bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ibrutinib in B-cell lymphoma: single fighter might be enough?
Authors: Xue Chao , Wang Xin , Zhang Lingyan , Qu Qingyuan , Zhang Qian , Jiang Yujie 
Published: September 2020

Abstract
Background
In recent years, the B cell receptor (BCR) signaling pathway has become a “hot point” because it plays a critical role in B-cell proliferation and function. Bruton’s tyrosine kinase (BTK) is overexpressed in many subtypes of B-cell lymphoma as a downstream kinase in the BCR signaling pathway. Ibrutinib, the first generation of BTK inhibitor, has shown excellent antitumor activity in both indolent and aggressive B-cell lymphoma.

Main body
Ibrutinib monotherapy has been confirmed to be effective with a high response rate (RR) and well-tolerated in many B-cell lymphoma subgroups. To achieve much deeper and faster remission, combination strategies contained ibrutinib were conducted to evaluate their synergistic anti-tumor effect.

Conclusions
For patients with indolent B-cell lymphoma, most of them respond well with ibrutinib monotherapy. Combination strategies contained ibrutinib might be a better choice to achieve deeper and faster remission in the treatment of aggressive subtypes of B-cell lymphoma. Further investigations on the long-term efficacy and safety of the ibrutinib will provide novel strategies for individualized treatment of B-cell lymphoma.
Local myocardial stiffness variations identified by high frame rate shear wave echocardiography
Authors: Strachinaru Mihai , Bosch Johan G. , Schinkel Arend F. L. , Michels Michelle , Feyz Lida , de Jong Nico , Geleijnse Marcel L. , Vos Hendrik J. 
Published: September 2020

Abstract
Background
Shear waves are generated by the closure of the heart valves. Significant differences in shear wave velocity have been found recently between normal myocardium and disease models of diffusely increased muscle stiffness. In this study we correlate in vivo myocardial shear wave imaging (SWI) with presence of scarred tissue, as model for local increase of stiffness. Stiffness variation is hypothesized to appear as velocity variation.

Methods
Ten healthy volunteers (group 1), 10 hypertrophic cardiomyopathy (HCM) patients without any cardiac intervention (group 2), and 10 HCM patients with prior septal reduction therapy (group 3) underwent high frame rate tissue Doppler echocardiography. The SW in the interventricular septum after aortic valve closure was mapped along two M-mode lines, in the inner and outer layer.

Results
We compared SWI to 3D echocardiography and strain imaging. In groups 1 and 2, no change in velocity was detected. In group 3, 8/10 patients showed a variation in SW velocity. All three patients having transmural scar showed a simultaneous velocity variation in both layers. Out of six patients with endocardial scar, five showed variations in the inner layer.

Conclusion
Local variations in stiffness, with myocardial remodeling post septal reduction therapy as model, can be detected by a local variation in the propagation velocity of naturally occurring shear waves.
Measurement properties of EQ-5D-3L and EQ-5D-5L in recording self-reported health status in older patients with substantial multimorbidity and polypharmacy
Authors: Bhadhuri Arjun , Kind Paul , Salari Paola , Jungo Katharina Tabea , Boland Benoît , Byrne Stephen , Hossmann Stefanie , Dalleur Olivia , Knol Wilma , Moutzouri Elisavet , O’Mahony Denis , Murphy Kevin D. , Wisselink Linda , Rodondi Nicolas , Schwenkglenks Matthias 
Published: September 2020

