bluuebunny/crossref_metadata_2025_split huggingface dataset:
Determinants of prescribing decisions for off-patent biological medicines in Belgium: a qualitative study
Authors: Vandenplas Yannick , Simoens Steven , Van Wilder Philippe , Vulto Arnold G. , Turk Florian , Huys Isabelle 
Published: September 2022

Abstract
Background
A competitive market for off-patent biologicals leads to more affordable and high-quality healthcare. In recent years, Belgium has been characterized by its low use of biosimilars and by its shifts from off-patent biologicals toward new alternative therapies. Yet, the prescribing decisions involved in these observations are poorly understood. This study aims to better understand prescribing choices among Belgian physicians in the ambulatory care setting.

Methods
This study consisted of two phases. First, a scoping literature review to identify determinants of prescribing choices was conducted. Scientific databases (Embase and PubMed) were searched until 4 November 2021. Second, the nominal group technique (NGT) was employed during focus group discussions with Belgian physicians to consider and validate these determinants for off-patent biologicals in the Belgian context. The qualitative data resulting from the literature review and focus group discussions were analyzed using the thematic framework method.

Results
Fifty-three scientific articles that discussed elements that determine prescribing choices were identified. Out of these, 17 determinants of prescribing choices were found. These were divided into five categories: (1) product-related, (2) physicians’ personal, (3) healthcare system-related, (4) patient-related, and (5) determinants related to the pharmaceutical company or brand. Nineteen Belgian physicians from different therapeutic areas that regularly prescribe biologicals then participated in focus group discussions. Using the NGT, the group discussions revealed that prescribing choices for off-patent biologicals are determined by a complex set of elements. Clinical data, geographical region, working environment, pharmaceutical marketing, patient profile, clinical guidelines, and preference of key opinion leaders (KOL) were considered most influential. Physicians indicated that the importance of these determinants differs depending on product classes or therapeutic domain.

Conclusions
Multiple elements determine the choice of an off-patent biological or biosimilar product. The importance of each of these determinants varies depending on the context in which the prescribing choice is made. To increase the prescription of best-value biologicals in the Belgian ambulatory care, a set of synergistic measures is required including information for healthcare providers (HCP) and patients, prescribing feedback, prescribing targets, tangible incentives, KOL involvement, guidelines regarding pharmaceutical promotion, and regular revision of reimbursement modalities.
Emerging nanobiotechnology for precise theranostics of hepatocellular carcinoma
Authors: Xu Mengjiao , Yang Liu , Lin Yanjie , Lu Yao , Bi Xiaoyue , Jiang Tingting , Deng Wen , Zhang Lu , Yi Wei , Xie Yao , Li Minghui 
Published: September 2022

AbstractPrimary liver cancer has become the second most fatal cancer in the world, and its five-year survival rate is only 10%. Most patients are in the middle and advanced stages at the time of diagnosis, losing the opportunity for radical treatment. Liver cancer is not sensitive to chemotherapy or radiotherapy. At present, conventional molecularly targeted drugs for liver cancer show some problems, such as short residence time, poor drug enrichment, and drug resistance. Therefore, developing new diagnosis and treatment methods to effectively improve the diagnosis, treatment, and long-term prognosis of liver cancer is urgent. As an emerging discipline, nanobiotechnology, based on safe, stable, and efficient nanomaterials, constructs highly targeted nanocarriers according to the unique characteristics of tumors and further derives a variety of efficient diagnosis and treatment methods based on this transport system, providing a new method for the accurate diagnosis and treatment of liver cancer. This paper aims to summarize the latest progress in this field according to existing research and the latest clinical diagnosis and treatment guidelines in hepatocellular carcinoma (HCC), as well as clarify the role, application limitations, and prospects of research on nanomaterials and the development and application of nanotechnology in the diagnosis and treatment of HCC.
A national analysis of the pharmacy workforce in Indonesia
Authors: Meilianti Sherly , Smith Felicity , Kristianto Franciscus , Himawan Roy , Ernawati Desak Ketut , Naya Rasta , Bates Ian 
Published: September 2022

Abstract
Background
Pharmacists play a fundamental role in healthcare systems and achieving Universal Health Coverage (UHC) through quality primary healthcare service provision. While the World Health Organization (WHO) forecasts a global shortage of health workforce by 2030, mainly affecting low- and middle-income nations (LMICs), limited published literature is found regarding pharmacy workforce capacity in LMICs, including Indonesia. This paper aims to analyse pharmacists’ capacity in Indonesia to identify emerging workforce planning gaps for future workforce planning and policies in Indonesia.

