bluuebunny/crossref_metadata_2025_split huggingface dataset:
Liver function tests and fibrosis scores in a rural population in Africa: a cross-sectional study to estimate the burden of disease and associated risk factors
Authors: O'Hara Geraldine , Mokaya Jolynne , Hau Jeffrey P , Downs Louise O , McNaughton Anna L , Karabarinde Alex , Asiki Gershim , Seeley Janet , Matthews Philippa C , Newton Robert 
Published: March 2020

ObjectivesLiver disease is a major cause of morbidity and mortality in sub-Saharan Africa, but its prevalence, distribution and aetiology have not been well characterised. We therefore set out to examine liver function tests (LFTs) and liver fibrosis scores in a rural African population.DesignWe undertook a cross-sectional survey of LFTs. We classified abnormal LFTs based on reference ranges set in America and in Africa. We derived fibrosis scores (aspartate aminotransferase (AST) to Platelet Ratio Index (APRI), fibrosis-4, gamma-glutamyl transferase (GGT) to platelet ratio (GPR), red cell distribution width to platelet ratio and S-index). We collected information about alcohol intake, and infection with HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV).SettingWe studied a population cohort in South-Western Uganda.ParticipantsData were available for 8099 adults (median age 30 years; 56% female).ResultsThe prevalence of HBV, HCV and HIV infection was 3%, 0.2% and 8%, respectively. The prevalence of abnormal LFTs was higher based on the American reference range compared with the African reference range (eg, for AST 13% vs 3%, respectively). Elevated AST/ALT ratio was significantly associated with self-reported alcohol consumption (p<0.001), and the overall prevalence of AST/ALT ratio >2 was 11% (suggesting alcoholic hepatitis). The highest prevalence of fibrosis was predicted by the GPR score, with 24% of the population falling above the threshold for fibrosis. There was an association between the presence of HIV or HBV and raised GPR (p=0.005) and S-index (p<0.001). By multivariate analysis, elevated LFTs and fibrosis scores were most consistently associated with older age, male sex, being under-weight, HIV or HBV infection and alcohol consumption.ConclusionsFurther work is required to determine normal reference ranges for LFTs in this setting, to evaluate the specificity and sensitivity of fibrosis scores and to determine the aetiology of liver disease.
Investigating the effectiveness of care delivery at an acute geriatric community hospital for older adults in the Netherlands: a protocol for a prospective controlled observational study
Authors: Ribbink Marthe E , Macneil-Vroomen Janet L , van Seben Rosanne , Oudejans Irène , Buurman Bianca M 
Published: March 2020

IntroductionHospital admission in older adults with multiple chronic conditions is associated with unwanted outcomes like readmission, institutionalisation, functional decline and mortality. Providing acute care in the community and integrating effective components of care models might lead to a reduction in negative outcomes. Recently, the first geriatrician-led Acute Geriatric Community Hospital (AGCH) was introduced in the Netherlands. Care at the AGCH is focused on the treatment of acute diseases, comprehensive geriatric assessment, setting patient-led goals, early rehabilitation and streamlined transitions of care.Methods and analysisThis prospective cohort study will investigate the effectiveness of care delivery at the AGCH on patient outcomes by comparing AGCH patients to two historic cohorts of hospitalised patients. Propensity score matching will correct for potential population differences. The primary outcome is the 3-month unplanned readmission rate. Secondary outcomes include functional decline, institutionalisation, healthcare utilisation, occurrence of delirium or falls, health-related quality of life, mortality and patient satisfaction. Measurements will be conducted at admission, discharge and 1, 3 and 6 months after discharge. Furthermore, an economic evaluation and qualitative process evaluation to assess facilitators and barriers to implementation are planned.Ethics and disseminationThe study will be conducted according to the Declaration of Helsinki. The Medical Ethics Research Committee confirmed that the Medical Research Involving Human Subjects Act did not apply to this research project and official approval was not required. The findings of this study will be disseminated through public lectures, scientific conferences and journal publications. Furthermore, the findings of this study will aid in the implementation and financing of this concept (inter)nationally.Trial registration numberNL7896; Pre-results.
Maternal multivitamin intake and orofacial clefts in offspring: Japan Environment and Children's Study (JECS) cohort study
Authors: Yoshida Satomi , Takeuchi Masato , Kawakami Chihiro , Kawakami Koji , Ito Shuichi 
Published: March 2020

