pocket payments. Government-specific strategies to increase the proportion of cost covered and to enroll the uninsured is crucial to achieving universal health coverage inclusive of surgical care.

Trial registration

Registered at www.clinical trials.gov identifier NCT03604458.
Negotiating bodily sensations between patients and GPs in the context of standardized cancer patient pathways – an observational study in primary care
Authors: Hultstrand Cecilia , Coe Anna-Britt , Lilja Mikael , Hajdarevic Senada
Published: January 2020

Background

How interactions during patient-provider encounters in Swedish primary care construct access to further care is rarely explored. This is especially relevant nowadays since Standardized Cancer Patient Pathways have been implemented as an organizational tool for standardizing the diagnostic process and increase equity in access. Most patients with symptoms indicating serious illness as cancer initially start their diagnostic trajectory in primary care. Furthermore, cancer symptoms are diverse and puts high demands on general practitioners (GPs). Hence, we aim to explore how presentation of bodily sensations were constructed and legitimized in primary care encounters within the context of Standardized Cancer Patient Pathways (CPPs).

Methods

Participant observations of patient-provider encounters (n = 18, on 18 unique patients and 13 GPs) were carried out at primary healthcare centres in one county in northern Sweden. Participants were consecutively sampled and inclusion criteria were i) patients (≥18 years) seeking care for sensations/symptoms that could indicate cancer, or had worries about cancer, Swedish speaking and with no cognitive disabilities, and ii) GPs who met with these patients during the encounter. A constructivist approach of grounded theory method guided the data collection and was used as a method for analysis, and the COREQ-checklist for qualitative studies (Equator guidelines) were employed.

Results

One conceptual model emerged from the analysis, consisting of one core category Negotiating bodily sensations to legitimize access, and four categories i) Justifying care-seeking, ii) Transmitting credibility, iii) Seeking and giving recognition, and iv) Balancing expectations with needs. We interpret the four categories as social processes that the patient and GP constructed interactively using different strategies to negotiate. Combined, these four processes illuminate how access was legitimized by negotiating bodily sensations.

Conclusions

Patients and GPs seem to be mutually dependent on each other and both patients’ expertise and GPs’ medical expertise need to be reconciled during the encounter. The four social processes reported in this study acknowledge the challenging task which both patients and primary healthcare face. Namely, negotiating sensations signaling possible cancer and further identifying and matching them with the best pathway for investigations corresponding as well to patients’ needs as to standardized routines as CPPs.
Examining health care providers’ and middle-level managers’ readiness for change: a qualitative study
Authors: Austin Tujuanna , Chreim Samia , Grudniewicz Agnes
Published: January 2020

Background

Readiness is a critical precursor of successful change; it denotes whether those involved in the change are motivated and empowered to participate in the change. Research on readiness tends to focus on frontline providers or individuals in non-managerial positions and offers limited attention to individuals in middle management positions who are expected to lead frontline providers in change implementation. Yet middle-level managers are also recipients of changes that are planned and decreed by those in higher positions. This study sought to examine both frontline provider and middle manager readiness for change in the context of primary care program integration.

Methods

Using a qualitative case study approach, we examined how frontline providers and middle managers experienced six readiness factors: discrepancy, appropriateness, valence, efficacy, fairness and trust in management. Data were collected through documents, meeting observation and semi-structured interviews with frontline providers and middle managers involved in the change.

Results

The findings highlighted similarities and differences in readiness experiences of frontline providers and middle managers. Across both types of participants, we found that the notion ofvalenceshould be expanded to consider individuals’ evaluation of benefits to patients and the health system;efficacyapplies to both content and process of change; fairness and trust in management findings require further exploration to determine their appropriateness to be incorporated in models of readiness for change; andtrust in management(or lack of trust) has a cascading influence across the levels in the organization.

Conclusions

Our study makes a contribution by nuancing and extending conceptualizations of individual readiness factors, and by highlighting the central role of middle manager readiness for change. Implications of the study include the need to consider readiness factors prior to the implementation of change and the importance of fostering readiness throughout all levels of the organization.
‘We spray and walk away’: wall modifications decrease the impact of indoor residual spray campaigns through reductions in post-spray coverage
Authors: Opiyo Mercy A. , Paaijmans Krijn P.
Published: January 2020