Method
Several data sources were accessed, including a database from the National Pharmacy Committee and the professional leadership body in Indonesia. Descriptive (frequencies, percentages, and mean), correlational and time-series analysis using curve estimation were conducted. Secondary data on the number of programmes, pharmacy students, pharmacy workforce (pharmacists and pharmacy technicians) per province were obtained from the Ministry websites and reports.

Result
There were a total of 77 191 registered pharmacists in Indonesia in 2019. The pharmacists’ pyramid showed a youth bulge as a general indication of market expansion in the education sector correlating to the pharmacy programme’s number and size. There was a variation in pharmacy workforce density and access to pharmacy programmes across islands, which also were strongly correlated. Forecasting estimates that by 2030, women will represent around 86% of pharmacists in Indonesia. More female pharmacists were found working in the hospital and primary healthcare (providing direct services to patients) than male pharmacists. Younger pharmacists worked in the industrial sector, while older pharmacists worked in governmental and educational institutions.

Conclusion
This study signposted workforce planning gaps for policy development in Indonesia, including a need to develop structured training to support early career pharmacists in their practice. There is also a need for better access to professional development programmes designed to support female pharmacists return to the regulated workforce following career breaks. National policy to promote equitable distribution and retention of pharmacists is recommended.
Association between glycosylated hemoglobin, diabetes mellitus, and preoperative deep vein thrombosis in patients undergoing total joint arthroplasty: a retrospective study
Authors: Xiong Xiaojuan , Li Ting , Cheng Bo 
Published: September 2022

Abstract
Background
To investigate the association between the level of glycosylated hemoglobin (HbA1c) and preoperative deep vein thrombosis (DVT) and that between diabetes mellitus (DM) and preoperative DVT in patient undergoing total joint arthroplasty (TJA).

Methods
A total of 1386 patients were enrolled. We created the receiver operating characteristic (ROC) curve of HbA1c, and based on the cutoff value, patients were divided into two groups. Risk factors were subsequently examined. Chi-square test or Fisher’s exact test was adopted for enumeration data. The results were expressed in percentages (%), and DVT-related variates were analyzed. We included the variates that were statistically significant in the univariate analysis in the multivariate binary logistic regression analysis and calculated the adjusted odds ratio (OR) and 95% confidence interval (95% CI).

Results
Preoperative DVT was 100 cases (7.22%) and DM in 301 cases (21.7%). We determined the cutoff value of HbA1c of 6.15% using the ROC curve as the area under the curve (AUC) was 0.548. Univariate logistic regression revealed that the risk of preoperative DVT in TJA patients with HbA1c ≥ 6.15%, HbA1c between 7 and 7.9%, HbA1c ≥ 8%, DM, female, and major surgery in the last 12 months increased by 1.84 (P = 0.005; 95% CI [1.20–2.80]), 2.22 (P = 0.028, 95% CI [1.09–4.52]), 2.47 (P = 0.013, 95% CI [1.21–5.04]), 2.03 (P = 0.004, 95% CI [1.25–3.30]); 1.85 (P = 0.010, 95% CI [1.16–2.95]); and 2.86 times (P = 0.006, 95% CI [1.35–6.05]), respectively. And multivariate logistic regression revealed that the risk of preoperative DVT in TJA patients with HbA1c ≥ 6.15%, HbA1c between 7 and 7.9%, HbA1c ≥ 8%, DM patients, female patients, and major surgery in the last 12 months increased by 1.77 (P = 0.009, 95% CI [1.16–2.72]); 2.10 (P = 0.043, 95% CI [1.02–4.30]); 2.50 (P = 0.013, 95% CI [1.22–5.14]); 2.01 (P = 0.005, 95% CI [1.23–3.28]); 1.80 (P = 0.014, 95% CI [1.13–2.89]); and 3.04 times (P = 0.004, 95% CI [1.42–6.49]), respectively.

