bluuebunny/crossref_metadata_2025 huggingface dataset:
Results of a survey of practices in chronic ankle instability in France
Authors: Lopes Ronny , Ghorbani Ali , Wackenheim Frederic Leiber , Cordier Guillaume , Amouyel Thomas
Published: February 2020

Background:

After a failed conservative treatment, surgical techniques used to treat chronic ankle instability are being more and more evaluated and proficiency is increasing. Two main procedures are available: - Ligament repairs associated with tissue reinforcement - Ligament reconstructions more or less in anatomic position. Anatomic techniques have proven to be superior to non-anatomic techniques. These different surgical techniques performed arthroscopically have the main advantage to manage simultaneously associated injuries that are very common in chronic ankle instability. For some, it is the last and best diagnostic test through which a decision can be made between repair and reconstruction. Despite all this knowledge, the indications remain very heterogeneous and essentially depend on surgeons’ preference. The primary objective was of this study was make an accurate assessment of practices in France. The secondary objective was to identify situations in which the choice of surgical treatement appeared to be consensual or controversial and to try to identify the parameters that influence these choices.

Methods:

A survey of practices was conducted among foot and ankle surgeons in France from 3 different societies (SFA, AFCP, and GRECMIP). The survey consisted of 2 parts; the first part focused on the surgeon’s characteristics and the second part presented 3 clinical cases. A therapeutic choice was validated for each situation.

Results:

Two hundred and twenty-eight responses were recorded. The average age of surgeons was 46 years and they had been treating ankle instability for an average of 14 years. 67% performed this procedure less than 20 times a year and only 7% more than 50 times. More than half of them adapted to each situation (56%) while 44% always use the same technique. In 9% of cases because they are only proficient in one technique and in the other cases because they believe the technique always provides good results. 63% used the technique in open surgery, 21% under arthroscopy, 13% in minimally invasive surgery and in 7% of the cases an initial arthroscopy is performed before open surgery for stabilization.

Conclusion:

This survey reflected the heterogeneity of surgical practices in ankle instability and provided indications for areas of research in clinical situations with the least consensus.
“Germany”, Asset Class Contagion, and Contagious Stability*
Authors: Engel Sascha
Published: February 2020

In this paper, I examine the effects of socially constructed financial market lending patterns in the Eurozone crisis. Under the assumption that the crisis is one of sovereign debt, the term “contagion” is frequently used to describe the doubts about governmental debt repayment abilities that were spreading from Greece to Ireland and Portugal and then to Spain and Italy from 2010 to 2012. Consequently, austerity policies are indiscriminately applied to the governments of all five of these countries to ensure the countries’ sustainable growth for their debt repayment. This paper, by contrast, argues that “contagion” is the origin of peripheral repayment troubles rather than their effect. The Eurozone crisis is the result of the procyclical lending patterns of the European banking system, which turns liquidity shortages into solvency problems for governments depending upon debt roll-over operations. I then apply the related analysis to Germany's funding situation during the crisis and argue that “stability,” i.e., the ability to maintain sustainable growth under Eurozone crisis conditions, is not the result of endogenous austere virtue. Rather, it is likewise largely a result of procyclical lending patterns: liquidity retracted from peripheral sovereign bonds is invested into core sovereign bonds. Moreover, I show that a similar effect has been in place prior to the crisis. “Stability” is as contagious as “contagion.”
Constellation to Constellation: Situation, Encounter & Doubt
Authors: Tallis Benjamin
Published: February 2020

Low was a reaction to having gone through that peculiar… that dull greenie-grey limelight of America and its repercussions; pulling myself out of it and getting to Europe and saying, For God's sake re-evaluate why you wanted to get into this in the first place? Did you really do it just to clown around in LA? Retire. What you need is to look at yourself a bit more accurately. Find some people you don't understand and a place you don't want to be and just put yourself into it.

David Bowie, to Charles Shaar Murray, NME, 12 November 19771
(Inter)National Reconstruction: Revising Poststructuralist Encounters with the War in Bosnia and Herzegovina
Authors: Dopita Tomáš
Published: February 2020

The most serious problems in Bosnia and Herzegovina today are linked to the political practices of conflicting visions of nationhood and statehood. The international intervention in the country was expected to create self-sustaining political institutions and then withdraw. However, the fact that the intervention is ongoing shows its failure to do so. Many scholars have engaged this issue, but this article shows that some of the analyses that have been most critical of the international intervention also bring problems of their own. The article focuses on the encounters between collective Subjects and the ways they have been constituted in relation to one another. It warns that without carefully identifying these Subjects we risk serious misinterpretations, such as equating Bosnian Muslims, Bosniaks, and Bosnians. This misinterpretation occurs in two major critical works in IR's ‘poststructuralist canon’ that purport to critically engage the situation and, particularly, the international intervention in Bosnia and Herzegovina – David Campbell's National Deconstruction and Lene Hansen's Security as Practice. Campbell and Hansen rightly criticize the International Community's ethno-cultural essentialism, but in their critique they apply Campbell's radical-idealist version of multiculturalism. Based upon the ideal of a community without essence and the principle of affirming cultural diversity without situating it, this approach is not able to identify the Subjects involved or the unwelcome radicalization of the excluded Subjects, which leads to flawed conclusions as to how to sustainably resolve their conflict. In providing an academic corrective to such a hyper-liberal bias, this article seeks to increase the room-for-manoeuvre of those who seek to create self-sustaining political institutions in Bosnia and Herzegovina.
Diagnosing Europe: Greece, Macedonia, and the Meaning of Crisis
Authors: Shelton Joel T.
Published: February 2020