Malaria prevalence has significantly reduced since 2000, largely due to the scale-up of vector control interventions, mainly indoor residual spraying (IRS) and long-lasting insecticide-treated nets (LLINs). Given their success, these tools remain the frontline interventions in the fight against malaria. Their effectiveness relies on three key ingredients: the intervention, the mosquito vector and the end-user. Regarding the intervention, factors such as the insecticide active ingredient(s) used and the durability and/or bio-efficacy of the tool over time are critical. For the vectors, these factors include biting and resting behaviours and the susceptibility to insecticides. Finally, the end-users need to accept and properly use the intervention. Whilst human attitude and behaviour towards LLINs are well-documented both during and after distribution, only initial coverage is monitored for IRS and in a few geographic settings the residual efficacy of the used product. Here, the historical evidence on end-users modifying their wall surfaces post-spraying is presented, a behaviour that has the potential to reduce actual IRS coverage, effectiveness and impact, as fewer people are truly protected. Therefore, clear guidelines on how to monitor IRS acceptability and/or coverage, both before, during and after spraying, are urgently needed as part of the Monitoring and Evaluation of malaria programmes.
A panel of recombinant proteins from human-infective Plasmodium species for serological surveillance
Authors: Müller-Sienerth Nicole , Shilts Jarrod , Kadir Khamisah Abdul , Yman Victor , Homann Manijeh Vafa , Asghar Muhammad , Ngasala Billy , Singh Balbir , Färnert Anna , Wright Gavin J.
Published: January 2020

Background

Malaria remains a global health problem and accurate surveillance of Plasmodium parasites that are responsible for this disease is required to guide the most effective distribution of control measures. Serological surveillance will be particularly important in areas of low or periodic transmission because patient antibody responses can provide a measure of historical exposure. While methods for detecting host antibody responses to Plasmodium falciparum and Plasmodium vivax are well established, development of serological assays for Plasmodium knowlesi, Plasmodium ovale and Plasmodium malariae have been inhibited by a lack of immunodiagnostic candidates due to the limited availability of genomic information.

Methods

Using the recently completed genome sequences from P. malariae, P. ovale and P. knowlesi, a set of 33 candidate cell surface and secreted blood-stage antigens was selected and expressed in a recombinant form using a mammalian expression system. These proteins were added to an existing panel of antigens from P. falciparum and P. vivax and the immunoreactivity of IgG, IgM and IgA immunoglobulins from individuals diagnosed with infections to each of the five different Plasmodium species was evaluated by ELISA. Logistic regression modelling was used to quantify the ability of the responses to determine prior exposure to the different Plasmodium species.

Results

Using sera from European travellers with diagnosed Plasmodium infections, antigens showing species-specific immunoreactivity were identified to select a panel of 22 proteins from five Plasmodium species for serological profiling. The immunoreactivity to the antigens in the panel of sera taken from travellers and individuals living in malaria-endemic regions with diagnosed infections showed moderate power to predict infections by each species, including P. ovale, P. malariae and P. knowlesi. Using a larger set of patient samples and logistic regression modelling it was shown that exposure to P. knowlesi could be accurately detected (AUC = 91%) using an antigen panel consisting of the P. knowlesi orthologues of MSP10, P12 and P38.

Conclusions

Using the recent availability of genome sequences to all human-infective Plasmodium spp. parasites and a method of expressing Plasmodium proteins in a secreted functional form, an antigen panel has been compiled that will be useful to determine exposure to these parasites.
The PI3K subunits, P110α and P110β are potential targets for overcoming P-gp and BCRP-mediated MDR in cancer
Authors: Zhang Lei , Li Yidong , Wang Qianchao , Chen Zhuo , Li Xiaoyun , Wu Zhuoxun , Hu Chaohua , Liao Dan , Zhang Wei , Chen Zhe-Sheng
Published: January 2020

Background

PI3K/AKT is a vital signaling pathway in humans. Recently, several PI3K/AKT inhibitors were reported to have the ability to reverse cancer multidrug resistance (MDR); however, specific targets in the PI3K/AKT pathways and the mechanisms associated with MDR have not been found because many of the inhibitors have multiple targets within a large candidate protein pool. AKT activation is one presumed mechanism by which MDR develops during cancer treatment.

Methods

The effects of inhibiting PI3K 110α and 110β by BAY-1082439 treatment and CRISPR/Cas9 knockout were examined to determine the possible functions of BAY-1082439 and the roles of PI3K 110α and 110β in the reversal of MDR that is mediated by the downregulation of P-gp and BCRP. Inhibition of AKT with GSK-2110183 showed that the downregulation of P-gp and BCRP is independent of generalized AKT inactivation. Immunofluorescence, immunoprecipitation, MTT, flow cytometry and JC-1 staining analyses were conducted to study the reversal of MDR that is mediated by P-gp and BCRP in cancer cells. An ATPase assay and a structural analysis were also used to analyze the potential mechanisms by which BAY-1082439 specifically targets PI3K 110α and 110β and nonspecifically influences P-gp and BCRP.

