bluuebunny/crossref_metadata_2025 huggingface dataset:
Breast Implant–Associated Anaplastic Large-Cell Lymphoma: Current Understanding and Recommendations for Management
Authors: St. Cyr Tessa L. , Pockaj Barbara A. , Northfelt Donald W. , Craig Fiona E. , Clemens Mark W. , Mahabir Raman C.
Published: May 2020

Worldwide, millions of women live with breast implants. Therefore, it is important that physicians be aware of an uncommon but possibly serious complication arising from breast implants: breast implant–associated anaplastic large cell lymphoma (BIA-ALCL). Breast implant–associated anaplastic large-cell lymphoma most commonly presents as a delayed fluid collection around a textured breast implant or as a mass in the capsule surrounding the implant. The exact pathogenesis of the disease remains unclear. The neoplastic cells of BIA-ALCL show strong uniform staining for CD30 and are consistently negative for activin receptor-like kinase 1. Patients with confirmed cases should be referred to a lymphoma specialist or breast medical oncologist for a complete oncologic evaluation before any surgical intervention. For disease confined to the fluid accumulation or capsule, or both, surgical removal of the implant and complete capsulectomy is the preferred treatment. Postoperative chemotherapy or radiation, or both, are not considered necessary for patients with limited-stage disease and are reserved for advanced disease stages. Generally, BIA-ALCL is a local disease that follows an indolent course and has an excellent prognosis. Although complete remission of disease has occurred in patients with BIA-ALCL, median overall survival is reduced. As of March 2018, approximately 529 unique, confirmed BIA-ALCL cases had been reported in 23 countries. To date, 16 patients have died from BIA-ALCL, and all had extracapsular involvement. The aim of this article is to summarize the diagnosis, evaluation, and management of BIA-ALCL, based on established guidelines, for all practitioners who may care for patients with breast implants.
Classification and Clinicopathologic Study of Orofacial Mesenchymal Tumors: A Retrospective Study
Authors: Akinyamoju Akindayo Olufunto , Adeyemi Bukola Folasade , Kolude Bamidele
Published: May 2020

Aim:

To determine the prevalence of orofacial mesenchymal neoplasms and classify them using the WHO criteria while appraising its applicability.

Materials and Methods:

This was a retrospective study involving a total sample of 192 entries diagnosed as mesenchymal tumors for the period 1990-2018 at the Oral Pathology Department, University College Hospital, Ibadan. The histopathology records were examined and clinicopathological data were obtained. Hematoxylin and Eosin slides of the cases were assessed to confirm the diagnosis. Tumors were classified using the WHO 2013 classification. Data were analyzed and presented using descriptive statistics.

Results:

Orofacial mesenchymal tumors constituted 7.9% of 2402 biopsies. There were 26 diagnoses in 161 tumors of the WHO classification. Male-to-female ratio was 1.1:1. Peak age group was in the third decade. Soft tissue tumors were 61.5%, while bone tumors were 38.5%. Benign tumors constituted 49.5%, while sarcomas and intermediate tumors were 45.8% and 4.7%, respectively. The mandibular region (29.7%) was the most commonly affected site. Adipocytic and osteogenic tumors were the most prevalent tumors in the soft tissue and osteoarticular series, respectively, representing 19.8% and 32.3% of all cases, while orofacial sarcomas constituted 3.6% of all lesions seen.

Conclusion:

The findings in this study are in line with those of previous studies. However, the WHO classification may not be suited for the orofacial region. Crafting of a classification system for mesenchymal tumors of the orofacial region would thus be necessary.
Successful Fibrinolytic Therapy in a Challenging Obstructive Prosthetic Mitral Valve Thrombosis
Authors: Essa Amr , Haddad Toufik , Slattery Terrence
Published: May 2020

Prosthetic valve thrombosis is a rare and severe complication of the mechanical prosthetic valve. Management can be challenging due to varying clinical presentation, overlapping features of differential diagnosis, and lack of randomized controlled trials on the therapeutic options. In this article, we report the case of a patient with a mechanical prosthetic mitral valve presented with symptoms of heart failure, and an echocardiography showing increased mean pressure gradient across the prosthesis along with a fixed posterior leaflet and a partially restricted anterior leaflet with no visible mass. That raised the concern for an obstructed prosthesis. After multimodality imaging and multidisciplinary team discussions, prosthetic valve thrombosis diagnosis was favored over other different diagnoses that included but not limited to pannus ingrowth. Fibrinolytic therapy was administrated, and the patient was discharged on optimal anticoagulation. Repeated echocardiography a month later showed normal mean gradient and normal functioning prosthetic mitral valve without the need for repeat mitral valve surgery.
Calciphylaxis in a Patient on Home Hemodialysis
Authors: Adapa Sreedhar , Naramala Srikanth , Gayam Vijay , Koduri Narayana Murty , Daggubati Subba Rao , Patel Pallav , Konala Venu Madhav
Published: May 2020