AbstractBackgroundThe EQ-5D-3L and EQ-5D-5L are two generic health-related quality of life measures, which may be used in clinical and health economic research. They measure impairment in 5 aspects of health: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The aim of this study was to assess the performance of the EQ-5D-3L and EQ-5D-5L in measuring the self-reported health status of older patients with substantial multimorbidity and associated polypharmacy.MethodsBetween 2017 and 2019, we administered EQ-5D-3L and EQ-5D-5L to a subset of patients participating in the OPERAM trial at 6 months and 12 months after enrolment. The OPERAM trial is a two-arm multinational cluster randomised controlled trial of structured medication review assisted by a software-based decision support system versus usual pharmaceutical care, for older people (aged ≥ 70 years) with multimorbidity and polypharmacy. In the psychometric analyses, we only included participants who completed the measures in full at 6 and 12 months. We assessed whether responses to the measures were consistent by assessing the proportion of EQ-5D-5L responses, which were 2 or more levels away from that person’s EQ-5D-3L response. We also compared the measures in terms of informativity, and discriminant validity and responsiveness relative to the Barthel Index, which measures independence in activities of daily living.Results224 patients (mean age of 77 years; 56% male) were included in the psychometric analyses. Ceiling effects reported with the EQ-5D-5L (22%) were lower than with the EQ-5D-3L (29%). For the mobility item, the EQ-5D-5L demonstrated better informativity (Shannon’s evenness index score of 0.86) than the EQ-5D-3L (Shannon’s evenness index score of 0.69). Both the 3L and 5L versions of EQ-5D demonstrated good performance in terms of discriminant validity, i.e. (out of all items of the EQ-5D-3L and EQ-5D-5L, the pain/discomfort and anxiety/depression items had the weakest correlation with the Barthel Index. Both the 3L and 5L versions of EQ-5D demonstrated good responsiveness to changes in the Barthel Index.ConclusionBoth EQ-5D-3L and EQ-5D-5L demonstrated validity and responsiveness when administered to older adults with substantial multimorbidity and polypharmacy who were able to complete the measures.
Assessing how information is packaged in rapid reviews for policy-makers and other stakeholders: a cross-sectional study
Authors: Garritty Chantelle , Hamel Candyce , Hersi Mona , Butler Claire , Monfaredi Zarah , Stevens Adrienne , Nussbaumer-Streit Barbara , Cheng Wei , Moher David 
Published: September 2020

Abstract
Background
Rapid reviews (RRs) are useful products to healthcare policy-makers and other stakeholders, who require timely evidence. Therefore, it is important to assess how well RRs convey useful information in a format that is easy to understand so that decision-makers can make best use of evidence to inform policy and practice.

Methods
We assessed a diverse sample of 103 RRs against the BRIDGE criteria, originally developed for communicating clearly to support healthcare policy-making. We modified the criteria to increase assessability and to align with RRs. We identified RRs from key database searches and through searching organisations known to produce RRs. We assessed each RR on 26 factors (e.g. organisation of information, lay language use). Results were descriptively analysed. Further, we explored differences between RRs published in journals and those published elsewhere.

Results
Certain criteria were well covered across the RRs (e.g. all aimed to synthesise research evidence and all provided references of included studies). Further, most RRs provided detail on the problem or issue (96%; n = 99) and described methods to conduct the RR (91%; n = 94), while several addressed political or health systems contexts (61%; n = 63). Many RRs targeted policy-makers and key stakeholders as the intended audience (66%; n = 68), yet only 32% (n = 33) involved their tacit knowledge, while fewer (27%; n = 28) directly involved them reviewing the content of the RR. Only six RRs involved patient partners in the process. Only 23% (n = 24) of RRs were prepared in a format considered to make information easy to absorb (i.e. graded entry) and 25% (n = 26) provided specific key messages. Readability assessment indicated that the text of key RR sections would be hard to understand for an average reader (i.e. would require post-secondary education) and would take 42 (± 36) minutes to read.

Conclusions
Overall, conformity of the RRs with the modified BRIDGE criteria was modest. By assessing RRs against these criteria, we now understand possible ways in which they could be improved to better meet the information needs of healthcare decision-makers and their potential for innovation as an information-packaging mechanism. The utility and validity of these items should be further explored.