ObjectivesOrofacial clefts are common birth defects with a lack of strong evidence regarding their association with maternal nutrition. We aimed to determine whether a relationship exists between maternal nutrient or multivitamin intake and orofacial clefts.DesignThis is a prospective, population-based nationwide cohort study.SettingThe study was conducted in 15 regional centres, consisting of local administrative units and study areas.ParticipantsA total of 98 787 eligible mother–child pairs of the Japan Environment and Children’s Study were included.InterventionExposures were maternal nutrition and the use of supplemental multivitamins in mothers.Primary and secondary outcome measuresOutcomes were the occurrence of any orofacial cleft at birth. Multinomial logistic regression analyses were used to evaluate the association between maternal multivitamin intake and the incidence of orofacial clefts.ResultsOf the 98 787 children, 69 (0.07%) were diagnosed with cleft lip alone, 113 (0.11%) were diagnosed with cleft lip and palate, and 52 (0.05%) were diagnosed with cleft palate within 1 month after birth. Regarding the total orofacial cleft outcome, statistically significant point estimates of relative risk ratios (RR) were determined for multivitamin intake before pregnancy (RR=1.71; 95% CI 1.06 to 2.77) and during the first trimester (RR=2.00; 95% CI 1.18 to 3.37), but the association was not significant for multivitamin intake after the first trimester (RR=1.34; 95% CI 0.59 to 3.01). Maternal micronutrient intake via food was not associated with the incidence of orofacial clefts in offspring.ConclusionsIntake of multivitamin supplements shortly before conception or during the first trimester of pregnancy was found to be associated with an increased incidence of orofacial clefts at birth. Pregnant women and those intending to become pregnant should be advised of the potential risks of multivitamin supplementation.
Evaluating a group-based Yoga of Stress Resilience programme: a pragmatic before–after interventional study protocol
Authors: Alvarez Elizabeth , Sutton Arielle , Barton Bria , Vaidya Shailla 
Published: March 2020

IntroductionRates of mental health illnesses and burnout are increasing internationally. Therapeutic yoga is increasingly used to improve and maintain physical, mental and emotional well-being and general health. This protocol describes a study to evaluate the effectiveness of an existing primary care group-based therapeutic yoga programme, the Yoga of Stress Resilience programme, which combines yoga and psychotherapeutic techniques, in improving mental health and decreasing burnout. Implementation factors will also be evaluated for potential scale-up.Methods and analysisA pragmatic before–after interventional trial design will be used to study changes in occupational participation and mental health outcomes, including anxiety, depression, burnout, functional impairment, insomnia, perceived stress, loneliness, self-compassion and readiness for change in adults experiencing anxiety and burnout. Repeated measures analysis of variance will be used to determine changes in outcome measures over time. Regression and multivariate analyses will be conducted to examine relationships between participant characteristics and outcomes and among various outcomes. The Reach, Effectiveness, Adoption, Implementation, and Maintenance framework will be used to guide the analyses.Ethics and disseminationApproval from the Hamilton Integrated Research Ethics Board has been waived: project number 7082 (full review waived). Informed consent will be obtained prior to enrolling any participant into the study. All data will be kept confidential. Peer-reviewed publications and presentations will target researchers and health professionals.Trial registration numberThe ClinicalTrials.gov registry (NCT03973216).
Associations of symptoms and quality of life with outcomes in patients with atrial fibrillation
Authors: Krisai Philipp , Blum Steffen , Aeschbacher Stefanie , Beer Jürg H , Moschovitis Giorgio , Witassek Fabienne , Kobza Richard , Rodondi Nicolas , Moutzouri Elisavet , Mahmood Aamina , Healey Jeff S , Zuern Christine S , Kühne Michael , Osswald Stefan , Conen David 
Published: March 2020