Accounts of crisis in Europe have proliferated since late 2009. This article investigates the relationship between the diagnosis of crisis and the cohesion and enlargement of the ‘European project’ in the context of Southeastern Europe. The article adopts Michel Foucault's understanding of diagnosis as a strategic activity of language in order to re-construct the diagnostic discourse in relation to ongoing events in Greece and the Republic of Macedonia. Diagnostic practice produces accounts of crisis that are clinical, moralising, and prescriptive, affixing meanings to complex and overdetermined events in order that they can be acted upon. Diagnoses of the crises in Greece and Macedonia converge in their identification of political and cultural features of the national political economy in need of expert correction. The diagnosis of crisis emerges as an essential feature of European Union governmentality, which functions to delimit the bounds of political contestation in times of uncertainty and upheaval in favor of technocratic interventions.
International Relations Scholarship at 100: Publicism, Truth-Pluralism and the Usefulness Problem
Authors: Michelsen Nicholas
Published: February 2020

Revisionist studies have shown that stories about International Relations’ (IR) supposed disciplinary birth in 1919 function to obfuscate the history of international thought. 1919 has nonetheless cast a long shadow over how the usefulness of professional scholarship in International Relations has been conceptualised. In this article, I trace how the 1919 birthstory orientated disciplinary constructions of the usefulness of the field as they relate to pluralist approaches to truth-seeking in IR. I argue that the centenary of 1919 reminds us of the publicist as well as pluralist scholarship of the inter-war years. Our discipline's supposed centenary should therefore foster a drive towards better communication with global IR's publics and, in this way, ensure that we are better equipped to deal with the so-called post-truth era.
Parties, Pavilions and Protests: The Heteronomous World Politics of the Russian Pavilion at the Venice Biennale
Authors: Bethwaite Julia , Kangas Anni
Published: February 2020

This paper focuses on the role of contemporary art in international relations and world politics. In IR, art is often examined within the framework of cultural diplomacy, country branding, and soft power, or approached as a site of resistance. We argue that the concept of heteronomy offers an alternative conceptual framework for analysing contemporary art in world politics. It highlights the interaction of various fields such as art, commerce, the state and media. We concretise this approach with an analysis of the Venice Biennale. We show that the Biennale is heteronomous in the sense of being an arena where actors from various fields struggle for power by accumulating different types of capital. We focus our analysis on the Russian national pavilion in 2011–2015 and show how the efforts of the country's elite to legitimise its position intertwined with the projects of the state, sponsors, artists, curators and art market actors.
Prospective Analysis of Health-Related Quality of Life in Older Adults With Cancer
Authors: Ximenes Coeli Regina Carneiro , Bergmann Anke , Lima Jurema Telles de Oliveira , Lima Wigna Rayssa Pereira , de Britto Murilo Carlos , de Mello Maria Júlia Gonçalves , Thuler Luiz Claudio Santos
Published: February 2020

Objective:

The aim of the present study was to evaluate health-related quality of life (HRQoL) changes at 6 to 12 months after cancer diagnosis and to assess the impact of age in older adults with cancer.

Methods:

A cohort study using patients ≥60 years old diagnosed with cancer. Health-related quality of life scores were calculated according to the European Organisation for Research and Treatment of Cancer questionnaire. Student’s t tests for paired samples and a binomial logistic regression were performed.

Results:

The study included 241 patients. At diagnosis, the affected HRQoL functions were physical and emotional functions, financial difficulties, pain, and insomnia. At follow-up, cognitive function ( P < .001) and dyspnea ( P = .004) worsened, while emotional function improved ( P = .003).

Discussion:

At the 6 to 12 months of follow-up, older adult cancer patients showed worsening cognitive function and dyspnea and improved emotional function. These HRQoL changes were not associated with age.
Priming the Project Talent Pipeline: Examining Work Readiness in Undergraduate Project Management Degree Programs
Authors: Borg Jessica , Scott-Young Christina M.
Published: February 2020

Undergraduate education is emerging as a direct pathway into the previously deemed ‘accidental profession’ of project management. We introduce the concept of graduate work readiness and explore whether undergraduate project management degrees are imparting industry-required work-readiness attributes. Documentary analysis of 12 Australian bachelor’s degree programs identified that many (but not all) of the work-ready attributes taught are consistent with those sought by industry. The results revealed that graduates’ work-readiness profiles vary according to university employer reputation. The findings suggest the need for a more industry-consultative approach to the way universities prepare their graduates for the project-based workplace.
Persistent leukocytosis in polycythemia vera is associated with disease evolution but not thrombosis
Authors: Ronner Lukas , Podoltsev Nikolai , Gotlib Jason , Heaney Mark L. , Kuykendall Andrew T. , O’Connell Casey , Shammo Jamile , Fleischman Angela G. , Scherber Robyn M. , Mesa Ruben , Yacoub Abdulraheem , Perkins Cecelia , Meckstroth Shelby , Behlman Lindsey , Chiaramonte Matthew , Salehi Mahta , Ziadkhanpour Kimia , Nguyen Hellen , Siwoski Olivia , Hung Annie Kwok , Janania Martinez Michelle , Nguyen Jenny , Patel Sagar , Kollipara Revathi , Dave Ami , Randall Megan , Grant Michael , Harrison Mitchell , Fernandez Soto Paola , Tremblay Douglas , Hoffman Ronald , Moshier Erin , Mascarenhas John
Published: February 2020