Protocol availability
The protocol, published on the Open Science Framework, is available at: osf.io/68tj7
Policy dialogue and participation: a new way of crafting a national health financing strategy in Morocco
Authors: Akhnif El Houcine , Hachri Hafid , Belmadani Abdelouahab , Mataria Awad , Bigdeli Maryam 
Published: September 2020

Abstract
Background
Policy dialogue for health policies has started to gain importance in recent years, especially for complex issues such as health financing. Moroccan health financing has faced several challenges during the last years. This study aims to document the Moroccan experience in developing a consolidated health financing strategy according to the policy dialogue approach. It especially considers the importance of conceptualising this process in the Moroccan context.

Method
We documented the process of developing a health financing strategy in Morocco. It concerned four steps, as follows: (1) summarising health financing evidence in preparation of the policy dialogue; (2) organising the health policy dialogue process with 250 participants (government, private sector, NGOs, civil society, parliamentarians, technical and financial partners); (3) a technical workshop to formulate the strategy actions; and (4) an ultimate workshop for validation with decision-makers. The process lasted 1 year from March 2019 to February 2020. We have reviewed all documents related to the four steps of the process through our active participation in the policy debate and the documentation of two technical workshops to produce the strategy document.

Results
The policy dialogue approach showed its usefulness in creating convergence among all health actors to define a national shared vision on health financing in Morocco. There was a high political commitment in the process and all actors officially adopted recommendations on health financing actions. A strategy document produced within a collaborative approach was the final output. This experience also marked a shift from previous top-down approaches in designing health policies for more participation and inclusion. The evidence synthesis played a crucial role in facilitating the debate. The collaborative approach seems to work in favouring national consensus on practical health financing actions.

Conclusion
The policy dialogue process adopted for health financing in Morocco helped to create collective ownership of health financing actions. Despite the positive results in terms of national mobilisation around the health financing vision in Morocco, there is a need to institutionalise the policy dialogue with a more decentralised approach to consider subnational specificities.
Characterization of the expression and immunological impact of the transcriptional activator CREB in renal cell carcinoma
Authors: Friedrich Michael , Stoehr Christine , Jasinski-Bergner Simon , Hartmann Arndt , Wach Sven , Wullich Bernd , Steven André , Seliger Barbara 
Published: September 2020

Abstract
Background
The non-classical human leukocyte antigen (HLA)-G is a strong immunomodulatory molecule. Under physiological conditions, HLA-G induces immunological tolerance in immune privileged tissues, while under pathophysiological situations it contributes to immune escape mechanisms. Therefore, HLA-G could act as a potential immune checkpoint for future anti-cancer immunotherapies. Recent data suggest an aberrant expression of the cAMP response element binding protein (CREB) in clear cell renal cell carcinoma (ccRCC), which is correlated with tumor grade and stage. Furthermore, preliminary reports demonstrated a connection of CREB as a control variable of HLA-G transcription due to CREB binding sites in the HLA-G promoter region. This study investigates the interaction between CREB and HLA-G in different renal cell carcinoma (RCC) subtypes and its correlation to clinical parameters.

Methods
The direct interaction of CREB with the HLA-G promoter was investigated by chromatin immunoprecipitation in RCC cell systems. Furthermore, the expression of CREB and HLA-G was determined by immunohistochemistry using a tissue microarray (TMA) consisting of 453 RCC samples of distinct subtypes. Staining results were assessed for correlations to clinical parameters as well as to the composition of the immune cell infiltrate.

Results
There exists a distinct expression pattern of HLA-G and CREB in the three main RCC subtypes. HLA-G and CREB expression were the lowest in chromophobe RCC lesions. However, the clinical relevance of CREB and HLA-G expression differed. Unlike HLA-G, high levels of CREB expression were positively associated to the overall survival of RCC patients. A slightly, but significantly elevated number of tumor infiltrating regulatory T cells was observed in tumors of high CREB expression. Whether this small increase is of clinical relevance has to be further investigated.

