bluuebunny/crossref_metadata_2025_split huggingface dataset:
Zanubrutinib monotherapy in relapsed/refractory indolent non-Hodgkin lymphoma
Authors: Phillips Tycel , Chan Henry , Tam Constantine S. , Tedeschi Alessandra , Johnston Patrick , Oh Sung Yong , Opat Stephen , Eom Hyeon-Seok , Allewelt Heather , Stern Jennifer C. , Tan Ziwen , Novotny William , Huang Jane , Trotman Judith 
Published: April 2022

Abstract
Outcomes for marginal zone lymphoma (MZL) and follicular lymphoma (FL) remain suboptimal, owing to the limited number of approved agents and the incurable nature of the diseases. BGB-3111-AU-003 was a phase 1/2, open-label, multicenter, single-agent study of the selective Bruton’s tyrosine kinase inhibitor zanubrutinib in 385 patients with B-cell malignancies. Here, we present safety and efficacy outcomes for the 53 enrolled patients with relapsed/refractory MZL (n = 20) and relapsed/refractory FL (n = 33), all of whom were enrolled during the part 2 dose expansion, and therefore received zanubrutinib at the recommended phase 2 dose. Treatment with zanubrutinib was generally well tolerated, with most adverse events being ≤ grade 2. Atrial fibrillation/flutter was not reported. Two patients required dose reduction, and 4 patients discontinued treatment because of adverse events. Response was assessed by an independent review committee for MZL and the investigators for FL, per Lugano 2014 classification for non-Hodgkin lymphoma. In patients with MZL, the overall response rate (ORR) was 80%, and the complete response (CR) rate was 20%. With median follow-up of 33.8 months, median progression-free survival (PFS) was not reached. In patients with FL, the ORR was 36.4%, and the CR rate was 18.2%. After a median follow-up of 33.9 months, median PFS was 10.4 months. In conclusion, the results of this study suggest a favorable benefit–risk profile and support zanubrutinib as a potentially meaningful addition to available therapies for patients with relapsed/refractory MZL and FL. This trial was registered at www.clinicaltrials.gov as #NCT02343120.
Blocking human protein C anticoagulant activity improves clotting defects of hemophilia mice expressing human protein C
Authors: Jiang Miao , Yang Fei , Jiang Yizhi , Cheng Lu , Han Jingjing , Yi Jiawei , Zhang Guige , Ma Zhenni , Cao Lijuan , Zuo Bin , Zhou Lixia , Huang Lulu , Niu Siying , Xia Zhisong , Zhou Xuefeng , Bai Xia , Esmon Naomi L. , Ruan Changgeng , Xia Lijun , Han Yue , Esmon Charles T. , Wu Depei , Xu Jun 
Published: April 2022

Abstract
Hemophilia A and B are hereditary coagulation defects resulting in unstable blood clotting and recurrent bleeding. Current factor replacement therapies have major limitations such as the short half-life of the factors and development of inhibitors. Alternative approaches to rebalance the hemostasis by inhibiting the anticoagulant pathways have recently gained considerable interest. In this study, we tested the therapeutic potential of a monoclonal antibody, HAPC1573, that selectively blocks the anticoagulant activity of human activated protein C (APC). We generated F8−/− or F9−/− hemophilia mice expressing human protein C by genetically replacing the murine Proc gene with the human PROC. The resulting PROC+/+;F8−/− or PROC+/+;F9−/− mice had bleeding characteristics similar to their corresponding F8−/− or F9−/− mice. Pretreating the PROC+/+;F8−/− mice with HAPC1573 shortened the tail bleeding time. HAPC1573 pretreatment significantly reduced mortality and alleviated joint swelling, similar to those treated with either FVIII or FIX, of either PROC+/+;F8−/− or PROC+/+;F9−/− mice in a needle puncture–induced knee-joint bleeding model. Additionally, we found that HAPC1573 significantly improved the thrombin generation of PROC+/+;F8−/− mice but not F8−/− mice, indicating that HAPC1573 enhanced the coagulant activity of hemophilia mice by modulating human APC in vivo. We further documented that HAPC1573 inhibited the APC anticoagulant activity to improve the clotting time of human plasma deficient of FVIII, FIX, FXI, FVII, VWF, FV, or FX. These results demonstrate that selectively blocking the anticoagulant activity of human APC may be an effective therapeutic and/or prophylactic approach for bleeding disorders lacking FVIII, FIX, or other clotting factors.
MGUS and clonal hematopoiesis show unrelated clinical and biological trajectories in an older population cohort
Authors: Da Vià Matteo Claudio , Lionetti Marta , Marella Alessio , Matera Antonio , Travaglino Erica , Signaroldi Elena , Galbussera Alessia Antonella , Lucca Ugo , Mandelli Sara , Riva Emma , Tettamanti Mauro , Pettine Loredana , Pompa Alessandra , Baldini Luca , Neri Antonino , Della Porta Matteo Giovanni , Bolli Niccolò 
Published: April 2022