There are unresolved questions regarding the association between persistent leukocytosis and risk of thrombosis and disease evolution in polycythemia vera (PV), as much of the published literature on the topic does not appropriately use repeated-measures data or time-dependent modeling to answer these questions. To address this knowledge gap, we analyzed a retrospective database of 520 PV patients seen at 10 academic institutions across the United States. Taking hematologic laboratory data at ∼3-month intervals (or as available) for all patients for duration of follow-up, we used group-based trajectory modeling to identify latent clusters of patients who follow distinct trajectories with regard to their leukocyte, hematocrit, and platelet counts over time. We then tested the association between trajectory membership and hazard of 2 major outcomes: thrombosis and disease evolution to myelofibrosis, myelodysplastic syndrome, or acute myeloid leukemia. Controlling for relevant covariates, we found that persistently elevated leukocyte trajectories were not associated with the hazard of a thrombotic event (P = .4163), but were significantly associated with increased hazard of disease evolution in an ascending stepwise manner (overall P = .0002). In addition, we found that neither hematocrit nor platelet count was significantly associated with the hazard of thrombosis or disease evolution.
Bleeding in patients with sickle cell disease: a population-based study
Authors: Hariharan Nisha , Brunson Ann , Mahajan Anjlee , Keegan Theresa H. M. , Wun Ted
Published: February 2020

Bleeding is a known complication of sickle cell disease (SCD) and includes hemorrhagic stroke, hematuria, and vitreous hemorrhage. However, the incidence of bleeding events in patients with SCD has not been well described. We present a retrospective, population-based study examining the cumulative incidence of bleeding in 6423 patients with SCD from 1991 to 2014. We also studied risk factors associated with bleeding and the effects of bleeding on mortality, using Cox proportional hazards regression models. We used California emergency department and hospitalization databases to identify patients with SCD with intracranial hemorrhage, gastrointestinal (GI) bleeding, hemophthalmos, gross hematuria, epistaxis, menorrhagia, and other bleeding events. The cumulative incidence of any first bleeding event at age 40 years was 21% (95% confidence interval [CI], 19.8%-22.3%), increasing with age to 41% by age 60 years (95% CI, 38.8%-43.1%). The majority of bleeding events were GI (41.6%), particularly from the upper GI tract. A higher bleeding risk was associated with increased frequency of hospitalization (hazard ratio [HR], 2.16; 95% CI, 1.93-2.42), venous thromboembolism 180 days before bleeding event (HR, 4.24; 95% CI, 2.86-6.28), osteonecrosis of the femoral head (HR, 1.25; 95% CI, 1.08-1.46), and ischemic stroke (HR, 1.65; 95% CI, 1.20-2.26). Bleeding was also associated with a twofold increased risk for death (HR, 2.09; 95% CI, 1.82-2.41) adjusted for other SCD-related complications. Our novel finding of a high incidence of bleeding in patients with SCD, particularly from the upper GI tract, suggests that patients with SCD may be predisposed to bleeding, with possible etiologies including increased use of nonsteroidal anti-inflammatory drugs, mucosal infarction from vascular occlusion by sickled red blood cells, and increased stress ulceration from frequent hospitalization.
Mild parenchymal lung disease and/or low diffusion capacity impacts survival and treatment response in patients diagnosed with idiopathic pulmonary arterial hypertension
Authors: Lewis Robert A. , Thompson A.A. Roger , Billings Catherine G. , Charalampopoulos Athanasios , Elliot Charlie A. , Hamilton Neil , Hill Catherine , Hurdman Judith , Rajaram Smitha , Sabroe Ian , Swift Andy J. , Kiely David G. , Condliffe Robin
Published: February 2020

There are limited published data defining survival and treatment response in patients with mild lung disease and/or reduced gas transfer who fulfil diagnostic criteria for idiopathic pulmonary arterial hypertension (IPAH).

Patients diagnosed with IPAH between 2001 and 2019 were identified in the ASPIRE (Assessing the Spectrum of Pulmonary Hypertension Identified at a Referral Centre) registry. Using prespecified criteria based on computed tomography (CT) imaging and spirometry, patients with a diagnosis of IPAH and no lung disease were termed IPAHno-LD(n=303), and those with minor/mild emphysema or fibrosis were described as IPAHmild-LD(n=190).

Survival was significantly better in IPAHno-LDthan in IPAHmild-LD(1- and 5-year survival 95% and 70%versus78% and 22%, respectively; p<0.0001). In the combined group of IPAHno-LDand IPAHmild-LD, independent predictors of higher mortality were increasing age, lower diffusing capacity of the lung for carbon monoxide (DLCO), lower exercise capacity and a diagnosis of IPAHmild-LD(all p<0.05). Exercise capacity and quality of life improved (both p<0.0001) following treatment in patients with IPAHno-LD, but not IPAHmild-LD. A proportion of patients with IPAHno-LDhad aDLCO<45%; these patients had poorer survival than patients withDLCO≥45%, although they demonstrated improved exercise capacity following treatment.

The presence of even mild parenchymal lung disease in patients who would be classified as IPAH according to current recommendations has a significant adverse effect on outcomes. This phenotype can be identified using lung function testing and clinical CT reports. Patients with IPAH, no lung disease and severely reducedDLCOmay represent a further distinct phenotype. These data suggest that randomised controlled trials of targeted therapies in patients with these phenotypes are required.
Lipids and ketones dominate metabolism at the expense of glucose control in pulmonary arterial hypertension: a hyperglycaemic clamp and metabolomics study
Authors: Mey Jacob T. , Hari Adithya , Axelrod Christopher L. , Fealy Ciarán E. , Erickson Melissa L. , Kirwan John P. , Dweik Raed A. , Heresi Gustavo A.
Published: February 2020

Individuals with idiopathic pulmonary arterial hypertension (PAH) display reduced oral glucose tolerance. This may involve defects in pancreatic function or insulin sensitivity but this hypothesis has not been tested; moreover, fasting nutrient metabolism remains poorly described in PAH. Thus, we aimed to characterise fasting nutrient metabolism and investigated the metabolic response to hyperglycaemia in PAH.