Results

By inhibiting the activation of the PI3K 110α and 110β catalytic subunits through both the administration of BAY-1082439 and the CRISPR/Cas9 deletion of Pik3ca and Pik3cb, the ATP-binding cassette transporters P-gp/ABCB1 and BCRP/ABCG2 were downregulated, thereby reestablishing the drug sensitivity of human epidermoid carcinoma and non-small cell lung cancer (NSCLC) MDR cells. Inhibition of AKT did not reverse the MDR mediated by P-gp or BCRP. The ABC family proteins and AKT may play MDR-enhancing roles independently.

Conclusions

The reversal of the dual functions of ABC-transporter-mediated and AKT-activation-enhanced MDR through the inhibition or knockout of PI3K 110α or 110β promises to improve current strategies based on combined drug treatments to overcome MDR challenges.
Development of elastin-like polypeptide for targeted specific gene delivery in vivo
Authors: Yi Aena , Sim Dahye , Lee Young-Jin , Sarangthem Vijaya , Park Rang-Woon
Published: January 2020

Background

The successful deliveries of siRNA depend on their stabilities under physiological conditions because greater in vivo stability enhances cellular uptake and enables endosomal escape. Viral-based systems appears as most efficient approaches for gene delivery but often compromised in terms of biocompatibility, patient safety and high cost scale up process. Here we describe a novel platform of gene delivery by elastin-like polypeptide (ELP) based targeting biopolymers.

Results

For better tumor targeting and membrane penetrating characteristics, we designed various chimeric ELP-based carriers containing a cell penetrating peptide (Tat), single or multiple copies of AP1 an IL-4 receptor targeting peptide along with coding sequence of ELP and referred as Tat-A1E28 or Tat-A4V48. These targeted polypeptides were further analyzed for its ability to deliver siRNA (Luciferase gene) in tumor cells in comparison with non-targeted controls (Tat-E28 or E28). The positively charged amino acids of these polypeptides enabled them to readily complex with negatively charged nucleic acids. The complexation of nucleic acid with respective polypeptides facilitated its transfection efficiency as well as stability. The targeted polypeptides (Tat-A1E28 or Tat-A4V48) selectively delivered siRNA into tumor cells in a receptor-specific fashion, achieved endosomal and lysosomal escape, and released gene into cytosol. The target specific delivery of siRNA by Tat-A1E28 or Tat-A4V48 was further validated in murine breast carcinoma 4T1 allograft mice model.

Conclusion

The designed delivery systems efficiently delivered siRNA to the target site of action thereby inducing significant gene silencing activity. The study shows Tat and AP1 functionalized ELPs constitute a novel gene delivery system with potential therapeutic applications.
Pre-treatment with the viral Toll-like receptor 3 agonist poly(I:C) modulates innate immunity and protects neutropenic mice infected intracerebrally with Escherichia coli
Authors: Ribes Sandra , Arcilla Christa , Ott Martina , Schütze Sandra , Hanisch Uwe-Karsten , Nessler Stefan , Nau Roland
Published: January 2020

Background

Individuals with impaired immunity are more susceptible to infections than immunocompetent subjects. No vaccines are currently available to induce protection againstE.colimeningoencephalitis. This study evaluated the potential of poly(I:C) pre-treatment to induce trained immunity. Poly(I:C) was administered as a non-specific stimulus of innate immune responses to protect immunocompetent and neutropenic wild-type mice from a subsequent challenge by the intracranial injection ofE.coliK1.

Methods

Three days prior to infection, mice received an intraperitoneal injection of poly(I:C) or vehicle. Kaplan-Meier survival curves were analyzed. In short-term experiments, bacterial titers and the inflammatory response were characterized in the blood, cerebellum, and spleen homogenates. NK cell subpopulations in the brain and spleen were analyzed by flow cytometry. Numbers of microglia and activation scores were evaluated by histopathology.

Results

Pre-treatment with 200 μg poly(I:C) increased survival time, reduced mortality, and enhanced bacterial clearance in the blood, cerebellum, and spleen at early infection in neutropenic mice. Poly(I:C)-mediated protection correlated with an augmented number of NK cells (CD45+NK1.1+CD3−) and Iba-1+microglial cells and a higher production of IFN-γ in the brain. In the spleen, levels of CCL5/RANTES and IFN-γ were increased and sustained in surviving poly(I:C)-treated animals for 14 days after infection. In immunocompetent animals, survival time was not significantly prolonged in poly(I:C)-treated animals although poly(I:C) priming reduced brain bacterial concentrations compared with vehicle-injected animals at early infection.