Calciphylaxis is a rare and severe complication characterized by calcification of arterioles and capillaries in the dermis and subcutaneous adipose tissue that leads to ischemia, necrosis, and painful skin lesions in patients with end-stage renal disease (ESRD). It is also known as calcific uremic arteriolopathy. Calciphylaxis occurs most commonly with the ESRD with skin ulceration as a predominant presenting feature. Calcium-phosphorus dysregulation in dialysis patients are traditionally considered as a risk factor for the development of calciphylaxis. The involvement of an integrated interdisciplinary and multifaceted approach is key to the success of the calciphylaxis treatment. We present a case of a 51-year-old female with ESRD on home hemodialysis who developed calciphylaxis, which was successfully managed with increasing dialysis prescription, diligent wound care, and sodium thiosulfate infusion. Management of calciphylaxis in a patient receiving home hemodialysis has never been reported as per the review of the literature. Calciphylaxis is a sporadic disease, frequently encountered in the patients undergoing hemodialysis and carries a very grave prognosis. Current treatment is rarely effective, so preventive strategies play an important role by modifying the risk factors that promote the development of calciphylaxis.
Associations Between Subjective Tinnitus and Cognitive Performance: Systematic Review and Meta-Analyses
Authors: Clarke Nathan A. , Henshaw Helen , Akeroyd Michael A. , Adams Bethany , Hoare Derek J.
Published: May 2020

Tinnitus is the perception of sound in the absence of a corresponding external sound source, and bothersome tinnitus has been linked to poorer cognitive performance. This review comprehensively quantifies the association between tinnitus and different domains of cognitive performance. The review protocol was preregistered and published in a peer-reviewed journal. The review and analyses were reported according to Preferred Reporting Items for Systematic Review and Meta-analysis guidelines. Peer-reviewed literature was searched using electronic databases to find studies featuring participants with tinnitus who had undertaken measures of cognitive performance. Studies were assessed for quality and categorized according to an established cognitive framework. Random-effects meta-analyses were performed on various cognitive domains with potential moderator variables assessed where possible. Thirty-eight records were included in the analysis from a total of 1,863 participants. Analyses showed that tinnitus is associated with poorer executive function, processing speed, general short-term memory, and general learning and retrieval. Narrow cognitive domains of Inhibition and Shifting (within executive function) and learning and retrieval (within general learning and retrieval) were also associated with tinnitus.
The combined effects of product and geographical diversification on performance: Evidence in manufacturing SMEs
Authors: Benito-Osorio Diana , Colino Alberto , Guerras-Martín Luis Ángel , Zúñiga-Vicente José Ángel
Published: May 2020

This study explores both the individual impact of geographical diversification and its effect combined with product diversification on small and medium-sized enterprises’ (SMEs) performance. Unlike most prior studies, this study distinguishes between related and unrelated product diversification. The research setting is a sample of manufacturing SMEs (1994–2014). By using dynamic panel data models, the results provide statistical support for the existence of a horizontal S-shaped relationship between geographical diversification and performance. The findings also indicate that while related product diversification positively enhances the performance of those SMEs engaged in geographical diversification (albeit not indefinitely), unrelated product diversification may significantly impair it, especially for SMEs opting for low and high levels of international diversification. Our study reveals that product and international diversification strategies in the case of SMEs are complementary or substitutive strategies depending on the specific type of product diversification strategy and the level of geographical diversification adopted.

JEL CLASSIFICATION: F23; L25; M16
Competitive strategies and international new ventures’ performance: Exploring the moderating effects of internationalization duration and preparation
Authors: Crespo Nuno Fernandes , Simões Vitor Corado , Fontes Margarida
Published: May 2020

The purpose of this article is twofold: to bring back to discussion the importance of strategy as a key element for international new ventures (INVs) to achieve higher international performance and to assess the relevance of contingency perspective, particularly two organizational contingency factors (internationalization duration and internationalization preparation), in moderating the strategy–performance relationship. The framework developed addresses the effects of four competitive strategies (cost leadership and innovation-based, marketing-based, and quality- and service-based differentiation) as determinants of INVs’ international performance. In addition, internationalization duration and internationalization preparation are included as moderators of these relationships. The hypotheses were tested using a sample of 319 INVs. The findings show that marketing and quality and service differentiation strategies are associated with higher INVs’ international performance and that internationalization duration and internationalization preparation play relevant moderating effects.

JEL CLASSIFICATION: M13; M16
Learning from foreign operation modes: The virtuous path for innovation
Authors: Villar Cristina , Pla-Barber José , Ghauri Pervez
Published: May 2020

In this article, we analyze the impact of learning from internationalization on small and medium enterprises’ (SMEs) performance along different development paths. Drawing on the exploitation versus exploration logic, we use an alternative view of foreign operation modes (the learning perspective) to provide insights into the impact of such learning on technological and organizational innovation as well as overall performance. Our results, which are derived from a sample of 132 SMEs active in traditional manufacturing industries, point to a path to superior performance that entails resource-augmenting operation modes and organizational innovation.