12 participants (six PAH, six controls) were administered a hyperglycaemic clamp, while 52 (21 PAH, 31 controls) underwent plasma metabolomic analysis. Glucose, insulin, C-peptide, free fatty acids and acylcarnitines were assessed from the clamp. Plasma metabolomics was conducted on fasting plasma samples.

The clamp verified a reduced insulin response to hyperglycaemia in PAH (−53%versuscontrol), but with similar pancreatic insulin secretion. Skeletal muscle insulin sensitivity was unexpectedly greater in PAH. Hepatic insulin extraction was elevated in PAH (+11%versuscontrol). Plasma metabolomics identified 862 metabolites: 213 elevated, 145 reduced in PAH (p<0.05). In both clamp and metabolomic cohorts, lipid oxidation and ketones were elevated in PAH. Insulin sensitivity, fatty acids, acylcarnitines and ketones correlated with PAH severity, while hepatic extraction and fatty acid:ketone ratio correlated with longer six-min walk distance.

Poor glucose control in PAH could not be explained by pancreatic β-cell function or skeletal muscle insulin sensitivity. Instead, elevated hepatic insulin extraction emerged as an underlying factor. In agreement, nutrient metabolism in PAH favours lipid and ketone metabolism at the expense of glucose control. Future research should investigate the therapeutic potential of reinforcing lipid and ketone metabolism on clinical outcomes in PAH.
Change in blood eosinophils following treatment with inhaled corticosteroids may predict long-term clinical response in COPD
Authors: Mathioudakis Alexander G. , Bikov Andras , Foden Philip , Lahousse Lies , Brusselle Guy , Singh Dave , Vestbo Jørgen
Published: February 2020

There is an emerging role for blood eosinophil count (EOS) as a biomarker to guide inhaled corticosteroid (ICS) therapy in COPD. Since ICS administration could influence EOS, we hypothesised that change in EOS following treatment with ICS may predict outcomes of long-term therapy.

In apost hocanalysis of ISOLDE, a 3-year, double-blind trial comparing 500 µg fluticasone propionate twice daily with placebo in 751 patients with moderate-to-severe COPD, we evaluated whether the initial changes in EOS during ICS treatment were predictive of ICS treatment response.

EOS change within 1 year after the introduction of ICS was strongly predictive of treatment response. A suppressed EOS was associated with treatment effect. Characteristically, in patients with EOS suppression of ≥200 cells·μL−1, ICS use was associated with a decelerated rate of decline of forced expiratory volume in 1 s (FEV1), by 32 mL·year−1, and a 30% reduction in the exacerbation rate. In contrast, in patients experiencing an increase in EOS of ≥200 cells·μL−1, ICS use was associated with an accelerated rate of decline of FEV1, by 37 mL·year−1and an 80% increase in the exacerbation rate (p<0.0001). EOS change was not predictive of clinical response with regards to health status evaluated using the St George's Respiratory Questionnaire.

These findings suggest that EOS change after ICS administration may predict clinical response to ICS therapy in patients with moderate-to-severe COPD at risk of exacerbations. ICS administration may be associated with more frequent exacerbations and an accelerated lung function decline in the 20% of patients in whom EOS increases after the administration of ICS. These hypothesis-generating observations will need validation in prospectively designed studies.

The ISOLDE trial was conducted before the ICJME recommended a prospective registration of RCT protocols.
A scoping review of core outcome sets and their ‘mapping’ onto real-world data using prostate cancer as a case study
Authors: Meregaglia Michela , Ciani Oriana , Banks Helen , Salcher-Konrad Maximilian , Carney Caroline , Jayawardana Sahan , Williamson Paula , Fattore Giovanni
Published: February 2020

Background

A Core Outcomes Set (COS) is an agreed minimum set of outcomes that should be reported in all clinical studies related to a specific condition. Using prostate cancer as a case study, we identified, summarized, and critically appraised published COS development studies and assessed the degree of overlap between them and selected real-world data (RWD) sources.

Methods

We conducted a scoping review of the Core Outcome Measures in Effectiveness Trials (COMET) Initiative database to identify all COS studies developed for prostate cancer. Several characteristics (i.e., study type, methods for consensus, type of participants, outcomes included in COS and corresponding measurement instruments, timing, and sources) were extracted from the studies; outcomes were classified according to a predefined 38-item taxonomy. The study methodology was assessed based on the recent COS-STAndards for Development (COS-STAD) recommendations. A ‘mapping’ exercise was conducted between the COS identified and RWD routinely collected in selected European countries.

Results

Eleven COS development studies published between 1995 and 2017 were retrieved, of which 8 were classified as ‘COS for clinical trials and clinical research’, 2 as ‘COS for practice’ and 1 as ‘COS patient reported outcomes’. Recommended outcomes were mainly categorized into ‘mortality and survival’ (17%), ‘outcomes related to neoplasm’ (18%), and ‘renal and urinary outcomes’ (13%) with no relevant differences among COS study types. The studies generally fulfilled the criteria for the COS-STAD ‘scope specification’ domain but not the ‘stakeholders involved’ and ‘consensus process’ domains. About 72% overlap existed between COS and linked administrative data sources, with important gaps. Linking with patient registries improved coverage (85%), but was sometimes limited to smaller follow-up patient groups.