ObjectiveWe aimed to investigate changes in atrial fibrillation (AF)-related symptoms and quality of life (QoL) over time, and their impact on prognosis.MethodsWe prospectively followed 3836 patients with known AF for a mean of 3.7 years. Information on AF-related symptoms and QoL was obtained yearly. The primary end point was a composite of stroke or systemic embolism. Main secondary end points included stroke subtypes, all-cause mortality, cardiovascular death, hospitalisation for congestive heart failure (CHF), myocardial infarction and major bleeding. We assessed associations using multivariable, time-updated Cox proportional hazards models.ResultsMean age was 72 years, 72% were male. Patients with AF-related symptoms (66%) were younger (70 vs 74 years, p<0.0001), more often had paroxysmal AF (56% vs 37%, p<0.0001) and had lower QoL (71 vs 72 points, p=0.009). The incidence of the primary end point was 1.05 and 1.02 per 100 person-years in patients with and without symptoms, respectively. The multivariable adjusted HR (aHR) (95% CIs) for the primary end point was 1.11 (0.77 to 1.59; p=0.56) for AF-related symptoms. AF-related symptoms were not associated with any of the secondary end points. QoL was not significantly related to the primary end point (aHR per 5-point increase 0.98 (0.94 to 1.03; p=0.37)), but was significantly related to CHF hospitalisations (0.92 (0.90 to 0.94; p<0.0001)), cardiovascular death (0.90 (0.86 to 0.95; p<0.0001)) and all-cause mortality (0.88 (0.86 to 0.90; p<0.0001)).ConclusionsAF-related symptoms were not associated with adverse outcomes and should therefore not be the basis for prognostic treatment decisions. QoL was strongly associated with CHF, cardiovascular death and all-cause mortality.
Conditional immune toxicity rate in patients with metastatic renal and urothelial cancer treated with immune checkpoint inhibitors
Authors: Nuzzo Pier Vitale , Pond Gregory R , Abou Alaiwi Sarah , Nassar Amin H , Flippot Ronan , Curran Catherine , Kilbridge Kerry L , Wei Xiao X , McGregor Bradley A , Choueiri Toni , Harshman Lauren C , Sonpavde Guru 
Published: March 2020

BackgroundImmune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs). Although the incidence and prevalence of irAEs have been well characterized in the literature, less is known about the cumulative incidence rate of irAEs. We studied the cumulative incidence of irAEs, defined as the probability of irAE occurrence over time and the risk factors for irAE development in metastatic urothelial carcinoma (mUC) and renal cell carcinoma (mRCC) patients treated with ICIs.MethodsWe identified a cohort of patients who received ICIs for mUC and mRCC. irAEs were classified using Common Terminology Criteria for Adverse Event (CTCAE) V.5.0 guidelines. The monthly incidence of irAEs over time was reported after landmark duration of therapy. Cumulative incidence of irAEs was calculated to evaluate the time to the first occurrence of an irAE accounting for the competing risk of death. Prognostic factors for irAE were assessed using the Fine and Gray method.ResultsA total of 470 patients were treated with ICIs between July 2013 and October 2018 (mUC: 199 (42.3%); mRCC: 271 (57.7%)). 341 (72.6%) patients received monotherapy, 86 (18.3%) received ICIs in combination with targeted therapies, and 43 (9.2%) received dual ICI therapy. Overall, 186 patients (39.5%) experienced an irAE at any time point. Common irAEs included hypothyroidism (n=42, 22.6%), rush and pruritus (n=36, 19.4%), diarrhea/colitis (n=35, 18.8%), transaminitis (n=32, 17.2%), and pneumonitis (n=14, 7.5%). Monthly incidence rates decreased over time; however, 17 of 109 (15.6%, 95% CI: 9.4% to 23.8%) experienced their first irAE at least 1 year after treatment initiation. No differences in cumulative incidence were observed based on cancer type, agent, or irAE grade. On multivariable analysis, combined ICI therapy with another ICI or with targeted therapy (p<0.001), first-line ICI therapy (p=0.011), and PD-1 inhibitor therapy (p=0.007) were all significantly associated with irAE development.ConclusionsThis study quantitates the incidence of developing irAEs due to ICI conditioned on time elapsed without irAE development. Although the monthly incidence of irAEs decreased over time on therapy, patients can still develop delayed irAEs beyond ICI discontinuation, and thus, continuous vigilant monitoring is warranted.
Comparison of the use of Alvarado and AIR scores as an adjunct to the clinical diagnosis of acute appendicitis in the pediatric population
Authors: Musbahi Aya , Rudd Darren , Dordea Matei , Gopinath Bussa , Kurup Vijay 
Published: March 2020