JEL CLASSIFICATION: O31; F23; L25; M10; M16
Prevalence and Patterns of Dental Care Utilization among US-Born and Non–US Born Hispanics in the Hispanic Community Health Study/Study of Latinos
Authors: Akinkugbe A.A. , Raskin S.E. , Donahue E.E. , Youngblood M.E. , Laniado N.N. , Perreira K.M.
Published: May 2020

Objectives:

Access to routine dental services is important to maintaining good oral health. The aims of this study were to describe the dental care utilization patterns of a diverse group of Hispanic/Latino men and women and assess differences in dental care utilization by perceived need for dental care and proxy measures of acculturation.

Methods:

Data from 13,792 participants of the Hispanic Community Health Study were analyzed with SAS 9.4. Time since last dental visit was dichotomized into <1 and ≥1 y. Acculturation measures included the language and social subscales of the Short Acculturation Scale for Hispanics, the Multiethnic Study of Atherosclerosis nativity subscore, and immigrant generation. Survey logistic regression adjusted for demographic (age and sex) and health-related variables, estimated associations among perceived need for dental care, acculturation measures, and dental care utilization.

Results:

About a quarter (23%) of the participants were born in the 50 US states, excluding territories, while 77% were non–US born. Overall, 74% perceived a need for dental care. Upon covariate adjustment, perceiving a need for dental care was associated with reduced odds of reporting a past-year dental visit (odds ratio, 0.32; 95% CI, 0.28 to 0.37), while there appeared to be no meaningful association between proxy measures of acculturation and past-year dental visit. Having health insurance was significantly associated with a past-year dental visit (odds ratio, 2.23; 95% CI, 1.99 to 2.49) for all groups combined and among the different Hispanic/Latino background groups.

Conclusions:

Acculturation affects general health and contributes to general health disparities; however, its role in dental care utilization remains questionable. Given that acculturation is a process that occurs over several years, longitudinal studies that evaluate oral health trajectories along the acculturation continuum are needed.

Knowledge Transfer Statement:

The results of this study are valuable for dental public health program planning and implementation for minority groups, as it describes the varying patterns of dental care utilization among US-born and non–US born Hispanics/Latinos and identifies factors that may partly explain dental care utilization patterns, such as acculturation.
Performing legitimacy in neighbourhood planning: Conflicting identities and hybrid governance
Authors: Yuille Andy
Published: May 2020

Neighbourhood planning in the UK is a striking example of the international turn to localism and public participation, the statutory weight afforded to it setting it apart from many other initiatives. Its promoters portray it as a straightforward transfer of power from state to community. However, its legitimacy relies upon complex, hybrid forms of representative, participatory and epistemological authority. A growing literature is interrogating the relations between neighbourhood planning groups – the collectives utilising these new powers – and the neighbourhoods for which they speak. This paper brings empirical evidence forward to build on such work by exploring how the identities of neighbourhood planning groups are constituted. Three different and sometimes conflicting relational identities are characterised. Each identity is associated with particular material relations, types of knowledge and ways of representing the neighbourhood, and consequently produces different forms of legitimacy. Analysing identities in this way aids understanding of the practices through which legitimacy is achieved in experiments in democracy that rely on hybrid forms of authority. It may also open possibilities for intervention that speak to some of the concerns raised in the literature about these hybrid forms.
Blurring the shoreline: De- and re-infrastructuring and the changing colors of European flood policy
Authors: Petersson Jesper
Published: May 2020

This paper provides a genealogy of the emergence of a common EU flood policy, including the scope and direction of this policy. Noticing how EU policy proposes green infrastructure (associated with using nature as a buffer zone in managing floods) as an alternative to grey infrastructure (implying fixed installations of concrete and cement), this paper adopts the theoretical lens of the so-called infrastructural turn, which advocates a relational investigation of infrastructure. By engaging this approach, the paper shows how flood infrastructure can contain very different compositions of (unruly) water and (settled) land. A narrative of a historically strong focus on guarding society from the powerful forces of nature through a fixed line of defense is increasingly giving way to more muddy states—quite literally—where society is expected to learn to live with flooding and show ecological consideration. To capture the EU’s, and especially the European Commission’s efforts to establish a pan-European flood infrastructure that accommodates this turn, the concepts of de- and re-infrastructuring are developed. These concepts act as heuristic devices to capture how policy performs some combinations between water and land as constituting an attractive and functional flood infrastructure, but constitutes other infrastructural relations of the aquatic and the terrestrial as undesirable and, hence, as malfunctioning. This performative act of distinguishing between what constitutes “good and proper” versus “bad and undesirable” infrastructure is referred to as a politics of infrastructure.
A Little AXER ABC: ATP, BiP, and Calcium Form a Triumvirate Orchestrating Energy Homeostasis of the Endoplasmic Reticulum
Authors: Zimmermann Richard , Lang Sven
Published: May 2020