Conclusions

This scoping review identified few COS development studies in prostate cancer, some quite dated and with a growing level of methodological quality over time. This study revealed promising overlap between COS and RWD sources, though with important limitations; linking established, national patient registries to administrative data provide the best means to additionally capture patient-reported and some clinical outcomes over time. Thus, increasing the combination of different data sources and the interoperability of systems to follow larger patient groups in RWD is required.
Eliminating viral hepatitis C in Belgium: the micro-elimination approach
Authors: Busschots Dana , Toghanian Samira , Bielen Rob , Salomonsson Stina , Koc Özgür M. , Hendrickx Greet , Jadoul Michel , Nevens Frederik , Sokal Etienne , Brixko Christian , Peerlinck Kathelijne , Apers Ludwig , Robaeys Geert , Lazarus Jeffrey V.
Published: February 2020

Background

Hepatitis C virus is one of the leading causes of chronic liver disease and liver-related deaths worldwide. The estimated prevalence of chronic hepatitis C viral infection among the general Belgian population was 0.57% (n = 64,000) in 2015. Although Belgium has had a ‘Hepatitis C Plan’ since 2014, elimination efforts are unclear. This study employs the best available data and modelling estimates to define the burden of hepatitis C viral infection among key subgroups in Belgium, identify information gaps and propose potential approaches to screening, linkage to care and treatment, and cure.

Methods

We examined the peer-reviewed and grey literature since 2012 for data on the prevalence of hepatitis C viral infection in Belgium in key subgroups identified by national experts and in the literature. Ultimately, this research is primarily based on data provided by the key stakeholders themselves due to a lack of reliable data in the literature. Based on this, we modelled the treatment rates required to reach elimination of hepatitis C in several subgroups.

Results

Eleven potential subgroups were identified. There were no data available for two subgroups: generational cohorts and men who have sex with men. In six subgroups, fewer than 3000 people were reported or estimated to have hepatitis C infection. Migrants and people who inject drugs were the most affected subgroups, and children were the least affected subgroup. Only two subgroups are on target to achieve elimination by 2030: patients living with haemophilia and transplant recipients.

Conclusions

Removing Belgian treatment reimbursement restrictions in January 2019 was a big step towards eliminating HCV. In addition, increasing surveillance, including with a national registry, treatment prescription by other health-care providers and availability of treatment in local pharmacies are central to improving the current situation and getting on track to reach the 2030 WHO hepatitis C elimination targets in Belgium.
Case report: a synonymous VHL mutation (c.414A > G, p.Pro138Pro) causes pathogenic familial hemangioblastoma through dysregulated splicing
Authors: Liu Fang , Calhoun Barbara , Alam Md. Suhail , Sun Miaomiao , Wang Xuechun , Zhang Chao , Haldar Kasturi , Lu Xin
Published: February 2020

Background

von Hippel-Lindau (VHL) disease is a familial neoplasia syndrome that results from the germline mutation of VHL. Pathogenic VHL mutations include deletion, frameshift, nonsense and missense mutations. Synonymous mutations are expected to be phenotypically silent and their role in VHL disease remains poorly understood.

Case presentation

We report a Caucasian male with a family history of pheochromocytoma and the synonymous VHL mutation c.414A > G (p.Pro138Pro). At 47-years, MRI revealed pheochromocytoma in the left adrenal gland and hemangioblastomas in the spine and brain. Pheochromocytoma was treated by adrenalectomy. Radiotherapy, followed by craniotomy and resection were needed to reduce hemangioblastomas to residual lesions. Two of three of the proband’s children inherited the mutation and both presented with retinal hemangioblastomas without pheochromocytoma at age 7: one twin needed four laser treatments. Primary skin fibroblasts carrying the heterozygous mutation or wild type VHL were established from the family. Mutant fibroblasts downregulated full-length VHL mRNA and protein, and upregulated the short VHL mRNA isoform (a result of exon 2 skipping in splicing) at the mRNA level but not at the protein level.

Conclusions

Our study shows that the synonymous VHL mutation c.414A > G can within 7 years induce pediatric retinal hemangioblastoma in absence of pheochromocytoma. This highlights the need to include splicing-altering synonymous mutations into the screening for VHL disease. This is also the first report on detecting and validating a synonymous VHL mutation using patient-derived fibroblasts. The mutation c.414A > G translates to p.Pro138Pro, yet it is not functionally silent, because it causes aberrant splicing by skipping exon 2. The reduced but not completely abolished pVHL protein in a loss-of-heterozygosity genetic backdrop may underlie the etiology of VHL disease.
The joint effect of maternal smoking during pregnancy and maternal pre-pregnancy overweight on infants’ term birth weight
Authors: Chattrapiban Thanin , Smit Henriette A. , Wijga Alet H. , Brunekreef Bert , Vonk Judith M. , Gehring Ulrike , van Rossem Lenie
Published: February 2020

Background

It is well known that maternal smoking during pregnancy and maternal pre-pregnancy overweight have opposite effects on the infants’ birth weight. We report on the association of the combination between both risk factors and the infants’ birth weight.

Methods

We studied 3241 infants born at term in the PIAMA birth cohort. Maternal smoking during pregnancy and pre-pregnancy height and weight were self-reported. Multivariable regression analysis was performed to assess the associations between infants of mothers who only smoked during pregnancy, who only had pre-pregnancy overweight and who had both risk factors simultaneously, on term birth weight and the risk of being SGA or LGA.