Conclusions
An interaction of CREB with the HLA-G promoter could be validated in RCC cell lines. Thus, for the first time the expression of CREB and its interaction with the HLA-G in human RCCs has been shown, which might be of clinical relevance.
Increased HIV-1 pretreatment drug resistance with consistent clade homogeneity among ART-naive HIV-1 infected individuals in Ethiopia
Authors: Kiros Mulugeta , Alemayehu Dawit Hailu , Geberekidan Eleni , Mihret Adane , Maier Melanie , Abegaz Woldaregay Erku , Mulu Andargachew 
Published: September 2020

AbstractBackgroundThe development of pretreatment drug resistance (PDR) is becoming an obstacle to the success of antiretroviral therapy (ART). Besides, data from developing settings including Ethiopia is still limited. Therefore, this study was aimed to assess HIV-1 genetic diversity and PDR mutations among ART-naive recently diagnosed HIV-1 infected individuals in Addis Ababa, Ethiopia.MethodsInstitutional based cross-sectional study was conducted from June to December 2018 in Addis Ababa among ART-naive recently diagnosed individuals. Partial HIV-1 pol region covering the entire protease (PR) and partial reverse transcriptase (RT) regions of 51 samples were amplified and sequenced using an in-house assay. Drug resistance mutations were examined using calibrated population resistance (CPR) tool version 6.0 from the Stanford HIV drug resistance database and the International Antiviral Society-USA (IAS-USA) 2019 mutation list.ResultsAccording to both algorithms used, 9.8% (5/51) of analyzed samples had at least one PDR Mutation. PDR mutations to Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) were the most frequently detected (7.8% and 9.8%, according to the CPR tool and IAS-USA algorithm, respectively). The most frequently observed NNRTIs-associated mutations common to both algorithms were K103N (2%), Y188L (2%), K101E (2%), and V106A (2%), while E138A (2%) was observed according to IAS-USA only. Y115F and M184V (mutations that confer resistance to NRTIs) dual mutations were detected according to both criteria in a single study participant (2%). PDR mutation to protease inhibitors was found to be low (only G73S; 2% according to the CPR tool). Phylogenetic analysis showed that 98% (50/51) of the study participants were infected with HIV-1C virus while one individual (2%) was infected with HIV-1A1 virus.ConclusionsThis study showed an increased level of PDR and persistence HIV-1C clade homogeneity after 15 years of the rollout of ART and 3 decades of HIV-1C circulation in Ethiopia, respectively. Therefore, we recommend routine baseline genotypic drug resistance testing for all newly diagnosed HIV infected patients before initiating treatment. This will aid the selection of appropriate therapy in achieving the 90% of patients having an undetectable viral load in consonance with the UN target.
Viruses of protozoan parasites and viral therapy: Is the time now right?
Authors: Barrow Paul , Dujardin Jean Claude , Fasel Nicolas , Greenwood Alex D. , Osterrieder Klaus , Lomonossoff George , Fiori Pier Luigi , Atterbury Robert , Rossi Matteo , Lalle Marco 
Published: September 2020

AbstractInfections caused by protozoan parasites burden the world with huge costs in terms of human and animal health. Most parasitic diseases caused by protozoans are neglected, particularly those associated with poverty and tropical countries, but the paucity of drug treatments and vaccines combined with increasing problems of drug resistance are becoming major concerns for their control and eradication. In this climate, the discovery/repurposing of new drugs and increasing effort in vaccine development should be supplemented with an exploration of new alternative/synergic treatment strategies. Viruses, either native or engineered, have been employed successfully as highly effective and selective therapeutic approaches to treat cancer (oncolytic viruses) and antibiotic-resistant bacterial diseases (phage therapy). Increasing evidence is accumulating that many protozoan, but also helminth, parasites harbour a range of different classes of viruses that are mostly absent from humans. Although some of these viruses appear to have no effect on their parasite hosts, others either have a clear direct negative impact on the parasite or may, in fact, contribute to the virulence of parasites for humans. This review will focus mainly on the viruses identified in protozoan parasites that are of medical importance. Inspired and informed by the experience gained from the application of oncolytic virus- and phage-therapy, rationally-driven strategies to employ these viruses successfully against parasitic diseases will be presented and discussed in the light of the current knowledge of the virus biology and the complex interplay between the viruses, the parasite hosts and the human host. We also highlight knowledge gaps that should be addressed to advance the potential of virotherapy against parasitic diseases.
Influence of multiple apolipoprotein A-I and B genetic variations on insulin resistance and metabolic syndrome in obstructive sleep apnea
Authors: Li Xinyi , Fu Zhihui , Xu Huajun , Zou Jianyin , Zhu Huaming , Li Zhiqiang , Su Kaiming , Huai De , Yi Hongliang , Guan Jian , Yin Shankai 
Published: September 2020