Pioneering work in the 1990s started to address an interesting question. How is the main cellular energy source, adenosine triphosphate (ATP), imported into the mammalian endoplasmic reticulum (ER)? Despite its high-energy demand, large volume, and structural as well as functional complexity, the ER harbors no intricate system for ATP synthesis or regeneration. Although the original biochemical reconstitution approaches established hallmarks of the ATP transport into the ER including nucleotide selectivity, affinity, and antiport mode, the more recent live-cell imaging methods employing sensitive, localized molecular probes identified the elusive ATP/adenosine diphosphate (ADP) exchanger. According to its selectivity and localization, the identified SLC35B1 protein was rebranded AXER. Here, we discuss the identification and regulation of AXER plus the cytosolic partners (AMP-activated protein kinase, AMPK) and subcellular structures (mitochondrial–ER contact sites, MERCs) acting in concert with it to orchestrate energy homeostasis of the mammalian ER. Furthermore, we combine the two seemingly controversial regulatory mechanisms (lowER and CaATiER) in a unifying hypothesis.
Plastic modification of human cornea in vivo: applications to clinical refractive procedures
Authors: Medina Antonio , Greene Peter R.
Published: May 2020

Purpose:

The purpose of this report is to quantify how pressure applied to the human cornea, either physiological or intentional, affects its curvature. In particular, how pneumatic procedures flatten the central cornea and keep it flat over time, thereby decreasing the patient’s myopia.

Methods:

A viscoelastic model is developed for plastic deformation which gives us the basic governing equations of the elastic and plastic strain of corneal stroma. The model is applied to data from corneas of six patients who underwent pneumatic keratology (NEumatica Keratologia) to reduce their myopia.

Results:

The model shows corneal dimensional stability for long periods of time after NEumatica Keratologia that decay with an exponential time constant. Separate equations are developed that relate corneal plastic strain to the pressure applied and its duration ε =  σ0 t1/ η1, to change in refraction ε = 2 × ΔRefr, to keratometry radius increase ε = Δ R/ R, and to corneal thinning ε = sqr (Δ h/ h). The average values obtained for ε from the patients’ data are 3%, 3.2%, 3%, and 2.6%, respectively, all in remarkable agreement. The average refraction change is found to remain stable at ΔRefr = +1.67D ± 5.2%. Clinical data yield good agreement of theory and treatment results.

Conclusions:

The model proposed is a good description of NEumatica Keratologia outcomes. Practical applications include the long-term stable correction of myopia with refractive procedures. High myopia subjects can benefit from this procedure because NEumatica Keratologia corrects and protects the central cornea radius by stretching the peripheral cornea.
Association of Lipid Profile with Sleep-Disordered Breathing in Patients with Acute Ischemic Stroke
Authors: Šiarnik Pavel , Kollár Branislav , Filippi Pavol , Klobučníková Katarína , Hlucháňová Alžbeta , Žitňanová Ingrid , Turčáni Peter
Published: May 2020

Background: Sleep-disordered breathing (SDB) and hyperlipidemia belong to known stroke risk factors. There is an increasing evidence that chronic intermittent hypoxia is independently associated with dyslipidemia. However, the clinical evidence linking SDB with dyslipidemia is poorly described. In this study, we aimed to find possible association between lipoprotein levels and sleep apnea parameters in acute ischemic stroke patients.

Methods: 90 patients with acute cerebral ischemia were prospectively enrolled. Blood samples were obtained in a fasting condition within 24 hours after the stroke onset for the analysis of total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides (TG). SDB was assessed using standard overnight polysomnography.

Results: SDB was present in 50%, hypercholesterolemia in 52.2%, and hypertriglyceridemia in 20% of the subjects. In linear regression analysis, apnea–hypopnea index (AHI) was the only independent variable significantly associated with LDL levels (β = 0.220, P = 0.04) and TC (β = 0.240, P = .02). Likewise, AHI (β = 0.258, P = .01) with diastolic blood pressure (β = 0.204, P = .05) were the only predictors of cholesterol ratio (TC/HDL) in linear regression analysis. We failed to find any significant association of sleep apnea parameters with the levels of TG and HDL in the regression analyses.

Conclusion: The results of our study suggest no significant association of sleep apnea parameters with TG and HDL. However, AHI was significantly associated with TC, LDL, and cholesterol ratio in patients with acute ischemic stroke.
Genome-wide transcriptome analysis of the STAT6-regulated genes in advanced-stage cutaneous T-cell lymphoma
Authors: Gaydosik Alyxzandria M. , Queen Dawn S. , Trager Megan H. , Akilov Oleg E. , Geskin Larisa J. , Fuschiotti Patrizia
Published: May 2020

The signal transducer and activator of transcription 6 (STAT6) is a critical up-stream mediator of interleukin-13 (IL-13) and IL-4 signaling and is constitutively activated in malignant lymphocytes from Sezary syndrome (SS) and mycosis fungoides (MF), the most common subtypes of cutaneous T-cell lymphomas. By combining genome-wide expression profiling with pharmacological STAT6 inhibition, we have identified the genes regulated by STAT6 in MF/SS tumors. We found that STAT6 regulates several common pathways in MF/SS malignant lymphocytes that are associated with control of cell-cycle progression and genomic stability as well as production of Th2 cytokines. Using ex vivo skin explants from cutaneous MF tumors as well as Sezary cells derived from the blood of SS patients, we demonstrated that inhibition of STAT6 activation downregulates cytokine production and induces cell-cycle arrest in MF/SS malignant lymphocytes, inhibiting their proliferation but not their survival. Furthermore, we show that STAT6 promotes the protumoral M2-like phenotype of tumor-associated macrophages in the tumor microenvironment of advanced stage MF by upregulating the expression of genes associated with immunosuppression, chemotaxis, and tumor matrix remodeling. Thus, we show STAT6 to be a major factor in the pathogenesis and progression of MF/SS, promoting proliferation and invasion of the malignant lymphocytes while inducing a progressive depression of the antitumor immune response. Together, our results provide new insights into disease pathogenesis and offer new prospective targets for therapeutic intervention.
Highly active RRMS and ocrelizumab after failure of alemtuzumab therapy
Authors: Vališ Martin , Ryška Pavel , Halúsková Simona , Klímová Blanka , Pavelek Zbyšek
Published: May 2020