Abstract
Monoclonal gammopathy of undetermined significance (MGUS) and clonal hematopoiesis (CH) are 2 preclinical clonal expansions of hematopoietic cells whose prevalence rises with age, reaching almost 10% in people of aged 70 years and older. The increased risk of myeloid malignancies in patients with myeloma is well defined, and the study of the association between CH and MGUS could help explain this phenomenon. Here, we analyzed a fully clinically annotated dataset of 777 older subjects (median age, 91 years) previously screened for prevalence of CH. The prevalence of MGUS and CH was 9.6% and 17.3%, respectively. We detected CH in 9.7% of the patients with MGUS and MGUS in 5.5% of the patients with CH. We did not find a significant correlation between the presence of MGUS and CH. Furthermore, the 2 conditions showed a differential association with clinical and laboratory covariates, suggesting that MGUS and CH may represent age-associated unrelated clonal drifts of hematopoietic cells. Confirmatory studies are needed to assess the relevance of CH in plasma cell disorders. This trial was registered at www.clinicaltrials.gov as #NCT03907553.
Causes and outcomes of ICU hospitalisations in patients with pulmonary arterial hypertension
Authors: Naranjo Mario , Mercurio Valentina , Hassan Hussein , Alturaif Noura , Cuomo Alessandra , Attanasio Umberto , Diab Nermin , Sahetya Sarina K. , Mukherjee Monica , Hsu Steven , Balasubramanian Aparna , Simpson Catherine E. , Damico Rachel , Kolb Todd M. , Mathai Stephen C. , Hassoun Paul M. 
Published: April 2022

RationalePulmonary arterial hypertension (PAH) is a rare disease characterised by limited survival despite remarkable improvements in therapy. The causes, clinical burden and outcomes of patients admitted to the intensive care unit (ICU) remain poorly characterised. The aim of this study was to describe patient characteristics, causes of ICU hospitalisation, and risk factors for ICU and 1-year mortality.MethodsData from patients enrolled in the Johns Hopkins Pulmonary Hypertension Registry were analysed for the period between January 2010 and December 2020. Clinical, functional, haemodynamic and laboratory data were collected.Measurements and main results102 adult patients with 155 consecutive ICU hospitalisations were included. The leading causes for admission were right heart failure (RHF, 53.3%), infection (17.4%) and arrhythmia (11.0%). ICU mortality was 27.1%. Mortality risk factors included Na <136 mEq·mL−1(OR: 3.10, 95% CI: 1.41–6.82), elevated pro-B-type natriuretic peptide (proBNP) (OR: 1.75, 95% CI: 1.03–2.98), hyperbilirubinaemia (OR: 1.40, 95% CI: 1.09–1.80), hyperlactaemia (OR: 1.42, 95% CI: 1.05–1.93), and need for vasopressors/inotropes (OR: 5.29, 95% CI: 2.28–12.28), mechanical ventilation (OR: 3.76, 95% CI: 1.63–8.76) and renal replacement therapy (OR: 5.57, 95% CI: 1.25–24.76). Mortality rates at 3, 6 and 12 months were 17.5%, 27.6% and 39.0%, respectively. Connective tissue disease-associated PAH has lower 1-year survival compared to idiopathic PAH (51.4%versus79.8%, log-rank test p=0.019).ConclusionsRHF is the most common cause for ICU admission. In-hospital and 1-year mortality remain exceedingly high despite improved ICU care. Recognising specific risk factors on admission can help identifying patients at risk for poor outcomes.
Prospective longitudinal evaluation of hospitalised COVID-19 survivors 3 and 12 months after discharge
Authors: Lorent Natalie , Vande Weygaerde Yannick , Claeys Eveline , Guler Caamano Fajardo Ipek , De Vos Nicolas , De Wever Walter , Salhi Bihiyga , Gyselinck Iwein , Bosteels Cedric , Lambrecht Bart N. , Everaerts Stephanie , Verschraegen Sven , Schepers Christophe , Demeyer Heleen , Heyns Arne , Depuydt Pieter , Oeyen Sandra , Van Bleyenbergh Pascal , Godinas Laurent , Dupont Lieven , Hermans Greet , Derom Eric , Gosselink Rik , Janssens Wim , Van Braeckel Eva 
Published: April 2022

