Miracle-dz/UniFAR-FTUs huggingface dataset:
Cost-effectiveness of a high-intensity versus a low-intensity smoking cessation intervention in a dental setting: long-term follow-up

Objectives The aim of this study was to conduct a cost-effectiveness analysis (CEA) of a high-intensity and a low-intensity smoking cessation treatment programme (HIT and LIT) using long-term follow-up effectiveness data and to validate the cost-effectiveness results based on short-term follow-up. Design and outcome measures Intervention effectiveness was estimated in a randomised controlled trial as numbers of abstinent participants after 1 and 5–8 years of follow-up. The economic evaluation was performed from a societal perspective using a Markov model by estimating future disease-related costs (in Euro (€) 2018) and health effects (in quality-adjusted life-years (QALYs)). Programmes were explicitly compared in an incremental analysis, and the results were presented as an incremental cost-effectiveness ratio. Setting The study was conducted in dental clinics in Sweden. Participants 294 smokers aged 19–71 years were included in the study. Interventions Behaviour therapy, coaching and pharmacological advice (HIT) was compared with one counselling session introducing a conventional self-help programme (LIT). Results The more costly HIT led to higher number of 6-month continuous abstinent participants after 1 year and higher number of sustained abstinent participants after 5–8 years, which translates into larger societal costs avoided and health gains than LIT. The incremental cost/QALY of HIT compared with LIT amounted to €918 and €3786 using short-term and long-term effectiveness, respectively, which is considered very cost-effective in Sweden. Conclusion CEA favours the more costly HIT if decision makers are willing to spend at least €4000/QALY for tobacco cessation treatment.
Long noncoding RNA ZNF667‐AS1 reduces tumor invasion and metastasis in cervical cancer by counteracting microRNA‐93‐3p‐dependent PEG3 downregulation

Zinc finger protein 667‐antisense RNA 1 (ZNF667‐AS1), located on human chromosome 19q13.43, is a member of the C2H2 zinc finger protein family. Herein, we aimed to analyze the interactions between ZNF667‐AS1, microRNA‐93‐3p (miR‐93‐3p), and paternally expressed gene 3 (PEG3) and to explore their roles in the tumorigenesis of cervical cancer (CC). Differentially expressed long noncoding RNAs and miRNAs related to CC were determined using gene expression datasets sourced from the Gene Expression Omnibus database. Subsequently, the regulatory relationships between ZNF667‐AS1 and miR‐93‐3p and between miR‐93‐3p and PEG3 were identified using the dual‐luciferase reporter gene assay. In addition, the expression of miR‐93‐3p and ZNF667‐AS1 was up‐ or downregulated in CC cells (HeLa), in order to assess their effects on cell cycle distribution and cell invasion in vitro, and tumor growth and metastasis in vivo. MiR‐93‐3p was found to be highly expressed, while ZNF667‐AS1 and PEG3 were poorly expressed in CC. ZNF667‐AS1 could competitively bind to miR‐93‐3p, which targeted PEG3. In addition, miR‐93‐3p downregulation and ZNF667‐AS1 overexpression led to increased expression of PEG3, tissue inhibitor of metalloproteinases, and p16 and decreased expression of cyclin D1, matrix metalloproteinase‐2 and ‐9. MiR‐93‐3p inhibition and ZNF667‐AS1 elevation also inhibited cell cycle entry and cell invasion in vitro, but repressed tumor growth and metastasis in vivo. These key findings demonstrated that upregulation of ZNF667‐AS1 could suppress the progression of CC via the modulation of miR‐93‐3p‐dependent PEG3, suggesting a potential therapeutic target for the treatment of CC.
Effect of Bazedoxifene and Conjugated Estrogen (Duavee) on Breast Cancer Risk Biomarkers in High-Risk Women: A Pilot Study