Conclusion
We conclude that HbA1c ≥ 6.15%, DM, female and major surgery in the last 12 months are the independent risk factors for preoperative DVT in patients undergoing TJA. And patients with a higher HbA1c level are at an increased risk of preoperative DVT.
Trial registration: ChiCRT2100054844.
Comprehensive analysis of potential ceRNA network and immune cell infiltration in intervertebral disc degeneration
Authors: Fang Xiaoyang , Tang Tian , Sun Daoxi , Chen Shuang , Wang Nan , Xie Lin 
Published: September 2022

Abstract
Background
Intervertebral disc degeneration (IDD) has become a serious public health problem, the mechanism of which is complex and still unclear. We aimed to construct a ceRNA network related to IDD to explore its pathogenesis.

Methods
We downloaded the GSE67566, GSE63492, GSE116726 and GSE124272 datasets from GEO database, and obtained the differentially expressed RNAs. Then, we constructed a ceRNA network and the KEGG and GO enrichment analysis were performed. Finally, we performed immune cell infiltration analysis on the GSE124272 dataset and analysed the correlation between immune cell abundance and hub genes expression levels.

Results
The ceRNA network included three down-regulated circRNAs: hsa_circ_0074817, hsa_circ_0002702, hsa_circ_0003600, three up-regulated miRNAs: hsa-miR-4741, hsa-miR-3158-5p, hsa-miR-508-5p, and 57 down-regulated mRNAs, including six hub genes: IGF1, CHEK1, CCNB1, OIP5, BIRC5, AR. GO and KEGG analysis revealed that the network is involved in various biological functions. Immune infiltration analysis showed that IDD was closely related to immune cell infiltration, and hub genes could further affect the development of IDD by affecting immune cell infiltration.

Conclusion
This study identified the hsa_circ_0074817-hsa-miR-508-5p-IGF1/CHEK1/CCNB1, the hsa_circ_0003600-hsa-miR-4741-BIRC5/OIP5/AR and the hsa_circ_0002702-hsa-miR-3158-5p-IGF1/AR as important regulatory axis of IDD, which will help us gain further insight into the pathogenesis of IDD and determine potential therapeutic targets.
The prognostic value of early measures of the ventilatory ratio in the ARDS ROSE trial
Authors: Monteiro Ana Carolina Costa , Vangala Sitaram , Wick Katherine D. , Delucchi Kevin L. , Siegel Emily R. , Thompson B. Taylor , Liu Kathleen D. , Sapru Anil , Sinha Pratik , Matthay Michael A. ,   NHLBI PETAL Network
Published: September 2022

Abstract
Background
The ventilatory ratio (VR, [minute ventilation × PaCO2]/[predicted body weight × 100 × 37.5]) is associated with mortality in ARDS. The aims of this study were to test whether baseline disease severity or neuromuscular blockade (NMB) modified the relationship between VR and mortality.

Methods
This was a post hoc analysis of the PETAL-ROSE trial, which randomized moderate-to-severe ARDS patients to NMB or control. Survival among patients with different VR trajectories or VR cutoff above and below the median was assessed by Kaplan–Meier analysis. The relationships between single-day or 48-h VR trajectories with 28- or 90-day mortality were tested by logistic regression. Randomization allocation to NMB and markers of disease severity were tested as confounders by multivariable regression and interaction term analyses.

Results
Patients with worsening VR trajectories had significantly lower survival compared to those with improving VR (n = 602, p < 0.05). Patients with VR > 2 (median) at day 1 had a significantly lower 90-day survival compared to patients with VR ≤ 2 (HR 1.36, 95% CI 1.10–1.69). VR at day 1 was significantly associated with 28-day mortality (OR = 1.40, 95% CI 1.15–1.72). There was no interaction between NMB and VR for 28-day mortality. APACHE-III had a significant interaction with VR at baseline for the outcome of 28-day mortality, such that the relationship between VR and mortality was stronger among patients with lower APACHE-III. There was a significant association between rising VR trajectory and mortality that was independent of NMB, baseline PaO2/FiO2 ratio and generalized markers of disease severity (Adjusted OR 1.81, 95% CI 1.28–2.84 for 28-day and OR 2.07 95% CI 1.41–3.10 for 90-day mortality). APACHE-III and NMB were not effect modifiers in the relationship between VR trajectory and mortality.