BackgroundLong-term outcome data of coronavirus disease 2019 (COVID-19) survivors are needed to understand their recovery trajectory and additional care needs.MethodsA prospective observational multicentre cohort study was carried out of adults hospitalised with COVID-19 from March through May 2020. Workup at 3 and 12 months following admission consisted of clinical review, pulmonary function testing, 6-min walk distance (6MWD), muscle strength, chest computed tomography (CT) and quality of life questionnaires. We evaluated factors correlating with recovery by linear mixed effects modelling.ResultsOf 695 patients admitted, 299 and 226 returned at 3 and 12 months, respectively (median age 59 years, 69% male, 31% severe disease). About half and a third of the patients reported fatigue, dyspnoea and/or cognitive impairment at 3 and 12 months, respectively. Reduced 6MWD and quadriceps strength were present in 20% and 60% at 3 monthsversus7% and 30% at 12 months. A high anxiety score and body mass index correlated with poor functional recovery. At 3 months, diffusing capacity for carbon monoxide (DLCO) and total lung capacity were below the lower limit of normal in 35% and 18%, decreasing to 21% and 16% at 12 months; predictors of poorDLCOrecovery were female sex, pre-existing lung disease, smoking and disease severity. Chest CT improved over time; 10% presented non-progressive fibrotic changes at 1 year.ConclusionMany COVID-19 survivors, especially those with severe disease, experienced limitations at 3 months. At 1 year, the majority showed improvement to almost complete recovery. To identify additional care or rehabilitation needs, we recommend a timely multidisciplinary follow-up visit following COVID-19 admission.
Breathing pattern and muscle activity using different inspiratory resistance devices in children with mouth breathing syndrome
Authors: Medeiros da Fonsêca Jéssica Danielle , Aliverti Andrea , Benício Kadja , de Farias Sales Valéria Soraya , Fontes Silva da Cunha Lima Luciana , Resqueti Vanessa Regiane , de Freitas Fregonezi Guilherme Augusto 
Published: April 2022

AimThe aim of this study was to evaluate the acute effects of different inspiratory resistance devices and intensity of loadsvianasal airway on the breathing pattern and activity of respiratory muscles in children with mouth breathing syndrome (MBS).MethodsChildren with MBS were randomised into two groups based on inspiratory load intensity (20% and 40% of the maximal inspiratory pressure). These subjects were assessed during quiet breathing, breathing against inspiratory loadvianasal airway and recovery. The measurements were repeated using two different devices (pressure threshold and flow resistance). Chest wall volumes and respiratory muscle activity were evaluated by optoelectronic plethysmography and surface electromyography, respectively.ResultsDuring the application of inspiratory load, there was a significant reduction in respiratory rate (p<0.04) and an increase in inspiratory time (p<0.02), total time of respiratory cycle (p<0.02), minute ventilation (p<0.03), tidal volume (p<0.01) and scalene and sternocleidomastoid muscles activity (root mean square values, p<0.01) when compared to quiet spontaneous breathing and recovery, regardless of load level or device applied. The application of inspiratory load using the flow resistance device showed an increase in the tidal volume (p<0.02) and end-inspiratory volume (p<0.02).ConclusionFor both devices, the addition of inspiratory loads using a nasal interface had a positive effect on the breathing pattern. However, the flow resistance device was more effective in generating volume and, therefore, has advantages compared to pressure threshold.
Characterization of tRNA expression profiles in large offspring syndrome
Authors: Goldkamp Anna K. , Li Yahan , Rivera Rocio M. , Hagen Darren E. 
Published: April 2022