Conclusions

Pre-treatment with the viral TLR3 agonist poly(I:C) modulated innate immune responses and strengthened the resistance of neutropenic mice againstE.coliK1 meningoencephalitis.
Down-regulated lncRNA SBF2-AS1 inhibits tumorigenesis and progression of breast cancer by sponging microRNA-143 and repressing RRS1
Authors: Xia Wenfei , Liu Yun , Cheng Teng , Xu Tao , Dong Menglu , Hu Xiaopeng
Published: January 2020

Background

Recently, the roles of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) in human diseases have been unveiled, this research was conducted to explore the impacts of lncRNA SET-binding factor 2-antisense RNA1 (SBF2-AS1), miR-143 and resistance to ralstonia solanacearum 1 (RRS1) on breast cancer (BC) development.

Methods

The expression of SBF2-AS1, miR-143 and RRS1 in BC tissues, as well as in MDA-MB-231 and MCF-7 cell lines were assessed. Subsequently, the cells were transfected with miR-143 mimics or/and silenced or overexpressed SBF2-AS1 plasmids, and their negative controls. Then the proliferation, colony formation ability, cell cycle arrest, apoptosis, invasion and migration of the cells were assessed through gain- and loss-of-function experiments. Furthermore, the tumor growth, ki-67 expression and apoptosis in vivo were observed by subcutaneous tumorigenesis in nude mice. Binding relation between SBF2-AS1 and miR-143, and that between miR-143 and RRS1 were confirmed.

Results

SBF2-AS1 and RRS1 were amplified, while miR-143 was reduced in BC tissues and cells. Reduced SBF2-AS1 and elevated miR-143 could repress the proliferation, invasion and migration via restraining RRS1 expression. Moreover, knockdown of SBF2-AS1 up-regulated miR-143 to promote the apoptosis of BC cells by downregulating RRS1, resulting in a prohibitive effect on the tumorigenesis and progression of BC. Results of in vivo experiments indicated that the inhibited SBF2-AS1 and overexpressed miR-143 could restrict BC cell proliferation and promote apoptosis, and decelerate tumor growth in xenografts.

Conclusion

We have discovered in this study that down-regulated SBF2-AS1 could inhibit tumorigenesis and progression of BC by up-regulation miR-143 and repressing RRS1, which provides basic therapeutic considerations for a novel target against BC.
Sublingual microcirculation does not reflect red blood cell transfusion thresholds in the intensive care unit—a prospective observational study in the intensive care unit
Authors: Scheuzger Jonas , Zehnder Anna , Meier Vera , Yeginsoy Desirée , Flükiger Julian , Siegemund Martin
Published: January 2020

Purpose

Hemoglobin (Hb) transfusion thresholds are established in intensive care units. A restrictive transfusion threshold (Hb 70–75 g/l) is recommended in septic patients, and a liberal transfusion threshold (Hb 90 g/l) for cardiogenic shock. It is unclear whether these historically adopted transfusion thresholds meet the challenges of individual patients.

Methods

We evaluated microvascular flow index (MFI) and proportion of perfused vessels (PPV) in the sublingual microcirculation with CytoCam-IDF microscopy and near-infrared spectroscopy (NIRS). A study team-independent, treating intensivist assigned a total of 64 patients to 1 of 2 two transfusion thresholds, 43 patients to the Hb 75 g/l threshold and 21 patients to the Hb 90 g/l threshold, at a surgical intensive care unit. We performed microcirculatory measurements 1 h before and 1 h after transfusion of 1 unit of red blood cells.

Results

Microcirculatory flow variables correlated negatively with pre-transfusion flow variables (ΔMFI: ρ = − 0.821, p <  0.001; ΔPPV: ρ = − 0.778, p <  0.001). Patients with good initial microcirculation (cutoffs: MFI > 2.84, PPV > 88%) showed a deteriorated microcirculation after red blood cell transfusion. An impaired microcirculation improved after transfusion. At both transfusion thresholds, approximately one third of the patients showed an initially impaired microcirculation. In contrast, one third in every group had good microcirculation above the cutoff variables and did not profit from the transfusion.

Conclusion

The data suggest that the established transfusion thresholds and other hemodynamic variables do not reflect microcirculatory perfusion of patients. Blood transfusion at both thresholds 75 g/l and 90 g/l hemoglobin can either improve or harm the microcirculatory blood flow, questioning the concept of arbitrary transfusion thresholds.
Performance difference of graph-based and alignment-based hybrid error correction methods for error-prone long reads
Authors: Wang Anqi , Au Kin Fai
Published: January 2020

The error-prone third-generation sequencing (TGS) long reads can be corrected by the high-quality second-generation sequencing (SGS) short reads, which is referred to as hybrid error correction. We here investigate the influences of the principal algorithmic factors of two major types of hybrid error correction methods by mathematical modeling and analysis on both simulated and real data. Our study reveals the distribution of accuracy gain with respect to the original long read error rate. We also demonstrate that the original error rate of 19% is the limit for perfect correction, beyond which long reads are too error-prone to be corrected by these methods.