Conclusions
Elevated baseline and day 1 VR were associated with higher 28-day mortality. The relationship between baseline VR and mortality was stronger among patients with lower APACHE-III. APACHE-III was not an effect modifier for the relationship between VR trajectory and mortality, so that the VR trajectory may be optimally suited for prognostication and predictive enrichment. VR was not different between patients randomized to NMB or control, indicating that VR can be utilized without correcting for NMB.
Breast cancer risk in papilloma patients: Osteopontin splice variants indicate prognosis
Authors: Ziółkowski Piotr , Woźniak Marta , Mansour Ahmad , An Yu , Weber Georg F. 
Published: September 2022

Abstract
Background
Papillomas of the breast pose challenges for treatment decisions as their risk for transformation to breast cancer is low but not negligible. To spare low-risk patients the burden of substantial treatment side effects, prognostic indicators are needed for cancerous progression. The secreted metastasis mediator Osteopontin (OPN) is a marker for breast cancer aggressiveness, and its variants are prognosticators for transformation in diverse premalignant breast lesions. Here, we test whether the presence of OPN-c or OPN-exon-4 in papillomatous lesions may reflect progression risk.

Methods
By immunohistochemistry, we analyze OPN-c and OPN-exon-4 in papillomas from 114 women as well as correlations between staining and progression. In departure from prior spliced OPN biomarker publications, we utilize novel monoclonal antibodies.

Results
Fewer than 5% of OPN-c pathology score 0–1 (intensity) versus almost 18% of score 2–3 experienced cancer in follow-up. Nine of 12 women, who progressed, had pathology scores of 2–3 for OPN-c intensity at the time of initial diagnosis, and none had a score of 0. When developing a combined risk score from intensity plus percent positivity for OPN-c, the progression risk for patients with low score was 3.2%, for intermediate score was 5.7%, and for high score was 18.8%. Papillomas in patients, who were later diagnosed with cancer in the contralateral breast, displayed stronger staining positivity than non-progressors.

Conclusion
OPN splice variant immunohistochemistry on biopsies of breast papillomas will allow counseling of the patients on their risk to develop breast cancer at a later time.
African-specific alleles modify risk for asthma at the 17q12-q21 locus in African Americans
Authors: Washington Charles , Dapas Matthew , Biddanda Arjun , Magnaye Kevin M. , Aneas Ivy , Helling Britney A. , Szczesny Brooke , Boorgula Meher Preethi , Taub Margaret A. , Kenny Eimear , Mathias Rasika A. , Barnes Kathleen C. ,   CAAPA, Campbell Monica , Figueiredo Camila , Hansel Nadia N. , Ober Carole , Olopade Christopher O. , Rotimi Charles N. , Watson Harold , Khurana Hershey Gurjit K. , Kercsmar Carolyn M. , Gereige Jessica D. , Makhija Melanie , Gruchalla Rebecca S. , Gill Michelle A. , Liu Andrew H. , Rastogi Deepa , Busse William , Gergen Peter J. , Visness Cynthia M. , Gold Diane R. , Hartert Tina , Johnson Christine C. , Lemanske Robert F. , Martinez Fernando D. , Miller Rachel L. , Ownby Dennis , Seroogy Christine M. , Wright Anne L. , Zoratti Edward M. , Bacharier Leonard B. , Kattan Meyer , O’Connor George T. , Wood Robert A. , Nobrega Marcelo A. , Altman Matthew C. , Jackson Daniel J. , Gern James E. , McKennan Christopher G. , Ober Carole 
Published: September 2022

Abstract
Background
Asthma is the most common chronic disease in children, occurring at higher frequencies and with more severe disease in children with African ancestry.

Methods
We tested for association with haplotypes at the most replicated and significant childhood-onset asthma locus at 17q12-q21 and asthma in European American and African American children. Following this, we used whole-genome sequencing data from 1060 African American and 100 European American individuals to identify novel variants on a high-risk African American–specific haplotype. We characterized these variants in silico using gene expression and ATAC-seq data from airway epithelial cells, functional annotations from ENCODE, and promoter capture (pc)Hi-C maps in airway epithelial cells. Candidate causal variants were then assessed for correlation with asthma-associated phenotypes in African American children and adults.

Results
Our studies revealed nine novel African-specific common variants, enriched on a high-risk asthma haplotype, which regulated the expression of GSDMA in airway epithelial cells and were associated with features of severe asthma. Using ENCODE annotations, ATAC-seq, and pcHi-C, we narrowed the associations to two candidate causal variants that are associated with features of T2 low severe asthma.