Abstract
Background
Assisted Reproductive Technologies (ART) use can increase the risk of congenital overgrowth syndromes, such as large offspring syndrome (LOS) in ruminants. Epigenetic variations are known to influence gene expression and differentially methylated regions (DMRs) were previously determined to be associated with LOS in cattle. We observed DMRs overlapping tRNA clusters which could affect tRNA abundance and be associated with tissue specificity or overgrowth. Variations in tRNA expression have been identified in several disease pathways suggesting an important role in the regulation of biological processes. Understanding the role of tRNA expression in cattle offers an opportunity to reveal mechanisms of regulation at the translational level. We analyzed tRNA expression in the skeletal muscle and liver tissues of day 105 artificial insemination-conceived, ART-conceived with a normal body weight, and ART-conceived bovine fetuses with a body weight above the 97th percentile compared to Control-AI.

Results
Despite the centrality of tRNAs to translation, in silico predictions have revealed dramatic differences in the number of tRNA genes between humans and cattle (597 vs 1,659). Consistent with reports in human, only a fraction of predicted tRNA genes are expressed. We detected the expression of 474 and 487 bovine tRNA genes in the muscle and liver with the remainder being unexpressed. 193 and 198 unique tRNA sequences were expressed in all treatment groups within muscle and liver respectively. In addition, an average of 193 tRNA sequences were expressed within the same treatment group in different tissues. Some tRNA isodecoders were differentially expressed between treatment groups. In the skeletal muscle and liver, we categorized 11 tRNA isoacceptors with undetected expression as well as an isodecoder that was unexpressed in the liver (SerGGA). Our results identified variation in the proportion of tRNA gene copies expressed between tissues and differences in the highest contributing tRNA anticodon within an amino acid family due to treatment and tissue type. Out of all amino acid families, roughly half of the most highly expressed tRNA isoacceptors correlated to their most frequent codon in the bovine genome.

Conclusion
Although the number of bovine tRNA genes is nearly triple of that of the tRNA genes in human, there is a shared occurrence of transcriptionally inactive tRNA genes in both species. We detected differential expression of tRNA genes as well as tissue- and treatment- specific tRNA transcripts with unique sequence variations that could modulate translation during protein homeostasis or cellular stress, and give rise to regulatory products targeting genes related to overgrowth in the skeletal muscle and/or tumor development in the liver of LOS individuals. While the absence of certain isodecoders may be relieved by wobble base pairing, missing tRNA species could increase the likelihood of mistranslation or mRNA degradation.
Perspectives on deployment of humanitarian workers through operational partnerships during the acute emergency health response to the Rohingya refugee crisis in Cox’s Bazar
Authors: Blackmore Claire , Evers Egmond Samir , Sazed S. M. Asif , Baidjoe Amrish , Vilas Victor Del Rio , Pesigan Art , Ofrin Roderico 
Published: April 2022

Abstract
Background
The unprecedented influx of Rohingya refugees into Cox’s Bazar, Bangladesh, in 2017 led to a humanitarian emergency requiring large numbers of humanitarian workers to be deployed to the region. The World Health Organization (WHO) contributed to this effort through well-established deployment mechanisms: the Global Outbreak Alert and Response Network (GOARN) and the Standby Partnerships (SBP). The study captures the views and experiences of those humanitarian workers deployed by WHO through operational partnerships between December 2017 and February 2019 with the purpose of identifying challenges and good practice during the deployment process, and steps to their improvement.

Methods
A mixed methods design was used. A desktop review was conducted to describe the demographics of the humanitarian workers deployed to Cox’s Bazar and the work that was undertaken. Interviews were conducted with a subset of the respondents to elicit their views relating to their experiences of working as part of the humanitarian response. Thematic analysis was used to identify key themes.

Results
We identified sixty-five deployments during the study period. Respondents’ previous experience ranged between 3 and 28 years (mean 9.7 years). The duration of deployment ranged from 8 to 278 days (mean 67 days) and there was a higher representation of workers from Western Pacific and European regions. Forty-one interviews were conducted with people who experienced differing aspects of the deployment process. Key themes elicited from interviews related to staffing, the deployment process, the office environment and capacity building. Various issues raised have since been addressed, including the establishment of a sub-office structure, introduction of online training prior to deployment, and a staff wellbeing committee.

