bluuebunny/crossref_metadata_2025_split huggingface dataset:
The protein landscape of chronic lymphocytic leukemia
Authors: Meier-Abt Fabienne , Lu Junyan , Cannizzaro Ester , Pohly Marcel F. , Kummer Sandra , Pfammatter Sibylle , Kunz Laura , Collins Ben C. , Nadeu Ferran , Lee Kwang Seok , Xue Peng , Gwerder Myriam , Roiss Michael , Hüllein Jennifer , Scheinost Sebastian , Dietrich Sascha , Campo Elias , Huber Wolfgang , Aebersold Ruedi , Zenz Thorsten 
Published: July 2021

Abstract
Many functional consequences of mutations on tumor phenotypes in chronic lymphocytic leukemia (CLL) are unknown. This may be in part due to a scarcity of information on the proteome of CLL. We profiled the proteome of 117 CLL patient samples with data-independent acquisition mass spectrometry and integrated the results with genomic, transcriptomic, ex vivo drug response, and clinical outcome data. We found trisomy 12, IGHV mutational status, mutated SF3B1, trisomy 19, del(17)(p13), del(11)(q22.3), mutated DDX3X and MED12 to influence protein expression (false discovery rate [FDR] = 5%). Trisomy 12 and IGHV status were the major determinants of protein expression variation in CLL as shown by principal-component analysis (1055 and 542 differentially expressed proteins, FDR = 5%). Gene set enrichment analyses of CLL with trisomy 12 implicated B-cell receptor (BCR)/phosphatidylinositol 3-kinase (PI3K)/AKT signaling as a tumor driver. These findings were supported by analyses of protein abundance buffering and protein complex formation, which identified limited protein abundance buffering and an upregulated protein complex involved in BCR, AKT, MAPK, and PI3K signaling in trisomy 12 CLL. A survey of proteins associated with trisomy 12/IGHV-independent drug response linked STAT2 protein expression with response to kinase inhibitors, including Bruton tyrosine kinase and mitogen-activated protein kinase kinase (MEK) inhibitors. STAT2 was upregulated in unmutated IGHV CLL and trisomy 12 CLL and required for chemokine/cytokine signaling (interferon response). This study highlights the importance of protein abundance data as a nonredundant layer of information in tumor biology and provides a protein expression reference map for CLL.
Immune control of cytomegalovirus reactivation in stem cell transplantation
Authors: Degli-Esposti Mariapia A. , Hill Geoffrey R. 
Published: July 2021

Abstract
The reactivation of viruses from latency after allogeneic stem cell transplantation (SCT) continues to represent a major clinical challenge requiring sophisticated monitoring strategies in the context of prophylactic and/or preemptive antiviral drugs that are associated with significant expense, toxicity and rates of failure. Accumulating evidence has demonstrated the association of polyfunctional virus-specific T cells with protection from viral reactivation, affirmed by the ability of adoptively transferred virus-specific T cells to prevent and treat reactivation and disease. The roles of natural killer cells in early viral surveillance and of dendritic cells in priming of T cells have also been delineated. Most recently, a role for strain-specific humoral responses in preventing early cytomegalovirus (CMV) reactivation has been demonstrated in preclinical models. Despite these advances, many unknowns remain: what are the critical innate and adaptive responses over time; are the origin (eg, recipient vs donor) and localization (eg, in parenchymal tissue vs lymphoid organs) of these responses important; how does graft-versus-host disease and the prevention and treatment thereof (eg, high-dose steroids) affect the functionality and relevance of a particular immune axis; do the immune parameters that control latency, reactivation, and dissemination differ; and what is the impact of new antiviral drugs on the development of enduring antiviral immunity. Thus, although antiviral drugs have provided major improvements over the past two decades, understanding the immunological paradigms underpinning protective antiviral immunity after SCT offers the potential to generate nontoxic, immune-based therapeutic approaches for lasting protection from viral reactivation.
CAR-HEMATOTOX: a model for CAR T-cell–related hematologic toxicity in relapsed/refractory large B-cell lymphoma
Authors: Rejeski Kai , Perez Ariel , Sesques Pierre , Hoster Eva , Berger Carolina , Jentzsch Liv , Mougiakakos Dimitrios , Frölich Lisa , Ackermann Josephine , Bücklein Veit , Blumenberg Viktoria , Schmidt Christian , Jallades Laurent , Fehse Boris , Faul Christoph , Karschnia Philipp , Weigert Oliver , Dreyling Martin , Locke Frederick L. , von Bergwelt-Baildon Michael , Mackensen Andreas , Bethge Wolfgang , Ayuk Francis , Bachy Emmanuel , Salles Gilles , Jain Michael D. , Subklewe Marion 
Published: July 2021