Background

A high multiple sclerosis activity while on alemtuzumab is rather uncommon compared to moderate-efficacy drugs. The purpose of this case report is to present a case of a 37-year-old female patient with bronchial asthma and no other medical history, whose disease activity required switching from dimethyl fumarate to fingolimod, then to alemtuzumab and finally to ocrelizumab.

Case presentation

In our patient, two severe attacks were observed and treated after administration of the first pulse of alemtuzumab. After six months of therapy, patient’s immunological profile showed the expected decrease in CD4+ and CD8+ T-cells and, markedly increased values of CD19+ B-cells. Surprisingly memory B-cells, which typically repopulate very slowly following alemtuzumab treatment, were above baseline levels. Regular administration of ocrelizumab based on a standardised scheme, after the alemtuzumab therapy failure, resulted in the stabilisation of the patient’s condition both clinically and radiologically.

Conclusion

Thus, when the alemtuzumab treatment is unsuccessful, the authors recommend testing T- and B-cell levels and proceeding with an early switch to ocrelizumab if high B-cell counts are found.
Thigh musculature stiffness during active muscle contraction after anterior cruciate ligament injury
Authors: McPherson April L. , Bates Nathaniel A. , Haider Clifton R. , Nagai Takashi , Hewett Timothy E. , Schilaty Nathan D.
Published: May 2020

Background

Altered motor unit (MU) activity has been identified after anterior cruciate ligament (ACL) injury, but its effect on muscle tissue properties is unknown. The purpose of this study was to compare thigh musculature muscle stiffness between control and ACL-injured subjects.

Methods

Thirty ACL-injured subjects and 25 control subjects were recruited. Subjects completed a randomized protocol of isometric contractions while electromyography (EMG) signals were recorded. Three maximum voluntary isometric contractions (MVIC) determined peak force for 10 and 25% MVIC trials. Shear wave elastography was captured during each 10 and 25% MVIC trials.

Results

Differences in muscle stiffness were assessed between limbs and groups. 12 months post-surgery had higher stiffness for VM 0% MVIC, VL 0 and 10% MVIC, and ST 10 and 25% MVIC (all p ≤ 0.04).

Conclusion

Thigh musculature stiffness changed throughout rehabilitation and remained altered at 12 months after ACL reconstruction.
The rise of rapid implementation: a worked example of solving an existing problem with a new method by combining concept analysis with a systematic integrative review
Authors: Smith James , Rapport Frances , O’Brien Tracey A. , Smith Stephanie , Tyrrell Vanessa J. , Mould Emily V. A. , Long Janet C. , Gul Hossai , Cullis Jeremy , Braithwaite Jeffrey
Published: May 2020

Background

The concept of rapid implementation has emerged in the literature recently, but without a precise definition. Further exploration is required to distinguish the concept’s unique meanings and significance from the perspective of implementation science. The study clarifies the concept of rapid implementation and identifies its attributes, antecedents, and consequences. We present a theoretical definition of rapid implementation to clarify its unique meaning and characteristics.

Methods

Rodgers evolutionary concept analysis method, combined with a systematic integrative review, were used to clarify the concept of rapid implementation. A comprehensive search of four databases, including EMBASE, MEDLINE, SCOPUS, and WEB OF SCIENCE was conducted, as well as relevant journals and reference lists of retrieved studies. After searching databases, 2442 papers were identified from 1963 to 2019; 24 articles were found to fit the inclusion criteria to capture data on rapid implementation from across healthcare settings in four countries. Data analysis was carried out using descriptive thematic analysis.

Results

The results locate the introduction of rapid implementation, informed by implementation science. Guidance for further conceptualisation to bridge the gap between research and practice and redefine rigour, adapting methods used (current approaches, procedures and frameworks), and challenging clinical trial design (efficacy-effectiveness-implementation pipeline) is provided.

Conclusions

It is possible that we are on the cusp of a paradigm shift within implementation brought about by the need for faster results into practice and policy. Researchers can benefit from a deeper understanding of the rapid implementation concept to guide future implementation of rapid actionable results in clinical practice.
Statin inhibits large hepatitis delta antigen-Smad3 -twist-mediated epithelial-to-mesenchymal transition and hepatitis D virus secretion
Authors: Liang Yuh-Jin , Sun Cheng-Pu , Hsu Yu-Chen , Chen Yi-Wen , Wang I-An , Su Chien-Wei , Tao Mi-Hua , Wu Jaw-Ching
Published: May 2020

Background

Hepatitis D virus (HDV) infection may induce fulminant hepatitis in chronic hepatitis B patients (CHB) or rapid progression of CHB to cirrhosis or hepatocellular carcinoma. There is no effective treatment for HDV infection. HDV encodes small delta antigens (S-HDAg) and large delta antigens (L-HDAg). S-HDAg is essential for HDV replication. Prenylated L-HDAg plays a key role in HDV assembly. Previous studies indicate that L-HDAg transactivates transforming growth factor beta (TGF-β) and induces epithelial-mesenchymal transition (EMT), possibly leading to liver fibrosis. However, the mechanism is unclear.