Results

Of 3241 infants, 421 infants (13%) were born to smoking, non-overweight mothers, 514 (15.8%) to non-smoking, overweight mothers, 129 (4%) to smoking and overweight mothers and 2177 (67%) to non-smoking, non-overweight mothers (reference group). Infants of mothers who smoked and also had pre-pregnancy overweight had similar term birth weight (− 26.6 g, 95%CI: − 113.0, 59.8), SGA risk (OR = 1.06, 95%CI: 0.56, 2.04), and LGA risk (OR = 1.09, 95%CI: 0.61, 1.96) as the reference group.

Conclusions

Our findings suggested that the effects of maternal smoking during pregnancy and maternal pre-pregnancy overweight on infants’ birth weight cancel each other out. Therefore, birth weight may not be a good indicator of an infant’s health status in perinatal practice because it may mask potential health risks due to these maternal risk factors when both present together.
Risk factors for severe rash with use of vemurafenib alone or in combination with cobimetinib for advanced melanoma: pooled analysis of clinical trials
Authors: Hopkins Ashley M. , Rathod Akash D. , Rowland Andrew , Kichenadasse Ganessan , Sorich Michael J.
Published: February 2020

Background

Rash is one of the most common severe adverse events associated with use of vemurafenib for the treatment of melanoma, either as monotherapy or in combination with cobimetinib. The study aimed to identify pre-treatment patient characteristics predictive of developing severe rash with vemurafenib therapy.

Methods

This was a secondary pooled analysis of individual patient data from the BRIM-2, BRIM-3 and coBRIM clinical trials, including all patients treated with vemurafenib alone and vemurafenib plus cobimetinib. Patient age, sex, performance status, body weight, body mass index, liver function markers and estimated glomerular filtration rate were assessed for association with development of severe (grade 3 or 4) rash using logistic regression.

Results

Of 962 patients treated with vemurafenib, 150 (16%) patients experienced severe rash. Female sex was identified as a significant risk factor for severe rash development (P < 0.001), having a two-fold increased risk compared to males (22% vs 11%, odds ratio [OR] 2.17; 95% CI 1.52 to 3.09). Low body weight was also associated with increased risk of severe rash (P = 0.002), but this association was not significant after adjustment for sex. The association between sex and risk of severe rash was consistent across clinical trials and treatments (vemurafenib monotherapy, vemurafenib plus cobimetinib).

Conclusion

Females had approximately two-fold increased risk of developing severe rash compared to males in clinical trials of vemurafenib alone or in combination with cobimetinib.
Evaluation of posterior capsule opacification of the Alcon Clareon IOL vs the Alcon Acrysof IOL using a human capsular bag model
Authors: Hillenmayer Anna , Wertheimer Christian M. , Kassumeh Stefan , von Studnitz Annabel , Luft Nikolaus , Ohlmann Andreas , Priglinger Siegfried , Mayer Wolfgang J.
Published: February 2020

Background

Posterior capsule opacification (PCO) after cataract surgery is influenced by intraocular lens (IOL) design and material. The following is an ex vivo comparison of PCO between the Clareon vs. the AcrySof IOL in human capsular bags.

Methods

Twenty cadaver capsular bags from 10 human donors were used, with the novel hydrophobic IOL (Clareon, CNA0T0) being implanted in one eye and the other eye of the same donor receiving the AcrySof IOL (SN60WF) following phacoemulsification cataract surgery. Five capsular bags of 3 donors served as controls without IOL. Cellular growth of lens epithelial cells was photo-documented daily. The primary endpoint was the time until full coverage of the posterior capsule by cells. Furthermore, immunofluorescence staining of capsular bags for the fibrotic markers f-actin, fibronectin, alpha smooth muscle actin, and collagen type 1 were performed.

Results

The new Clareon IOL did not show any disadvantages in terms of days until full cell coverage of the posterior capsule in comparison to the AcrySof (p > 0.99). Both, the Clareon (p = 0.01, 14.8 days) and the AcrySof IOL (p = 0.005, 15.7 days) showed a slower PCO development in comparison to the control (8.6 days). The fibrotic markers f-actin, fibronectin, alpha smooth muscle actin, and collagen type 1 were equally distributed between the two IOLs and differed from the control.

Conclusions

A comparable performance has been found in the ex vivo formation of PCO between the two IOLs. Long-term clinical studies are necessary to reach final conclusions.
Perceived barriers to early diagnosis of breast Cancer in south and southwestern Ethiopia: a qualitative study
Authors: Getachew Sefonias , Tesfaw Aragaw , Kaba Mirgissa , Wienke Andreas , Taylor Lesley , Kantelhardt Eva J. , Addissie Adamu
Published: February 2020

Background

Early diagnosis is a key determinant of breast cancer prognosis and survival. More than half of breast cancer cases are diagnosed at an advanced stage in Ethiopia, and the barriers to early diagnosis in this country are not well understood. We aimed to identify the perceived barriers to early diagnosis of breast cancer from the perspective of patients and health care providers in south and southwestern Ethiopia.

Methods

A qualitative study was conducted from March to April 2018 using in-depth interviews of breast cancer patients and breast cancer health care providers from six public hospitals located in urban and rural areas of south and southwestern Ethiopia. All participants provided verbal consent before participating. A thematic analysis was performed using Open Code 4.02.