Interventions that relieve vasomotor symptoms while reducing risk for breast cancer would likely improve uptake of chemoprevention for perimenopausal and postmenopausal women. We conducted a pilot study with 6 months of the tissue selective estrogen complex bazedoxifene (20 mg) and conjugated estrogen (0.45 mg; Duavee) to assess feasibility and effects on risk biomarkers for postmenopausal breast cancer. Risk biomarkers included fully automated mammographic volumetric density (Volpara), benign breast tissue Ki-67 (MIB-1 immunochemistry), and serum levels of progesterone, IGF-1, and IGFBP3, bioavailable estradiol and testosterone. Twenty-eight perimenopausal and postmenopausal women at increased risk for breast cancer were enrolled: 13 in cohort A with baseline Ki-67 < 1% and 15 in cohort B with baseline Ki-67 of 1% to 4%. All completed the study with > 85% drug adherence. Significant changes in biomarkers, uncorrected for multiple comparisons, were a decrease in mammographic fibroglandular volume (P = 0.043); decreases in serum progesterone, bioavailable testosterone, and IGF-1 (P < 0.01), an increase in serum bioavailable estradiol (P < 0.001), and for women from cohort B a reduction in Ki-67 (P = 0.017). An improvement in median hot flash score from 15 at baseline to 0 at 6 months, and menopause-specific quality-of-life total, vasomotor, and sexual domain scores were also observed (P < 0.001). Given the favorable effects on risk biomarkers and patient reported outcomes, a placebo-controlled phase IIB trial is warranted.
Artificial Intelligence in Clinical Decision Support: a Focused Literature Survey

Summary Objectives: This survey analyses the latest literature contributions to clinical decision support systems (DSSs) on a two-year period (2017-2018), focusing on the approaches that adopt Artificial Intelligence (AI) techniques in a broad sense. The goal is to analyse the distribution of data-driven AI approaches with respect to “classical" knowledge-based ones, and to consider the issues raised and their possible solutions. Methods: We included PubMed and Web of ScienceTM publications, focusing on contributions describing clinical DSSs that adopted one or more AI methodologies. Results: We selected 75 papers, 49 of which describe approaches in the data-driven AI area, 20 present purely knowledge-based DSSs, and 6 adopt hybrid approaches relying on both formalized knowledge and data. Conclusions: Recent studies in the clinical DSS area demonstrate a prevalence of data-driven AI, which can be adopted autonomously in purely data-driven systems, or in cooperation with domain knowledge in hybrid systems. Such hybrid approaches, able to conjugate all available knowledge sources through proper knowledge integration steps, represent an interesting example of synergy between the two AI categories. This synergy can lead to the resolution of some existing issues, such as the need for transparency and explainability, nowadays recognized as central themes to be addressed by both AI and medical informatics research.
Quantifying the Vial-Capping Process: Reexamination Using Micro-Computed Tomography

A vial-capping process for lyophilization stopper configurations was previously quantified using residual seal force (RSF). A correlation between RSF and container closure integrity (CCI) was established, and component positional offsets were identified to be the primary source of variability in RSF measurements. To gain insight into the effects of stopper geometry on CCI, serum stoppers with the same rubber formulation were investigated in this study. Unlike lyophilization stoppers that passed CCI (per helium leak testing) even with RSF of 0 N owing to their excellent valve seal, serum stoppers consistently failed CCI when RSF was <15.8 N. When the plug was removed, both types of stoppers exhibited a comparable critical lower RSF limit (19–20 N), below which CCI could not be maintained. When CCI was retested at later time points (up to 6 mo), some previously failed vials passed CCI, suggesting that CCI improvement might be related to rubber relaxation (viscous flow), which can fill minor imperfections on the vial finish. To confirm component positional offsets are the primary sources of RSF variability, a novel quantification tool—micro-computed tomography (micro-CT)—was used in this study. Micro-CT provided images for quantification of positional offsets of the cap and stopper that directly correlated with RSF fluctuations. Serum stoppers and lyophilization stoppers are comparable in RSF variations, although lyophilization stoppers are more robust in CCI. The use of micro-CT provides a nondestructive and innovative tool in quantitatively analyzing component features of capped vials that would otherwise be difficult to investigate.
Single-Cell RNA Transcriptome Helps Define the Limbal/Corneal Epithelial Stem/Early Transit Amplifying Cells and How Autophagy Affects This Population