Methods

The mechanisms of the activation of Twist promoter by L-HDAg were investigated by luciferase reporter assay, chromatin immunoprecipitation, and co-immunoprecipitation analysis. ELISA and Western blotting were used to analyze L-HDAg prenylation, TGF-β secretion, expression of EMT markers, and to evaluate efficacy of statins for HDV treatment.

Results

We found that L-HDAg activated Twist expression, TGF-β expression and consequently induced EMT, based on its interaction with Smad3 on Twist promoter. The treatment of statin, a prenylation inhibitor, resulted in reduction of Twist promoter activity, TGF-β expression, and EMT, and reduces the release of HDV virions into the culture medium.

Conclusions

We demonstrate that L-HDAg activates EMT via Twist and TGF-β activation. Treatment with statins suppressed Twist expression, and TGF-β secretion, leading to downregulation of EMT. Our findings clarify the mechanism of HDV-induced EMT, and provide a basis for possible novel therapeutic strategies against HDV infection.
Fatty acid profile and estimated desaturase activities in whole blood are associated with metabolic health
Authors: Svendsen Karianne , Olsen Thomas , Nordstrand Rusvik Tove C. , Ulven Stine M. , Holven Kirsten B. , Retterstøl Kjetil , Telle-Hansen Vibeke H.
Published: May 2020

Background

The aim was to investigate if fatty acid profile and estimated desaturase activities; stearoyl CoA-desaturase (SCD), delta-5-desaturase and delta-6-desaturase (D5D; D6D), differ between individuals with metabolically healthy (MH) and unhealthy (MU) phenotypes. We also explored these associations according to BMI categories.

Methods

Men and women at moderately elevated risk of cardiovascular disease were included in this cross-sectional study (n = 321). If subjects met ≥4 out of 5 criteria (elevated triglycerides, total and LDL-cholesterol, HbA1c and low HDL-cholesterol), they were classified as MU (n = 52). If levels were within reference ranges for ≥3 of the same criteria, subjects were classified as MH (n = 150). Utilizing the entire population, a score ranging from 0 to 5 denoting the number of MU criteria met was computed. Estimated desaturase activities were calculated as product-to-precursor ratio of fatty acids in whole blood (SCD16 [16:1n7/16:0], SCD18 [18:1n9/18:0], D5D [18:3n6/18:2n6], D6D [20:4n6/20:3n6]).

Results

Individuals with MH had lower estimated SCD16 and SCD18 activities, whereas estimated D6D activity was higher compared to MU. Similar, SCD16 and SCD18 increased, whereas D6D decreased with increasing criteria of MU. Trends were similar across BMI categories.

Conclusions

This study supports the notion of estimated desaturase activities as possible novel biomarkers of metabolic health irrespectively of BMI.
Efficacy and safety of abacavir/lamivudine plus rilpivirine as a first-line regimen in treatment-naïve HIV-1 infected adults
Authors: Ho Sharlene , Wong Joshua Guoxian , Ng Oon Tek , Lee Cheng Chuan , Leo Yee Sin , Lye David Chien Boon , Wong Chen Seong
Published: May 2020

Background

The anti-retroviral combination of abacavir/lamivudine plus rilpivirine (ABC/3TC/RPV) is not recommended by international guidelines as the first-line regimen. However, it is potent, well-tolerated, and affordable, especially in resource-limited settings. This study evaluates the efficacy and safety of ABC/3TC/RPV as an initial regimen for treatment-naïve HIV-1 infected patients.

Methods

A retrospective study was conducted in the largest HIV care centre in Singapore, with data collected June 2011 to September 2017. All treatment-naïve HIV-1 infected adults prescribed ABC/3TC as part of their initial anti-retroviral therapy regimen were included. The third drug was a non-nucleoside reverse-transcriptase inhibitor (NNRTI) such as RPV or efavirenz (EFV), or boosted protease-inhibitor (PI). Patients were followed up for 48 weeks. The primary end-point was the percentage of patients achieving virologic suppression, analysed using on-treatment analysis. Secondary outcomes included CD4-count change, treatment discontinuation and treatment-related adverse events.

Results

170 patients were included in the study, 66 patients in the RPV group, 104 patients in the comparator group (EFV or boosted PI). 96% (n = 24) in the RPV group and 87% (n = 26) in the comparator group achieved viral suppression at 48 weeks (p = 0.28). Median (interquartile range) time to viral suppression was similar: 17 (14–24) weeks in the RPV group, and 21 (13–26) weeks in the comparator group. There were no statistically significant differences in the CD4 count between the two groups. 14% (n = 9) of patients on RPV discontinued treatment before 48 weeks, compared to 30% (n = 31) from the comparator group (p = 0.053). Of these, 23 discontinuations were due to drug adverse effects, and only 1 attributed to RPV (p < 0.01). One patient in each group had virologic failure.