Conclusions
This study identified successes and areas for improvement for deployments during emergencies. The themes and subthemes elicited can be used to inform policy and practice changes, as well as the development of performance indicators. Common findings between this study and previous literature indicate the pivotal role of staff deployments through partnership agreements during health emergency response operations and a need for continuous improvements of processes to ensure maximum effectiveness.
Specialist wait time reporting using family physicians’ electronic medical record data: a mixed method study of feasibility and clinical utility
Authors: Naimer Michelle S. , Aliarzadeh Babak , Bell Chaim M. , Ivers Noah , Jaakkimainen Liisa , McIsaac Warren , Meaney Christopher , Moineddin Rahim , Permaul Joanne A. , Makuwaza Tutsirai , Kukan Sahana 
Published: April 2022

Abstract
Background
More than 50% of Canadian adult patients wait longer than four weeks to see a specialist after referral from primary care. Access to accurate wait time information may help primary care physicians choose the timeliest specialist to address a patient’s specific needs. We conducted a mixed-methods study to assess if primary to specialist care wait times can be extracted from electronic medical records (EMR), analyzed the wait time information, and used focus groups and interviews to assess the potential clinical utility of the wait time information.

Methods
Two family practices were recruited to examine primary care physician to specialist wait times between January 2016 and December 2017, using EMR data. The primary outcome was the median wait time from physician referral to specialist appointment for each specialty service. Secondary outcomes included the physician and patient characteristics associated with wait times as well as qualitative analyses of physician interviews about the resulting wait time reports.

Results
Wait time data can be extracted from the primary care EMR and converted to a report format for family physicians and specialists to review. After data cleaning, there were 7141 referrals included from 4967 unique patients. The 5 most common specialties referred to were Dermatology, Gastroenterology, Ear Nose and Throat, Obstetrics and Gynecology and Urology. Half of the patients were seen by a specialist within 42 days, 75% seen within 80 days and all patients within 760 days. There were significant differences in wait times by specialty, for younger patients, and those with urgently labelled medical situations. Overall, wait time reports were perceived by clinicians to be important since they could help family physicians decide how to triage referrals and might lead to system improvements.

Conclusions
Wait time information from primary to specialist care can aid in decision-making around specialist referrals, identify bottlenecks, and help with system planning. This mixed method study is a starting point to review the importance of providing wait time data for both family physicians, specialists and local health systems. Future work can be directed towards developing wait time reporting functionality and evaluating if wait time information will help increase system efficiency and/or improve provider and patient satisfaction.
Health behaviour and its determinants in elderly patients with chronic diseases: evidence from Jiangsu Province, China
Authors: Chen Li , Gong Yinghua , Yuan Liang 
Published: April 2022

Abstract
Background
Chronic disease is a major cause of mortality among elderly individuals in China, and treatment is a substantial public health burden. However, behavioural interventions may be more important than mere clinical treatment of these chronic diseases.

Objective
The paper aimed to assess the health behaviour of a sample of elderly individuals with chronic diseases in Jiangsu Province, China and to identify how demographic characteristics influence health behaviour. Furthermore, the group that would likely need the most health intervention was identified.

Design
A version of the Health Promoting Lifestyle Profile II (HPLP-II) was adapted to Chinese to evaluate health behaviours in six dimensions: nutrition, tobacco and alcohol use, physical activity, stress management, health responsibility, and spiritual growth. Multistage random sampling was conducted from October 2020 to May 2021. Questionnaires incorporating the adapted HPLP-II were distributed to 900 elderly patients (i.e., aged 60 and above) with chronic diseases in the three sampled prefectures of Jiangsu Province; of these questionnaires, 791 were completed. Univariate t tests, principal component analysis, and multivariate linear regressions were employed in the analysis.

Results
The average total score of respondents on health behaviour was 73.73. The dimensions (ordered from highest to lowest scores) are as follows: “nutrition”, “tobacco and alcohol use”, “health responsibility”, “spiritual growth”, “stress management”, and “physical activity”. The multivariate linear regression suggested that the determinants (P < 0.05) of health behaviour (total score) were income, sex, age, relationship status, residence, and education.

Conclusions
Elderly patients with chronic diseases in Jiangsu Province generally behaved in a healthy manner. “Physical activity”, “stress management”, and “spiritual growth” were the dimensions that would most benefit from health intervention, while elderly single/divorced/widowed patients with lower income and less education should be the target group for health intervention.