Conclusions
Previously unknown genetic variation at the 17q12-21 childhood-onset asthma locus contributes to asthma severity in individuals with African ancestries. We suggest that many other population-specific variants that have not been discovered in GWAS contribute to the genetic risk for asthma and other common diseases.
Effects of porcine reproductive and respiratory syndrome virus (PRRSV) on thyroid hormone metabolism in the late gestation fetus
Authors: Ison Erin K. , Hopf-Jannasch Amber S. , Harding John C. S. , Alex Pasternak J. 
Published: September 2022

AbstractPorcine reproductive and respiratory syndrome virus (PRRSV) in late gestation causes a profound suppression of circulating maternal and fetal thyroid hormone during a critical window of development. To understand this relationship, we evaluated thyroid hormone metabolism at the maternal–fetal interface and within fetal tissues, along with hormone metabolite levels in serum. Fetuses were classified using an established model based on viral load in serum and thymus, and preservation status, including uninfected (UNIF), high-viral load viable (HV-VIA), and high-viral load meconium-stained (HV-MEC), with additional controls from sham-inoculated gilts (CON). Expression of three iodothyronine deiodinases, five sulfotransferases, sulfatase, and two solute carriers known to transport thyroid hormone were evaluated in maternal endometrium and fetal placenta, liver, and kidney. Serum thyroxin (T4), reverse triiodothyronine (rT3), and diiodothyronine (T2) were evaluated via liquid chromatography tandem mass spectrometry. Significant changes in gene expression were observed in all four tissues, with the liver being the most severely impacted. We observed local and fetal specific regulation of maternal tissues through significant upregulation of DIO2 and DIO3 expression in the endometrium corresponding to infected but viable fetuses relative to uninfected and control fetuses. Expression levels of DIO2 and DIO3 were significantly higher in the resilient (HV-VIA) fetuses relative to the susceptible (HV-MEC) fetuses. A substantial decrease in serum T4 was confirmed, with no corresponding increase in rT3 or T2. Collectively, these results show that thyroid hormone metabolism is altered at the maternal–fetal interface and within the PRRSV infected fetus and is associated with fetal viability.
Pharmacokinetics, efficacy and tolerance of cefoxitin in the treatment of cefoxitin-susceptible extended-spectrum beta-lactamase producing Enterobacterales infections in critically ill patients: a retrospective single-center study
Authors: Chabert Paul , Provoost Judith , Cohen Sabine , Dupieux-Chabert Céline , Bitker Laurent , Ferry Tristan , Goutelle Sylvain , Richard Jean-Christophe 
Published: September 2022

Abstract
Background
Cefoxitin is active against some extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-PE), but has not been evaluated so far in the intensive care unit (ICU) settings. Data upon its pharmacokinetics (PK), tolerance and efficacy in critical conditions are scanty. We performed a retrospective single-center study in a university hospital medical ICU, in subjects presenting with cefoxitin-susceptible ESBL-PE infection and treated with cefoxitin. The primary aim was to determine cefoxitin PK. Secondary endpoints were efficacy, tolerance, and emergence of cephamycin-resistance.

Results
Forty-one patients were included in this study, mainly with ESBL-PE pneumonia (35 patients, 85%). Cefoxitin was administered during a median [interquartile range (IQR)] duration of 5 [4–7] days. Cefoxitin serum concentrations strongly depended on renal function. Target serum concentration (> 5 × minimum inhibitory concentration (MIC) 24 h after cefoxitin onset was obtained in 34 patients (83%), using a median [IQR] daily dose of 6 [6–6] g with continuous administration. The standard dosage of 6 g/24 h was not sufficient to achieve the PK/PD target serum concentration for MIC up to 4–8 mg/L, except in patients with severe renal impairment and those treated with renal replacement therapy. Treatment failure occurred in 26 cases (63%), among whom 12 patients (29%) died, 13 patients (32%) were switched to alternative antibiotic therapy and 11 patients (27%) presented with relapse of infection with the same ESBL-PE. Serious adverse events attributed to cefoxitin occurred in 7 patients (17%). Acquisition of cephamycin-resistance with the same Enterobacterales was identified in 13 patients (32%), and was associated with underdosage.

Conclusion
Continuous administration of large doses of cefoxitin appears necessary to achieve the PK/PD target in patients with normal renal function. Renal status, MIC determination and therapeutic drug monitoring may be useful for treatment individualization in this setting. The treatment failure rate was 63%. The cefoxitin safety profile was favorable, but we observed a high rate of cephamycin-resistance emergence.