BackgroundAcute appendicitis is one of the most common causes of acute abdominal pain with an incidence of 1.17 per 1000 and lifetime risk of approximately 7%. It remains the most common indication for emergency abdominal surgery in childhood. Diagnosis of acute appendicitis is particularly difficult in young women and the pediatric population. In the USA, CT imaging is used to avert diagnostic dilemma, however the procedure is associated with radiation risk in this vulnerable population. Additionally, the procedure has high cost and variable availability.MethodsA retrospective study involving all suspected pediatric cases of appendicitis between the ages of 5 and 17 who were operated on between 2012 and 2015 was carried out. Data were collated from clinical notes on age, sex, ultrasound findings; postoperative complications, white cell count, neutrophils, C-reactive protein, histology result, and number of days to theater. All patients in the time period were retrospectively scored on the Alvarado and Appendicitis Inflammatory Response (AIR) scores.ResultsA total of 239 patients between 11 and 17 (mean 13.6±SE) years of age were included in the study. Of these, 79 had preoperative ultrasound, of which 52 were negative, and only one patient had CT scan. 213 of the patients had an appendicectomy and 26 had diagnostic laparoscopy with no appendicectomy. Of the 213 appendixes removed, 71 were histopathologically normal, giving a negative appendectomy rate of 33.3%. 28 appendixes were perforated. The average number of days from admission to theater was 1.0 SE in males and 1.424 in females (p=0.0498). The average number of days from admission to theater in those who had ultrasound was 2.03 days compared with 0.75 in those who did not have ultrasound (p<0.0001). AIR scoring that was high and medium risk showed slightly lower negative appendicectomy rates but not significantly different.ConclusionsOur study has found no significant difference between the AIR scores and Alvarado. There is a role for scoring systems to be used to aid in the decision to undergo imaging and as an adjunct to clinical diagnosis.
Exploring the flavour structure of the high-scale MSSM
Authors: Isidori Gino , Trifinopoulos Sokratis 
Published: March 2020

AbstractWe analyse the sensitivity of quark flavour-changing observables to the MSSM, in a regime of heavy superpartners. We analyse four distinct and motivated frameworks characterising the structure of the soft-breaking terms by means of approximate flavour symmetries. We show that a set of six low-energy observables with realistic chances of improvement in the near future, namely $$\Delta M_{s,d}$$ΔMs,d, $$\epsilon _K$$ϵK, $$\epsilon _K'/\epsilon _K$$ϵK′/ϵK, $$\mathcal {B} (K\rightarrow \pi \nu {{\bar{\nu }}})$$B(K→πνν¯), and the phase of D–$${\bar{D}}$$D¯ mixing, could play a very important role in characterising these frameworks for superpartner masses up to $$\mathcal {O}(100)$$O(100) TeV. We show that these observables remain very interesting even in a long-term perspective, i.e. even taking into account the direct mass reach of the most ambitious future high-energy colliders.
MAFB Promotes Cancer Stemness and Tumorigenesis in Osteosarcoma through a Sox9-Mediated Positive Feedback Loop
Authors: Chen Yanyan , Wang Tao , Huang Mengxi , Liu Qin , Hu Chao , Wang Bin , Han Dong , Chen Cheng , Zhang Junliang , Li Zhiping , Liu Chao , Lei Wenbin , Chang Yue , Wu Meijuan , Xiang Dan , Chen Yitian , Wang Rui , Huang Weiqian , Lei Zengjie , Chu Xiaoyuan 
Published: March 2020

Abstract

Despite the fact that osteosarcoma is one of the most common primary bone malignancies with poor prognosis, the mechanism behind the pathogenesis of osteosarcoma is only partially known. Here we characterized differentially expressed genes by extensive analysis of several publicly available gene expression profile datasets and identified musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) as a key transcriptional regulator in osteosarcoma progression. MAFB was highly expressed in tumor tissues and required for proliferation and tumorigenicity of osteosarcoma cells. MAFB expression was elevated in osteosarcoma stem cells to maintain their self-renewal potential in vitro and in vivo through upregulation of stem cell regulator Sox9 at the transcriptional level. Sox9 in turn activated MAFB expression via direct recognition of its sequence binding enrichment motif on the MAFB locus, thereby forming a positive feedback regulatory loop. Sox9-mediated feedback activation of MAFB was pivotal to tumorsphere-forming and tumor-initiating capacities of osteosarcoma stem cells. Moreover, expression of MAFB and Sox9 was highly correlated in osteosarcoma and associated with disease progression. Combined detection of both MAFB and Sox9 represented a promising prognostic biomarker that stratified a subset of patients with osteosarcoma with shortest overall survival. Taken together, these findings reveal a MAFB–Sox9 reciprocal regulatory axis driving cancer stemness and malignancy in osteosarcoma and identify novel molecular targets that might be therapeutically applicable in clinical settings.