Purpose Single-cell RNA-sequencing (scRNA-seq) was used to interrogate the relatively rare stem (SC) and early transit amplifying (TA) cell populations in limbal/corneal epithelia from wild-type and autophagy-compromised mice. Methods We conducted scRNA-seq on ocular anterior segmental tissue from wild-type and beclin 1–deficient (beclin1+/−) mice, using a 10X Gemomics pipeline. Cell populations were distinguished by t-distributed stochastic neighbor embedding. Seurat analysis was conducted to compare gene expression profiles between these two groups of mice. Differential protein expression patterns were validated by immunofluorescence staining and immunoblotting. Results Unbiased clustering detected 10 distinct populations: three clusters of mesenchymal and seven clusters of epithelial cells, based on their unique molecular signatures. A discrete group of mesenchymal cells expressed genes associated with corneal stromal SCs. We identified three limbal/corneal epithelial cell subpopulations designated as stem/early TA, mature TA, and differentiated corneal epithelial cells. Thioredoxin-interacting protein and PDZ-binding kinase (PBK) were identified as novel regulators of stem/early TA cell quiescence. PBK arrested corneal epithelial cells in G2/M phase of the cell cycle. Beclin1+/− mice displayed a decrease in proliferation-associated (Ki67, Lrig1) and stress-response (H2ax) genes. The most increased gene in beclin1+/− mice was transcription factor ATF3, which negatively regulates limbal epithelial cell proliferation. Conclusions Establishment of a comprehensive atlas of genes expressed by stromal and epithelial cells from limbus and cornea forms the foundation for unraveling regulatory networks among these distinct tissues. Similarly, scRNA-seq profiling of the anterior segmental epithelia from wild-type and autophagy-deficient mice provides new insights into how autophagy influences proliferation in these tissues.
Double burden of malnutrition at household level: A comparative study among Bangladesh, Nepal, Pakistan, and Myanmar

Background The coexistence of overweight mother and stunted child at the same household is a type of Double Burden of Malnutrition at Household Level (DBMHL). This particular public health concern is now emerging at an alarming rate among most of the South Asian and its neighboring lower-and-middle income countries which are going through nutritional transition. This study has examined the prevalence rate and the risk factors of DBMHL along with the socio-economic inequality in DBMHL among Bangladesh, Nepal, Pakistan, and Myanmar. Methods Latest Demographic and Health Survey datasets were used in this study. To identify the significant association of DBMHL with socio-demographic characteristics, a multivariate technique named as logistic regression model, and for measuring socio-economic inequalities in DBMHL prevalence, relative index of inequality (RII) and slope index of inequality (SII) were used. Results The prevalence rates of DBMHL were 4.10% (urban: 5.57%, rural: 3.51%), 1.54% (urban: 1.63%, rural: 1.42%), 3.93% (urban: 5.62%, rural: 3.20%), and 5.54% (urban: 6.16%, rural: 5.33%) respectively in Bangladesh, Nepal, Pakistan, and Myanmar. The risk ratios (RR) obtained from RII for Bangladesh, Nepal, Pakistan and Myanmar were 1.25, 1.25, 1.14, and 1.09, respectively, and β coefficient from SII were 0.01, 0.004, 0.005, and 0.006 unit respectively. In addition to not breastfeeding [Bangladesh (AOR: 1.55; 95% CI: 1.11–2.15), Myanmar (AOR: 1.74; 95% CI: 1.02–2.95)], respondent’s older age (in Bangladesh, Nepal, and Myanmar), child’s older age (in Pakistan and Myanmar), and middle and rich groups of wealth-index (in Bangladesh and Pakistan) were strong risk factors for DBMHL. On the other hand, female child [Nepal (AOR: 0.50; 95% CI: 0.26–0.95), Pakistan (AOR: 0.58; 95% CI: 0.41–0.84)], higher education [in Pakistan], respondent not participated in decision making [in Bangladesh and Nepal] and media access [Nepal (AOR: 0.44; 95% CI: 0.20–0.98)] had negative association with DBMHL. Conclusion The DBMHL persists in all selected countries, with a higher prevalence in urban areas than in rural areas. In order to control the higher prevalence of DBMHL in urban areas, respective countries need urgent implementation of multisectoral actions through effective policies and empowering local communities.
The prognostic value of tumour‐associated macrophages in Non‐Hodgkin's lymphoma: A systematic review and meta‐analysis