Results

Twelve breast cancer patients and thirteen health care providers were included in the study. Patient and health-system related barriers to early diagnosis of breast cancer were identified. Patient-related barriers were lack of knowledge and awareness of breast cancer, belief in traditional medicine and religious practices for treatment, and lack of social and financial support to seek care at a medical facility. Health-system related barriers were misdiagnosis of breast cancer, long distance to referral facilities, high cost of diagnostic services, long waiting time for diagnostic tests, and lack of screening and diagnostic tests in local facilities.

Conclusions

Early diagnosis of breast cancer is affected by multiple barriers in south and southwestern Ethiopia. Awareness campaigns and education about the disease, prevention, and early detection are needed to increase early diagnosis of breast cancer. Opportunities exist to improve early diagnosis and timely treatment in rural areas.
Acute care pathways for patients calling the out-of-hours services
Authors: Søvsø Morten Breinholt , Huibers Linda , Bech Bodil Hammer , Christensen Helle Collatz , Christensen Morten Bondo , Christensen Erika Frischknecht
Published: February 2020

Background

In Western countries, patients with acute illness or injury out-of-hours (OOH) can call either emergency medical services (EMS) for emergencies or primary care services (OOH-PC) in less urgent situations. Callers initially choose which service to contact; whether this choice reflect the intended differences in urgency and severity is unknown. Hospital diagnoses and admission rates following an OOH service contact could elucidate this. We aimed to investigate and compare the prevalence of patient contacts, subsequent hospital contacts, and the age-related pattern of hospital diagnoses following an out-of-hours contact to EMS or OOH-PC services in Denmark.

Methods

Population-based observational cohort study including patients from two Danish regions with contact to EMS or OOH-PC in 2016. Hospital contacts were defined as short (< 24 h) or admissions (≥24 h) on the date of OOH service contact. Both regions have EMS, whereas the North Denmark Region has a general practitioner cooperative (GPC) as OOH-PC service and the Capital Region of Copenhagen the Medical Helpline 1813 (MH-1813), together representing all Danish OOH service types. Calling an OOH service is mandatory prior to a hospital contact outside office hours.

Results

OOH-PC handled 91% (1,107,297) of all contacts (1,219,963). Subsequent hospital contacts were most frequent for EMS contacts (46–54%) followed by MH-1813 (41%) and GPC contacts (9%). EMS had more admissions (52–56%) than OOH-PC. For both EMS and OOH-PC, short hospital contacts often concerned injuries (32–63%) and non-specific diagnoses (20–45%). The proportion of circulatory disease was almost twice as large following EMS (13–17%) compared to OOH-PC (7–9%) in admitted patients, whereas respiratory diseases (11–14%), injuries (15–22%) and non-specific symptoms (22–29%) were more equally distributed. Generally, admitted patients were older.

Conclusions

EMS contacts were fewer, but with a higher percentage of hospital contacts, admissions and prevalence of circulatory diseases compared to OOH-PC, perhaps indicating that patients more often contact EMS in case of severe disease. However, hospital diagnoses only elucidate severity of diseases to some extent, and other measures of severity could be considered in future studies. Moreover, the socio-demographic pattern of patients calling OOH needs exploration as this may play an important role in choice of entrance.
Delirium misdiagnosis risk in psychiatry: a machine learning-logistic regression predictive algorithm
Authors: Hercus Catherine , Hudaib Abdul-Rahman
Published: February 2020

Background

Delirium is a frequent diagnosis made by Consultation-Liaison Psychiatry (CLP). Numerous studies have demonstrated misdiagnosis prior to referral to CLP. Few studies have considered the factors underlying misdiagnosis using multivariate approaches.

Objectives

To determine the number of cases referred to CLP, which are misdiagnosed at time of referral, to build an accurate predictive classifier algorithm, using input variables related to delirium misdiagnosis.

Method

A retrospective observational study was conducted at Alfred Hospital in Melbourne, collecting data from a record of all patients seen by CLP for a period of 5 months. Data was collected pertaining to putative factors underlying misdiagnosis. A Machine Learning-Logistic Regression classifier model was built, to classify cases of accurate delirium diagnosis vs. misdiagnosis.

Results

Thirty five of 74 new cases referred were misdiagnosed. The proposed predictive algorithm achieved a mean Receiver Operating Characteristic (ROC) Area under the curve (AUC) of 79%, an average 72% classification accuracy, 77% sensitivity and 67% specificity.

CONCLUSIONS: Delirium is commonly misdiagnosed in hospital settings. Our findings support the potential application of Machine Leaning-logistic predictive classifier in health care settings.
Relationship between placenta malaria and mother to child transmission of HIV infection in pregnant women in South East Nigeria
Authors: Mbachu Ikechukwu I. , Ejikunle Samson D. , Anolue Frederick , Mbachu Chioma N. , Dike Ephraim , Ejikem Eke , Okeudo Chijioke
Published: February 2020

Background

This study determined the rate of mother-to-child transmission (MTCT) of HIV among HIV positive women with placenta malaria and factors associated with placenta malaria.

Methods

This was a prospective observational study of booked HIV positive pregnant women in labour. A smear for malaria parasite was made from blood taken from the placental tissue post-delivery. The baby HIV testing was done with DNA polymerase chain reaction at 6 weeks postpartum. Data on age, parity, gestational age, religion, address, highest educational attainment and knowledge about malaria prevention in pregnancy was obtained with questionnaires and analysed using SPSS version 20. The P-value was set at 0.05 providing a confidence interval of 95%.