Conclusion

RPV is effective, safe and considerably more tolerable than compared to NNRTI or boosted PI in ABC/3TC-containing regimens for treatment-naïve patients. It offers an affordable and attractive option, especially in resource-limited settings.
The impact of reimbursement negotiations on cost and availability of new pharmaceuticals: evidence from an online experiment
Authors: Wettstein Dominik J. , Boes Stefan
Published: May 2020

Background

The necessity to measure and reward “value for money” of new pharmaceuticals has become central in health policy debates, as much as the requirement to assess the “willingness to pay” for an additional, quality-adjusted life year (QALY). There is a clear need to understand the capacity of “value-based” pricing policies to impact societal goals, like timely access to new treatments, sustainable health budgets, or incentivizing research to improve patient outcomes. Not only the pricing mechanics, but also the process of value assessment and price negotiation are subject to reform demands. This study assesses the impact of a negotiation situation for life-extending pharmaceuticals on societal outcomes. Of interest were general effects of the bargaining behaviour, as well as differences caused by the assigned role and the magnitude of prices.

Methods

We ran an online experiment (n = 404) on Amazon Mechanical Turk (MTurk). Participants were randomly assigned into four treatment groups for a reimbursement negotiation between two roles (health minister, pharma representative) in two price framings. Payoff to players consisted of a fixed salary and a potential bonus, depending on their preferences, their price offer and the counter offer of a randomly paired negotiation partner. Success had real social consequences on other MTurk users (premium payers, investors) and via donations to a patient association.

Results

Margins between reservation prices and price offers increased throughout the game. Yet, 47% of players reduced at least once and 15% always their bonus probability to zero in favour of an agreement. 61% of simulated negotiation pairs could have reached an agreement, based on their preferences. 63% of these were successful, leaving 61% of patients with no access to the new treatment. The group with “real world” prices had lower prices and less agreements than the unconverted payoff group. The successful markets redistributed 20% of total assets from premium payers to investors over five innovation cycles.

Conclusions

The negotiation situation for pharmaceutical reimbursement has notable impact on societal outcomes. Further research should evaluate policies that align preferences and increase negotiation success.
The microbiome as a biosensor: functional profiles elucidate hidden stress in hosts
Authors: Zolti Avihai , Green Stefan J. , Sela Noa , Hadar Yitzhak , Minz Dror
Published: May 2020

Background

Microbial communities are highly responsive to environmental cues, and both their structure and activity can be altered in response to changing conditions. We hypothesized that host-associated microbial communities, particularly those colonizing host surfaces, can serve as in situ sensors to reveal environmental conditions experienced by both microorganisms and the host. For a proof-of-concept, we studied a model plant-soil system and employed a non-deterministic gene-centric approach. A holistic analysis was performed using plants of two species and irrigation with water of low quality to induce host stress. Our analyses examined the genetic potential (DNA) and gene expression patterns (RNA) of plant-associated microbial communities, as well as transcriptional profiling of host plants.

Results

Transcriptional analysis of plants irrigated with treated wastewater revealed significant enrichment of general stress-associated root transcripts relative to plants irrigated with fresh water. Metagenomic analysis of root-associated microbial communities in treated wastewater-irrigated plants, however, revealed enrichment of more specific stress-associated genes relating to high levels of salt, high pH and lower levels of oxygen. Meta-analysis of these differentially abundant genes obtained from other metagenome studies, provided evidence of the link between environmental factors such as pH and oxygen and these genes. Analysis of microbial transcriptional response demonstrated that enriched gene content was actively expressed, which implies contemporary response to elevated levels of pH and salt.

Conclusions

We demonstrate here that microbial profiling can elucidate stress signals that cannot be observed even through interrogation of host transcriptome, leading to an alternate mechanism for evaluating in situ conditions experienced by host organisms.

This study is a proof-of-concept for the use of microbial communities as microsensors, with great potential for interrogation of a wide range of host systems.
Feasibility and predictors of change of narrative exposure therapy for displaced populations: a repeated measures design
Authors: Ghafoerkhan Rina S. , van Heemstra Henriette E. , Scholte Willem F. , van der Kolk Joriene R. J. , ter Heide Jackie June F. , de la Rie Simone M. , Verhaak Linda M. , Snippe Evelien , Boelen Paul A.
Published: May 2020

Background

Displaced victims of interpersonal violence, such as refugees, asylum seekers, and victims of sexual exploitation, are growing in numbers and are often suffering from a post-traumatic stress disorder (PTSD). At the same time, these victims are known to benefit less from trauma-focused therapy (TFT) and to be less compliant to treatment. The objective of this paper is to describe the rationale and research protocol of an ongoing trial that aims to evaluate different variables that might influence the feasibility of TFT for the study population. Specifically, perceived daily stress, emotion regulation, and mood are investigated as predictors of change in PTSD symptoms during a trauma-focused therapy (narrative exposure therapy (NET)). The feasibility of administering measures tapping these constructs repeatedly during treatment will also be evaluated.