Abstract
Hematotoxicity represents a frequent chimeric antigen receptor (CAR) T-cell–related adverse event and remains poorly understood. In this multicenter analysis, we studied patterns of hematopoietic reconstitution and evaluated potential predictive markers in 258 patients receiving axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) for relapsed/refractory large B-cell lymphoma. We observed profound (absolute neutrophil count [ANC] &lt;100 cells per µL) neutropenia in 72% of patients and prolonged (21 days or longer) neutropenia in 64% of patients. The median duration of severe neutropenia (ANC &lt; 500 cells per µL) was 9 days. We aimed to identify predictive biomarkers of hematotoxicity using the duration of severe neutropenia until day +60 as the primary end point. In the training cohort (n = 58), we observed a significant correlation with baseline thrombocytopenia (r = −0.43; P = .001) and hyperferritinemia (r = 0.54; P &lt; .0001) on univariate and multivariate analysis. Incidence and severity of cytokine-release syndrome, immune effector cell–associated neurotoxicity syndrome, and peak cytokine levels were not associated with the primary end point. We created the CAR-HEMATOTOX model, which included markers associated with hematopoietic reserve (eg, platelet count, hemoglobin, and ANC) and baseline inflammation (eg, C-reactive protein and ferritin). This model was validated in independent cohorts, one from Europe (n = 91) and one from the United States (n = 109) and discriminated patients with severe neutropenia ≥14 days to &lt;14 days (pooled validation: area under the curve, 0.89; sensitivity, 89%; specificity, 68%). A high CAR-HEMATOTOX score resulted in a longer duration of neutropenia (12 vs 5.5 days; P &lt; .001) and a higher incidence of severe thrombocytopenia (87% vs 34%; P &lt; .001) and anemia (96% vs 40%; P &lt; .001). The score implicates bone marrow reserve and inflammation prior to CAR T-cell therapy as key features associated with delayed cytopenia and will be useful for risk-adapted management of hematotoxicity.
Psychological stress and health-related quality of life among tuberculosis patients: a prospective cohort study
Authors: Febi Ann Roy , Manu Mohan K. , Mohapatra Aswini Kumar , Praharaj Samir Kumar , Guddattu Vasudeva 
Published: July 2021

Economic, social and psychological distress is common in individuals affected by tuberculosis (TB). However, the magnitude of distress, psychological interventions and their effect on the treatment outcomes are often under-evaluated. We examined the level of psychological stress and health-related quality of life (HRQoL) of such patients and the effect of antituberculosis therapy on them. Our prospective cohort study included newly diagnosed adult pulmonary and extrapulmonary TB patients. Assessment of psychological stress was done using the seven-item Generalised Anxiety Disorder questionnaire for anxiety and the nine-item Patient Health Questionnaire for depression. HRQoL was assessed by using the WHOQOL-BREF questionnaire. Of the 86 patients studied, 21 (24.4%) had anxiety symptoms at the baseline, which reduced to 5.8% and 1.2% at 2 months and treatment completion, respectively (p<0.001). Among the subjects, 18 (20.9%) patients had depression, which reduced to 7% and 2.3% at 2 months and treatment completion, respectively (p<0.001). All the mean domain scores of HRQoL were poor at the baseline, which showed improvement at treatment completion (p<0.001). Anxiety and depression were common among TB patients, and there was significant progressive reduction during and after treatment. TB had remarkable negative impacts on HRQoL, with the physical domain being the most affected, and all the domain scores showed significant improvement at treatment completion. Routine screening for depression and anxiety and timely referral to a psychiatrist are required in TB patients to improve the outcome of the disease and quality of life.
Genome-wide identification of ZmSnRK2 genes and functional analysis of ZmSnRK2.10 in ABA signaling pathway in maize (Zea mays L)
Authors: Long Tiandan , Xu Binjie , Hu Yufeng , Wang Yayun , Mao Changqing , Wang Yongbin , Zhang Junjie , Liu Hanmei , Huang Huanhuan , Liu Yinghong , Yu Guowu , Zhao Chunzhao , Li Yangping , Huang Yubi 
Published: July 2021