Abstract
Background
The relationships between apolipoprotein A-I (APOA-I), apolipoprotein B (APOB) with insulin resistance, metabolic syndrome (MetS) are unclear in OSA. We aimed to evaluate whether the multiple single nucleotide polymorphism (SNP) variants of APOA-I and APOB exert a collaborative effect on insulin resistance and MetS in OSA.

Methods
Initially, 12 APOA-I SNPs and 30 APOB SNPs in 5259 subjects were examined. After strict screening, four APOA-I SNPs and five APOB SNPs in 4007 participants were included. For each participant, the genetic risk score (GRS) was calculated based on the cumulative effect of multiple genetic variants of APOA-I and APOB. Logistic regression analyses were used to evaluate the relationships between APOA-I/APOB genetic polymorphisms, insulin resistance, and MetS in OSA.

Results
Serum APOB levels increased the risk of insulin resistance and MetS adjusting for age, gender and BMI [odds ratio (OR = 3.168, P < 0.001; OR = 6.098, P < 0.001, respectively]. APOA-I GRS decreased the risk of insulin resistance and MetS after adjustments (OR = 0.917, P = 0.001; OR = 0.870, P < 0.001, respectively). APOB GRS had no association with insulin resistance (OR = 1.364, P = 0.610), and had weak association with MetS after adjustments (OR = 1.072, P = 0.042). In addition, individuals in the top quintile of the APOA-I genetic score distribution had a lower risk of insulin resistance and MetS after adjustments (OR = 0.761, P = 0.007; OR = 0.637, P < 0.001, respectively).

Conclusions
In patients with OSA, cumulative effects of APOA-I genetic variations decreased the risk of insulin resistance and MetS, whereas multiple APOB genetic variations had no associations with insulin resistance and weak association with MetS.
Costing the implementation of public health interventions in resource-limited settings: a conceptual framework
Authors: Sohn Hojoon , Tucker Austin , Ferguson Olivia , Gomes Isabella , Dowdy David 
Published: September 2020

Abstract
Background
Failing to account for the resources required to successfully implement public health interventions can lead to an underestimation of costs and budget impact, optimistic cost-effectiveness estimates, and ultimately a disconnect between published evidence and public health decision-making.

Methods
We developed a conceptual framework for assessing implementation costs. We illustrate the use of this framework with case studies involving interventions for tuberculosis and HIV/AIDS in resource-limited settings.

Results
Costs of implementing public health interventions may be conceptualized as occurring across three phases: design, initiation, and maintenance. In the design phase, activities include developing intervention components and establishing necessary infrastructure (e.g., technology, standard operating procedures). Initiation phase activities include training, initiation of supply chains and quality assurance procedures, and installation of equipment. Implementation costs in the maintenance phase include ongoing technical support, monitoring and evaluation, and troubleshooting unexpected obstacles. Within each phase, implementation costs can be incurred at the site of delivery (“site-specific” costs) or more centrally (“above-service” or “central” costs). For interventions evaluated in the context of research studies, implementation costs should be classified as programmatic, research-related, or shared research/program costs. Purely research-related costs are often excluded from analysis of programmatic implementation.

Conclusions
In evaluating public health interventions in resource-limited settings, accounting for implementation costs enables more realistic estimates of budget impact and cost-effectiveness and provides important insights into program feasibility, scale-up, and sustainability. Assessment of implementation costs should be planned prospectively and performed in a standardized manner to ensure generalizability.