Tumour‐associated macrophages (TAMs) play an important role in the tumour environment and were reported to be associated with poor prognosis in several tumours. However, the prognostic significance of TAMs in Non‐Hodgkin's Lymphoma (NHL) remains controversial. Consequently, we aimed to evaluate the relationship between subpopulations of TAMs and clinical outcomes in NHL patients. We did a comprehensive search of the PubMed, elsevier ScienceDirect, and Cochrane databases and extracted hazard ratio (HR) and their corresponding 95% confidence intervals (95% CIs) from eligible studies. Pooling total effect value by the stata statistical software and analysing correlation of TAMs with overall survival (OS) and progression‐free survival (PFS). Furthermore, subgroup analysis and sensitivity analysis were also conducted. We deemed eleven studies, including 1211 NHL patients. Our study demonstrated that high‐density CD68+ TAMs are associated with poor OS (HR: 1.17; 95% CI, 0.81‐1.54; P = .000) and poor PFS (HR: 1.15; 95% CI, 0.63‐1.67; P = .000) compared with low‐density CD68+ TAMs in the tumour microenvironment. Similarly, high‐density CD163+ TAMs can also predict poor OS (HR: 1.52; 95% CI, 1.11‐1.92; P = .000) and shorter PFS (HR: 1.52; 95% CI, 0.73‐2.30; P = .000). In addition, the high CD163+/CD68+ TAMs ratio is significantly correlated with poor OS (HR: 3.59; 95% CI, 0.77‐6.40; P = .013). However, in our subgroup analysis, high‐density CD68+ TAMs in the tumour microenvironment is associated with better OS (HR: 0.75; 95% CI, 0.41‐1.09; P = .000) in NHL patients treated with rituximab chemotherapy. Our results suggest that TAMs are a robust predictor of outcomes in NHL.
Effect of a Nationwide Real‐Time Drug Utilization Review System on Duplicated Nonsteroidal Antiinflammatory Drug Prescriptions in Korea

Since January 2013, a nationwide drug utilization review (DUR) system for therapeutic duplication (TD) of nonsteroidal antiinflammatory drugs (NSAIDs) has been implemented in Korea. Our objective was to perform an interrupted time series study to assess changes in the pattern of NSAIDs use in knee osteoarthritis patients after implementation of the regulations.
Induction and kinetics of complement-fixing antibodies against Plasmodium vivax MSP3α and relationship with IgG subclasses and IgM.

BACKGROUND Complement-fixing antibodies are important mediators of protection against Plasmodium falciparum malaria. However, complement-fixing antibodies remain uncharacterised for P. vivax malaria. Plasmodium vivax merozoite Surface Protein-3α (PvMSP3α) is a target of acquired immunity and a potential vaccine candidate. METHODS Plasma from children and adults with P. vivax malaria in Sabah, Malaysia, were collected during acute infection, 7 and 28 days following drug treatment. Complement-fixing antibodies and IgM and IgG, targeting three distinctive regions of PvMSP3α were measured by ELISA. RESULTS Seroprevalence of complement-fixing antibodies was highest against PvMSP3α Central region (77.6%). IgG1, IgG3, and IgM were significantly correlated with C1q-fixation and both purified IgG and IgM were capable of mediating C1q-fixation to PvMSP3α. Complement-fixing antibody levels were similar between age groups, but IgM was predominant in children and IgG3 more prevalent in adults. Functional antibodies increased following acute infection to 7 days after treatment, however rapidly waned by day 28. CONCLUSION Our study demonstrates PvMSP3α antibodies acquired during P. vivax infection can mediate complement-fixation and shows the important influence of age in shaping these specific antibody responses. Further studies are warranted to understand the role of these functional antibodies in protective immunity against P. vivax malaria.
Diverse repertoire of human adipocyte subtypes develops from transcriptionally distinct mesenchymal progenitor cells

Significance Single-cell sequencing technologies are providing unexpected insights on how seemingly homogenous cell populations differ markedly in their functional properties, and how diverse cell repertoires mediate the functions of tissues and organs. Adipose tissue controls multiple key aspects of systemic energy homeostasis, but only 2 human adipocyte subtypes have been recognized so far. Here we developed methods to characterize single human mesenchymal progenitors and discovered 4 previously unknown adipocyte subtypes specialized for distinct adipose tissue functions, which are derived from distinct progenitors. Recognizing the existence of these different adipocyte subtypes and their progenitors will allow us to elucidate mechanisms that control their abundance and properties, and to better understand how dysregulation of these mechanisms can lead to metabolic disease. Single-cell sequencing technologies have revealed an unexpectedly broad repertoire of cells required to mediate complex functions in multicellular organisms. Despite the multiple roles of adipose tissue in maintaining systemic metabolic homeostasis, adipocytes are thought to be largely homogenous with only 2 major subtypes recognized in humans so far. Here we report the existence and characteristics of 4 distinct human adipocyte subtypes, and of their respective mesenchymal progenitors. The phenotypes of these distinct adipocyte subtypes are differentially associated with key adipose tissue functions, including thermogenesis, lipid storage, and adipokine secretion. The transcriptomic signature of “brite/beige” thermogenic adipocytes reveals mechanisms for iron accumulation and protection from oxidative stress, necessary for mitochondrial biogenesis and respiration upon activation. Importantly, this signature is enriched in human supraclavicular adipose tissue, confirming that these cells comprise thermogenic depots in vivo, and explain previous findings of a rate-limiting role of iron in adipose tissue browning. The mesenchymal progenitors that give rise to beige/brite adipocytes express a unique set of cytokines and transcriptional regulators involved in immune cell modulation of adipose tissue browning. Unexpectedly, we also find adipocyte subtypes specialized for high-level expression of the adipokines adiponectin or leptin, associated with distinct transcription factors previously implicated in adipocyte differentiation. The finding of a broad adipocyte repertoire derived from a distinct set of mesenchymal progenitors, and of the transcriptional regulators that can control their development, provides a framework for understanding human adipose tissue function and role in metabolic disease.
Physiologically Based Pharmacokinetic Models for Adults and Children Reveal a Role of Intracellular Tubulin Binding in Vincristine Disposition