Abstract
Background
Phytohormone abscisic acid (ABA) is involved in the regulation of a wide range of biological processes. In Arabidopsis, it has been well-known that SnRK2s are the central components of the ABA signaling pathway that control the balance between plant growth and stress response, but the functions of ZmSnRK2 in maize are rarely reported. Therefore, the study of ZmSnRK2 is of great importance to understand the ABA signaling pathways in maize.

Results
In this study, 14 ZmSnRK2 genes were identified in the latest version of maize genome database. Phylogenetic analysis revealed that ZmSnRK2s are divided into three subclasses based on their diversity of C-terminal domains. The exon-intron structures, phylogenetic, synteny and collinearity analysis indicated that SnRK2s, especially the subclass III of SnRK2, are evolutionally conserved in maize, rice and Arabidopsis. Subcellular localization showed that ZmSnRK2 proteins are localized in the nucleus and cytoplasm. The RNA-Seq datasets and qRT-PCR analysis showed that ZmSnRK2 genes exhibit spatial and temporal expression patterns during the growth and development of different maize tissues, and the transcript levels of some ZmSnRK2 genes in kernel are significantly induced by ABA and sucrose treatment. In addition, we found that ZmSnRK2.10, which belongs to subclass III, is highly expressed in kernel and activated by ABA. Overexpression of ZmSnRK2.10 partially rescued the ABA-insensitive phenotype of snrk2.2/2.3 double and snrk2.2/2.3/2.6 triple mutants and led to delaying plant flowering in Arabidopsis.

Conclusion
The SnRK2 gene family exhibits a high evolutionary conservation and has expanded with whole-genome duplication events in plants. The ZmSnRK2s expanded in maize with whole-genome and segmental duplication, not tandem duplication. The expression pattern analysis of ZmSnRK2s in maize offers important information to study their functions. Study of the functions of ZmSnRK.10 in Arabidopsis suggests that the ABA-dependent members of SnRK2s are evolutionarily conserved in plants. Our study elucidated the structure and evolution of SnRK2 genes in plants and provided a basis for the functional study of ZmSnRK2s protein in maize.
Primary care implementation study to scale up early identification and brief intervention and reduce alcohol-related negative outcomes at the community level (PINO): study protocol for a quasi-experimental 3-arm study
Authors: Pussig Bram , Pas Lodewijk , Li Ann , Vermandere Mieke , Aertgeerts Bert , Matheï Catharina 
Published: July 2021

Abstract
Background
Primary healthcare-based Early Identification and Brief Intervention (EIBI) for hazardous and harmful alcohol use is both a clinically relevant and cost-effective strategy to reduce heavy drinking. Unfortunately, it remains poorly implemented in daily practice. Multiple studies have shown that training and support (T&S) programs can increase the use of EIBI. Nonetheless, gains have only been modest and short-term at best. Suggestions have been made to rely more on multicomponent programs that simultaneously address several barriers to the implementation of EIBI. The PINO-project aims to evaluate the added value of such a multicomponent program to improve EIBI delivery in daily practice.

Methods/design
A quasi-experimental three-arm implementation study in Flanders (Belgium) will assess the effects of tailored T&S to General Practitioners (GPs) with or without community mobilisation on EIBI delivery in general practice. The study lasts 18 months and will take place in three comparable municipalities. In municipality 1 and 2, GPs receive a tailored T&S program. The T&S is theoretically founded and tailored to the GPs’ views, needs and practice characteristics. Furthermore, community actions will be embedded within municipality 1 providing additional, contextual, support. In municipality 3, GPs are offered a minimal intervention to facilitate data collection.
The primary outcome is the proportion of adult patients screened for hazardous and harmful alcohol use at the end of an 18-month implementation period. The secondary outcome is the scaling up activity at municipal level in screening rates, as assessed every 3 months, and the proportion of patients who received an additional brief intervention when necessary. Furthermore, the correlation between the opinions and needs of the GP’s, their practice organisation and their EIBI performance will be explored.