Results

A total of 174 booked HIV women participated in this study. The placental malaria parasitaemia prevalence was 44.8%. Overall rate of MTCT of HIV infection was 17.2%. Number of infants with HIV infection among women with maternal placental malarial parasitaemia was 30/78 (38.5%), while it was 0/96 (0%) for women without placenta malaria. There was significant relationship between placenta malaria density and infant HIV status (P-value = 0.001). The relative risk for MTCT of HIV for women with placenta malaria Density > 5000 was 25% with 95% confidence interval of 11.41–54.76%.

Conclusion

The mother-to-child transmission rate of HIV was high among HIV positive women with placental malaria parasitaemia. There is the need to review the malarial treatment and prophylactic measures at least in this group of women and to establish the nature of relationship between placenta malaria and MTCT of HIV infection.
m6A demethylase ALKBH5 inhibits tumor growth and metastasis by reducing YTHDFs-mediated YAP expression and inhibiting miR-107/LATS2–mediated YAP activity in NSCLC
Authors: Jin Dan , Guo Jiwei , Wu Yan , Yang Lijuan , Wang Xiaohong , Du Jing , Dai Juanjuan , Chen Weiwei , Gong Kaikai , Miao Shuang , Li Xuelin , Sun Hongliang
Published: February 2020

Background

The importance of mRNA methylation erased by ALKBH5 in mRNA biogenesis, decay, and translation control is an emerging research focus. Ectopically activated YAP is associated with the development of many human cancers. However, the mechanism whereby ALKBH5 regulates YAP expression and activity to inhibit NSCLC tumor growth and metastasis is not clear.

Methods

Protein and transcript interactions were analyzed in normal lung cell and NSCLC cells. Gene expression was evaluated by qPCR and reporter assays. Protein levels were determined by immunochemical approaches. Nucleic acid interactions and status were analyzed by immunoprecipitation. Cell behavior was analyzed by standard biochemical tests. The m6A modification was analyzed by MeRIP.

Results

Our results show that YAP expression is negatively correlated with ALKBH5 expression and plays an opposite role in the regulation of cellular proliferation, invasion, migration, and EMT of NSCLC cells. ALKBH5 reduced m6A modification of YAP. YTHDF3 combined YAP pre-mRNA depending on m6A modification. YTHDF1 and YTHDF2 competitively interacted with YTHDF3 in an m6A-independent manner to regulate YAP expression. YTHDF2 facilitated YAP mRNA decay via the AGO2 system, whereas YTHDF1 promoted YAP mRNA translation by interacting with eIF3a; both these activities are regulated by m6A modification. Furthermore, ALKBH5 decreased YAP activity by regulating miR-107/LATS2 axis in an HuR-dependent manner. Further, ALKBH5 inhibited tumor growth and metastasis in vivo by reducing the expression and activity of YAP.

Conclusions

The presented findings suggest m6A demethylase ALKBH5 inhibits tumor growth and metastasis by reducing YTHDFs-mediated YAP expression and inhibiting miR-107/LATS2–mediated YAP activity in NSCLC. Moreover, effective inhibition of m6A modification of ALKBH5 might constitute a potential treatment strategy for lung cancer.
Preparation of antibacterial and osteoconductive 3D-printed PLGA/Cu(I)@ZIF-8 nanocomposite scaffolds for infected bone repair
Authors: Zou Fei , Jiang Jianyuan , Lv Feizhou , Xia Xinlei , Ma Xiaosheng
Published: February 2020

Background

The repair of large bone defects is a great challenge in clinical practice. In this study, copper-loaded-ZIF-8 nanoparticles and poly (lactide-co-glycolide) (PLGA) were combined to fabricate porous PLGA/Cu(I)@ZIF-8 scaffolds using three-dimensional printing technology for infected bone repair.

Methods

The surface morphology of PLGA/Cu(I)@ZIF-8 scaffolds was investigated by transmission electron microscopy and scanning electron microscopy. The PLGA/Cu(I)@ZIF-8 scaffolds were co-cultured with bacteria to determine their antibacterial properties, and with murine mesenchymal stem cells (MSCs) to explore their biocompatibility and osteoconductive properties. The bioactivity of the PLGA/Cu(I)@ZIF-8 scaffolds was evaluated by incubating in simulated body fluid.

Results

The results revealed that the PLGA/Cu(I)@ZIF-8 scaffolds had porosities of 80.04 ± 5.6% and exhibited good mechanical properties. When incubated with H2O2, Cu(I)@ZIF-8 nanoparticles resulted generated reactive oxygen species, which contributed to their antibacterial properties. The mMSCs cultured on the surface of PLGA/Cu(I)@ZIF-8 scaffolds were well-spread and adherent with a high proliferation rate, and staining with alkaline phosphatase and alizarin red was increased compared with the pure PLGA scaffolds. The mineralization assay showed an apatite-rich layer was formed on the surface of PLGA/Cu(I)@ZIF-8 scaffolds, while there was hardly any apatite on the surface of the PLGA scaffolds. Additionally, in vitro, Staphylococcus aureus cultured on the PLGA/Cu(I)@ZIF-8 scaffolds were almost all dead, while in vivo inflammatory cell infiltration and bacteria numbers were dramatically reduced in infected rats implanted with PLGA/Cu@ZIF-8 scaffolds.

Conclusion

All these findings demonstrate that PLGA/Cu(I)@ZIF-8 scaffolds possess excellent antibacterial and osteoconductive properties, as well as good biocompatibility and high bioactivity. This study suggests that the PLGA/Cu(I)@ZIF-8 scaffolds could be used as a promising biomaterial for bone tissue engineering, especially for infected bone repair.