Vincristine is a cytotoxic chemotherapeutic agent used as first‐line therapy for pediatric acute lymphocytic leukemia. It is cleared by hepatic oxidative metabolism by CYP3A4 and CYP3A5 and via hepatic (biliary) efflux mediated by P‐glycoprotein (P‐gp) transporter. Bottom‐up physiologically based pharmacokinetic (PBPK) models were developed to predict vincristine disposition in pediatric and adult populations. The models incorporated physicochemical properties, metabolism by CYP3A4/5, efflux by P‐gp, and intracellular binding to β‐tubulin. The adult and pediatric PBPK models predicted pharmacokinetics (PK) within twofold of the observed PK parameters (area under the curve, terminal half‐life, volume of distribution, and clearance). Simulating a higher hypothetical (4.9‐fold) pediatric expression of β‐tubulin relative to adult improved predictions of vincristine PKs. To our knowledge, this is the first time that intracellular binding has been incorporated into a pediatric PBPK model. Utilizing this PBPK modeling approach, safe and effective doses of vincristine could be predicted.
First-in-Human Study of Mivebresib (ABBV-075), an Oral Pan-Inhibitor of Bromodomain and Extra Terminal Proteins, in Patients with Relapsed/Refractory Solid Tumors

Purpose: Bromodomain and extraterminal (BET) proteins play important roles in transcriptional regulation relevant to cancer pathogenesis, and therapeutic targeting/inhibition of BET causes apoptosis of cancer cells in vitro. In this first-in-human study of the pan-BET inhibitor mivebresib (ABBV-075), the safety profile, MTD, and recommended phase II dose (RP2D) were determined in patients with advanced solid tumors. Patients and Methods: A 3 + 3 dose escalation for different mivebresib dosing schedules [daily, Monday/Wednesday/Friday (M-W-F), 4 days on/3 off (4/7)] was followed by dose expansion in patients with prostate cancer. Endpoints were safety, tolerability, pharmacokinetics, and preliminary antitumor activity. Results: Seventy-two patients with solid tumors (14% uveal melanoma; 11% colorectal; 11% breast; 8% pancreatic; 7% head/neck; 49% others) were treated with mivebresib during dose escalation, and 12 additional patients with prostate cancer in expansion cohort. Most common treatment-emergent adverse events (TEAE) related to mivebresib were dysgeusia (49%), thrombocytopenia (48%), fatigue (26%), and nausea (25%). Most common grade 3/4 TEAEs related to mivebresib were thrombocytopenia (35%) and anemia (6%). Dose-limiting toxicities included thrombocytopenia (2 mg daily; 4.5 mg M-W-F), gastrointestinal bleed (2 mg daily), hypertension (2–3 mg 4/7), fatigue, decreased appetite, and aspartate aminotransferase elevation (4 mg M-W-F). Of 61 evaluable patients from dose escalation, 26 (43%) had stable disease and 35 (57%) had progressive disease. Median progression-free survival was 1.8 months (95% confidence interval, 1.8–1.9). Conclusions: On the basis of safety and tolerability, mivebresib RP2D is 1.5 mg for the daily schedule, 2.5 mg for 4/7, and 3 mg for M-W-F. Mivebresib has a tolerable safety profile, and stable disease was observed in some patients with malignant solid tumors.