Discussion
The PINO-project addresses the gap between what is theoretically possible and the current practice. This is an innovative study combining T&S at GP level with community actions. At the same time, it implements and evaluates practice T&S based on the theoretical domains framework.

Trial registration
This trial was approved by the Ethics Committee for Research of UZ/KU Leuven (reference number s63342 and G-2020-2177-R2(MAR)) and is registered on clinicaltrials.gov (NCT04398576) in May 2020.
E-prescribing and access to prescription medicines during lockdown: experience of patients in Aotearoa/New Zealand
Authors: Imlach Fiona , McKinlay Eileen , Kennedy Jonathan , Morris Caroline , Pledger Megan , Cumming Jacqueline , McBride-Henry Karen 
Published: July 2021

Abstract
Background
Health services internationally have been compelled to change their methods of service delivery in response to the global COVID-19 pandemic, to mitigate the spread of infection amongst health professionals and patients. In Aotearoa/New Zealand, widespread electronic delivery of prescriptions (e-prescribing) was enabled. The aim of the research was to explore patients’ experiences of how lockdown, changes to prescribing and the interface between general practices and community pharmacy affected access to prescription medications.

Method
The research employed a mixed-method approach. This included an online survey (n = 1,010) and in-depth interviews with a subset of survey respondents (n = 38) during the first COVID-19 lockdown (March–May 2020). Respondents were recruited through a snowballing approach, starting with social media and email list contacts of the research team. In keeping with the approach, descriptive statistics of survey data and thematic analysis of qualitative interview and open-ended questions in survey data were combined.

Results
For most respondents who received a prescription during lockdown, this was sent directly to the pharmacy. Most people picked up their medication from the pharmacy; home delivery of medication was rare (4%). Survey and interview respondents wanted e-prescribing to continue post-lockdown and described where things worked well and where they encountered delays in the process of acquiring prescription medication.

Conclusions
E-prescribing has the potential to improve access to prescription medication and is convenient for patients. The increase in e-prescribing during lockdown highlighted how the system could be improved, through better feedback about errors, more consistency across practices and pharmacies, more proactive communication with patients, and equitable prescribing costs.
The first report of co-existence of pulmonary tuberculosis and lung malignancy in a kidney transplant recipient: a case report and literature review
Authors: Fang Gang , Cheng Ning-Chang , Huang Li-Li , Xie Wei-Ping , Hu Chun-Mei , Chen Wei 
Published: July 2021

Abstract
Background
Along with the medical development, organ transplant patients increase dramatically. Since these transplant patients take immunosuppressants for a long term, their immune functions are in a suppressed state, prone to all kinds of opportunistic infections and cancer. However, it is rarely reported that the kidney transplant recipients (KTRs) have pulmonary tuberculosis and lung cancer simultaneously.

Case presentation
A 60-year-old male was admitted because of persistent lung shadow for 2 years without any obvious symptom 8 years after renal transplant. T-SPOT test was positive but other etiological examinations for Mycobacterium tuberculosis were negative. Chest CT scan revealed two pulmonary lesions in the right upper and lower lobe respectively. 18F-fluorodesoxyglucose positron-emission tomography (FDG-PET) CT found FDG intake increased in both pulmonary consolidation lesions. CT-guided percutaneous transthoracic needle biopsy revealed lung adenocarcinoma and tuberculosis. The video-assisted thoracoscopic surgery was operated to resect the malignancy lesions. The patient received specific anti-tuberculosis therapy and was discharged. At the follow-up of 6 months post drug withdrawal, the patient was recovered very well.