Methods/design

Using an observational treatment design, 80 displaced victims of interpersonal violence will be measured before, during, and after partaking in NET. Several questionnaires tapping PTSD plus the aforementioned possible predictors of PTSD change will be administered: Post-traumatic Stress Disorder Checklist-5, Perceived Stress Scale, Difficulties in Emotion Regulation Scale-18 (pre-test, post-test, and follow-up),subscale impulsivity of the Difficulties in Emotion Regulation Scale-18, Perceived Stress Scale short version, Primary Care Post-traumatic Stress Disorder and a single Mood item (each session). Multilevel modelling will be used to examine the relation between the possible predictors and treatment outcome.

Discussion

The present study is the first to examine the interplay of facilitating and interfering factors possibly impacting treatment feasibility and effectiveness in displaced victims of interpersonal violence with PTSD receiving NET, using repeated measures. The current study can help to improve future treatment based on individual characteristics.

Trial registration

Netherlands Trial Register:NTR7353, retrospectively registered. Date of registration: July 11, 2018.
New Frontiers in Retina: highlights of the 2020 angiogenesis, exudation and degeneration symposium
Authors: Puliafito Carmen A. , Wykoff Charles C.
Published: May 2020

We summarize the most important findings presented at the 2020 angiogenesis, exudation and degeneration symposium in five topic areas: (1) epidemiology of retinal vascular disease and macular degeneration; (2) dry AMD and geographic atrophy; (3) neovascular age-related macular degeneration; (4) drug delivery and devices and (5) diabetic retinopathy.
Subacute Thyroiditis After Sars-COV-2 Infection
Authors: Brancatella Alessandro , Ricci Debora , Viola Nicola , Sgrò Daniele , Santini Ferruccio , Latrofa Francesco
Published: May 2020

Context

Subacute thyroiditis (SAT) is a thyroid disease of viral or postviral origin. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that began in Wuhan, China, has spread rapidly worldwide and Italy has been severely affected by this outbreak.

Objectives

The objective of this work is to report the first case of SAT related to SARS-CoV-2 infection.

Methods

We describe the clinical, laboratory, and imaging features of an 18-year-old woman who came to our attention for fever, neck pain radiated to the jaw, and palpitations occurring 15 days after a SARS-CoV-2–positive oropharyngeal swab. Coronavirus disease 2019 (COVID-19) had been mild and the patient had completely recovered in a few days.

Results

At physical examination the patient presented with a slightly increased heart rate and a painful and enlarged thyroid on palpation. At laboratory exams free thyroxine and free triiodothyronine were high, thyrotropin undetectable, and inflammatory markers and white blood cell count elevated. Bilateral and diffuse hypoechoic areas were detected at neck ultrasound. One month earlier, thyroid function and imaging both were normal. We diagnosed SAT and the patient started prednisone. Neck pain and fever recovered within 2 days and the remaining symptoms within 1 week. Thyroid function and inflammatory markers normalized in 40 days.

Conclusions

We report the first case of SAT after a SARS-CoV-2 infection. We alert clinicians to additional and unreported clinical manifestations associated with COVID-19.
Longitudinal Study on Metabolic Health in Adults SGA During 5 Years After GH With or Without 2 Years of GnRHa Treatment
Authors: Goedegebuure Wesley J , van der Steen Manouk , Kerkhof Gerthe F , Hokken-Koelega Anita C S
Published: May 2020

Background

In children born small for gestational age (SGA) with persistent short stature, 2 years of gonadotropin-releasing hormone analogue (GnRHa), in addition to long-term growth hormone (GH) treatment, can improve adult height. We assessed safety on metabolic and bone health of GnRHa/GH treatment during 5 years after cessation of GH.

Methods

A total of 363 young adults born SGA, previously treated with combined GnRHa/GH or GH-only, were followed for 5 years after attainment of adult height at GH cessation and 2 and 5 years thereafter. Data at 5 years after GH cessation, at age 21 years, were also compared with 145 age-matched adults born appropriate for gestational age (AGA). Frequently sampled intravenous glucose tolerance (FSIGT) tests were used to assess insulin sensitivity, acute insulin response, and β-cell function. Body composition and bone mineral density (BMD) was determined by dual-energy x-ray absorptiometry (DXA) scans.

Findings

In the GnRHa/GH and GH-only groups, fat mass increased during the 5 years after GH cessation, but the changes in FSIGT results, body composition, blood pressure, serum lipid levels, and BMD were similar in both groups. At age 21 years, the GnRHa/GH group had similar fat mass, FSIGT results, blood pressure, serum lipid levels and BMD-total body as the GH-only group and the AGA control group, a higher BMD-lumbar spine and lower lean body mass than the AGA control group.

Interpretation

This study during 5 years after GH cessation shows that addition of 2 years of GnRHa treatment to long-term GH treatment of children short in stature born SGA has no unfavorable effects on metabolic and bone health in early adulthood.

Clinical trial registration

ISRCTN96883876, ISRCTN65230311 and ISRCTN18062389.