Significance:
Transcription factors MAFB and Sox9 form a positive feedback loop to maintain cell stemness and tumor growth in vitro and in vivo, revealing a potential target pathway for therapeutic intervention in osteosarcoma.
Projected Reductions in Absolute Cancer–Related Deaths from Diagnosing Cancers Before Metastasis, 2006–2015
Authors: Clarke Christina A. , Hubbell Earl , Kurian Allison W. , Colditz Graham A. , Hartman Anne-Renee , Gomez Scarlett Lin 
Published: March 2020

Abstract

Background:
New technologies are being developed for early detection of multiple types of cancer simultaneously. To quantify the potential benefit, we estimated reductions in absolute cancer–related deaths that could occur if cancers diagnosed after metastasis (stage IV) were instead diagnosed at earlier stages.

Methods:
We obtained stage-specific incidence and survival data from the Surveillance, Epidemiology, and End Results Program for 17 cancer types for all persons diagnosed ages 50 to 79 years in 18 geographic regions between 2006 and 2015. For a hypothetical cohort of 100,000 persons, we estimated cancer-related deaths under assumptions that cancers diagnosed at stage IV were diagnosed at earlier stages.

Results:
Stage IV cancers represented 18% of all estimated diagnoses but 48% of all estimated cancer-related deaths within 5 years. Assuming all stage IV cancers were diagnosed at stage III, 51 fewer cancer-related deaths would be expected per 100,000, a reduction of 15% of all cancer-related deaths. Assuming one third of metastatic cancers were diagnosed at stage III, one third diagnosed at stage II, and one third diagnosed at stage I, 81 fewer cancer-related deaths would be expected per 100,000, a reduction of 24% of all cancer-related deaths, corresponding to a reduction in all-cause mortality comparable in magnitude to eliminating deaths due to cerebrovascular disease.

Conclusions:
Detection of multiple cancer types earlier than stage IV could reduce at least 15% of cancer-related deaths within 5 years, affecting not only cancer-specific but all-cause mortality.

Impact:
Detecting cancer before stage IV, including modest shifts to stage III, could offer substantial population benefit.
Metastatic Melanoma Patient–Derived Xenografts Respond to MDM2 Inhibition as a Single Agent or in Combination with BRAF/MEK Inhibition
Authors: Shattuck-Brandt Rebecca L. , Chen Sheau-Chiann , Murray Emily , Johnson Christopher Andrew , Crandall Holly , O'Neal Jamye F. , Al-Rohil Rami Nayef , Nebhan Caroline A. , Bharti Vijaya , Dahlman Kimberly B. , Ayers Gregory D. , Yan Chi , Kelley Mark C. , Kauffmann Rondi M. , Hooks Mary , Grau Ana , Johnson Douglas B. , Vilgelm Anna E. , Richmond Ann 
Published: March 2020

Abstract

Purpose:
Over 60% of patients with melanoma respond to immune checkpoint inhibitor (ICI) therapy, but many subsequently progress on these therapies. Second-line targeted therapy is based on BRAF mutation status, but no available agents are available for NRAS, NF1, CDKN2A, PTEN, and TP53 mutations. Over 70% of melanoma tumors have activation of the MAPK pathway due to BRAF or NRAS mutations, while loss or mutation of CDKN2A occurs in approximately 40% of melanomas, resulting in unregulated MDM2-mediated ubiquitination and degradation of p53. Here, we investigated the therapeutic efficacy of over-riding MDM2-mediated degradation of p53 in melanoma with an MDM2 inhibitor that interrupts MDM2 ubiquitination of p53, treating tumor-bearing mice with the MDM2 inhibitor alone or combined with MAPK-targeted therapy.

Experimental Design:
To characterize the ability of the MDM2 antagonist, KRT-232, to inhibit tumor growth, we established patient-derived xenografts (PDX) from 15 patients with melanoma. Mice were treated with KRT-232 or a combination with BRAF and/or MEK inhibitors. Tumor growth, gene mutation status, as well as protein and protein–phosphoprotein changes, were analyzed.

Results:
One-hundred percent of the 15 PDX tumors exhibited significant growth inhibition either in response to KRT-232 alone or in combination with BRAF and/or MEK inhibitors. Only BRAFV600WT tumors responded to KRT-232 treatment alone while BRAFV600E/M PDXs exhibited a synergistic response to the combination of KRT-232 and BRAF/MEK inhibitors.

Conclusions:
KRT-232 is an effective therapy for the treatment of either BRAFWT or PANWT (BRAFWT, NRASWT) TP53WT melanomas. In combination with BRAF and/or MEK inhibitors, KRT-232 may be an effective treatment strategy for BRAFV600-mutant tumors.