Conclusions
We for the first time reported co-existence of smear-negative pulmonary TB and lung adenocarcinoma in a KTR, which highlighted the clinical awareness of co-occurrence of TB and malignancy after renal transplant and emphasized the value of biopsy and 18F-FDG-PET in early diagnosis of TB and cancer.
Evaluation of algorithms using administrative health and structured electronic medical record data to determine breast and colorectal cancer recurrence in a Canadian province
Authors: Lambert Pascal , Pitz Marshall , Singh Harminder , Decker Kathleen 
Published: July 2021

Abstract
Background
Algorithms that use administrative health and electronic medical record (EMR) data to determine cancer recurrence have the potential to replace chart reviews. This study evaluated algorithms to determine breast and colorectal cancer recurrence in a Canadian province with a universal health care system.

Methods
Individuals diagnosed with stage I-III breast or colorectal cancer diagnosed from 2004 to 2012 in Manitoba, Canada were included. Pre-specified and conditional inference tree algorithms using administrative health and structured EMR data were developed. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) correct classification, and scaled Brier scores were measured.

Results
The weighted pre-specified variable algorithm for the breast cancer validation cohort (N = 1181, 167 recurrences) demonstrated 81.1% sensitivity, 93.2% specificity, 61.4% PPV, 97.4% NPV, 91.8% correct classification, and scaled Brier score of 0.21. The weighted conditional inference tree algorithm demonstrated 68.5% sensitivity, 97.0% specificity, 75.4% PPV, 95.8% NPV, 93.6% correct classification, and scaled Brier score of 0.39. The weighted pre-specified variable algorithm for the colorectal validation cohort (N = 693, 136 recurrences) demonstrated 77.7% sensitivity, 92.8% specificity, 70.7% PPV, 94.9% NPV, 90.1% correct classification, and scaled Brier score of 0.33. The conditional inference tree algorithm demonstrated 62.6% sensitivity, 97.8% specificity, 86.4% PPV, 92.2% NPV, 91.4% correct classification, and scaled Brier score of 0.42.

Conclusions
Algorithms developed in this study using administrative health and structured EMR data to determine breast and colorectal cancer recurrence had moderate sensitivity and PPV, high specificity, NPV, and correct classification, but low accuracy. The accuracy is similar to other algorithms developed to classify recurrence only (i.e., distinguished from second primary) and inferior to algorithms that do not make this distinction. The accuracy of algorithms for determining cancer recurrence only must improve before replacing chart reviews.
Content analysis of digital media coverage of the human papillomavirus vaccine school-entry requirement policy in Puerto Rico
Authors: Colón-López Vivian , Rivera-Figueroa Vilnery , Arroyo-Morales Glizette O. , Medina-Laabes Diana T. , Soto-Abreu Roxana , Rivera-Encarnación Manuel , Díaz-Miranda Olga L. , Ortiz Ana P. , Wells Katelyn B. , Vázquez-Otero Coralia , Hull Pamela C. 
Published: July 2021

Abstract
Background
In August 2018, Puerto Rico (PR) became the 4th state or territory in the United States to adopt a human papillomavirus (HPV) vaccine school-entry requirement, for students 11–12 years old. Evidence suggests that the content of media coverage may impact people’s perception of HPV vaccine and their willingness to vaccinate. This study aimed to analyze the content of digital news coverage related to the implementation of the policy in PR.

Methods
A content review was conducted of digital media published from January 2017 through December 2018. The content reviewed was carried out in two steps: 1) creating a matrix to summarize each article’s content about the policy and 2) qualitative analysis using a grounded theory approach.

Results
The search resulted in 34 articles obtained from 17 online local and international news outlets that reported the policy's implementation. Analyses showed that 61% of the news articles did not mention the number of required doses, and 79% discussed the new policy concerning cancer prevention. In 2017, news coverage focused mostly on describing the policy, while 2018 coverage focused on controversies surrounding the implementation. Neutral emergent codes included: 1) Description of the policy; 2) Information about HPV related cancers; and 3) General information about HPV vaccine. Negative emergent codes included: 1) infringement to patient and parental autonomy; 2) Hesitancy from the political sector, and 3) Hesitancy from groups and coalitions. Positive content included: 1) knowledge and acceptance of HPV vaccine for cancer prevention; 2) importance of education and protective sexual behaviors; and 3) new vaccination law proposal.

Conclusions
Most of the media coverage in PR was neutral and included limited information related to the vaccine, HPV, and HPV-related cancers. Neutral and negative themes could influence public concerns regarding the new policy, as well as HPV vaccination rates in PR.