bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of learning objectives for a medical assistance in dying curriculum for Family Medicine Residency
Authors: LeBlanc Sarah , MacDonald Susan , Martin Mary , Dalgarno Nancy , Schultz Karen 
Published: March 2022

Abstract
Background
Medical assistance in dying (MAID) became legal across Canada when Bill C-14 was passed in 2016. Currently, little is known about the most effective strategies for providing MAID education, and the importance of integrating MAID into existing curricula. In this study, a set of learning objectives (LOs) was developed to inform a foundational MAID curriculum in Canadian Family Medicine (FM) residency training programs.

Methods
Mixed methods were used to develop LOs based on a published needs assessment from a large, four-site family medicine residency program in southeastern Ontario. Draft LOs were evaluated and revised by faculty and resident leaders using a modified Delphi process and a focus group. LOs were mapped to the existing family medicine residency curriculum, as well as the College of Family Physicians of Canada’s Priority Topics.

Results
Nine LOs were developed to provide a foundational education regarding MAID. While all LOs could be mapped to the Domains of Clinical Care within the departmental curriculum, they mapped inconsistently to departmental Entrustable Professional Activities and the Priority Topics. LOs focused on patient education and identification of patient goals were most readily mapped to existing curricular framework, while LOs with MAID-exclusive content revealed gaps in the current curriculum.

Conclusions
The developed LOs provide a guide to ensure family medicine residents obtain generalist-level knowledge to counsel their patients about MAID. These LOs can serve as a model for developing LOs for both family medicine and specialist residency programs in Canada and in countries where MAID is legal.
The impact of introducing multidisciplinary care assessments on access to rheumatology care in British Columbia: an interrupted time series analysis
Authors: Duncan Ross , Cheng Lucy , Law Michael R. , Shojania Kam , De Vera Mary A. , Harrison Mark 
Published: March 2022

Abstract
Background
In 2011 the British Columbia (BC) Ministry of Health introduced a new fee-for-service billing code that allowed “Multidisciplinary Care Assessment” (MCA). This change has the potential to change access to and quality of care for patients. This study aimed to explore the impact on access to rheumatology services in the province.

Methods
Fee-for-service rheumatology billings were evaluated for each rheumatologist 2 years before and after use of the MCA code. Numbers of 1) unique patients and 2) services provided per month were used as proxy measures of access to care. A multiple-baseline interrupted time series model assessed the impact of the MCA on levels and trends of the access outcomes.

Results
Our analysis consisted of 82,360 patients cared for by 26 rheumatologists who billed for an MCA. In our primary analysis we observed a sustained increase in the mean number of unique patients of 4.9% (95% CI: 0.0% to 9.9%, p = 0.049) and the mean number of services of 7.1% (95% CI: 1.0% to 13.6%, (p = 0.021), per month provided by a rheumatologist, corresponding to the initial use of MCA.

Conclusion
The introduction of the MCA code was associated with an initial increase in the measures of access, which was maintained but did not increase over time. Our study suggests that the use of Multidisciplinary Care Assessment can contribute to expanding and/or sustaining access to care for people with complex chronic conditions, like rheumatic diseases.
Infant, pediatric and adult well visit trends before and during the COVID-19 pandemic: a retrospective cohort study
Authors: Salas Joanne , Hinyard Leslie , Cappellari Ann , Sniffen Katie , Jacobs Christine , Karius Natalie , Grucza Richard A. , Scherrer Jeffrey F. 
Published: March 2022

AbstractBackgroundAdult well visits declined during COVID-19, but literature is inconsistent in regard to whether childhood well visits declined. We determined if the COVID-19 pandemic was associated with a change in well visits among infants, children, adolescents and adults before, compared to during the COVID-19 pandemic, including through the emergence of the Delta variant.MethodsDe-identified electronic health care data came from a multi-state Midwest health care system. Eligible patients (n = 798,571) had ≥ 1 well visit between 7/1/2018 and 6/30/2021. Trends in well visits per month for children (< 1, 1–4, 5–11, 12–17 years) and adults (18–39, 40–64, ≥ 65 years) over 3-years were assessed using Joinpoint regression models and monthly percent change (MPC).ResultsWell visits remained stable for infants (< 1 year of age) (MPC = -0.1; 95% CI = -0.3, 0.1). For children 1–4 years and all adults, visits were stable prior to 2020, decreased from 1/2020 to 4/2020 (MPC range -20 to -40), increased from 4/2020–7/2020 (MPC range 30 to 72), and remained stable after 7/2020. Children 5–17 had seasonal variation in visits where low points occurred in Jan/Feb 2019 and high points in Aug 2019 (start of school year); however, the low point in 2020 occurred in April 2020 and the seasonal variation normalized after this.ConclusionsIn a large Mid-western health care system, infant well visits did not decline at the onset (3/1/2020) of the COVID-19 pandemic. Although well visits for all other ages decreased to a low point in 4/2020, a rapid return to pre-pandemic utilization rates occurred by 7/2020. The brief decrease in preventive care may have had little impact on health.
Targeted therapies for cancer
Authors: Zhou Zhijun , Li Min 
Published: March 2022

AbstractTargeted therapy is the key for improving overall survival while decreasing the undesirable adverse effects of cancer treatment. Patients who received matched targeted therapies showed dramatically improved overall survival (OS) and progression-free survival (PFS) compared to those without matched therapies. However, each patient responds to targeted therapy differently due to their unique genomic profile. The discrepancy of treatment response between clinical trials and real-world clinical practice highlights an unmet need to develop tailored therapies for individual patients. The development of cutting-edge technologies, such as next-generation sequencing, has enabled us to identify more actionable targets. In this special issue of BMC Medicine, a collection of highly translational and clinical oncology papers presented a series of studies on targeted therapies for a variety of cancer types, aiming to bridge the gap between genomic testing and precision medicine and spark innovations on improving the efficacy of targeted therapies.
Association between triglyceride glucose index and carotid artery plaque in different glucose metabolic states in patients with coronary heart disease: a RCSCD-TCM study in China
Authors: Li Zhu , He Yuanyuan , Wang Shuo , Li Lin , Yang Rongrong , Liu Yijia , Cheng Qi , Yu Lu , Zheng Yanchao , Zheng Hongmei , Gao Shan , Yu Chunquan 
Published: March 2022

Abstract
Background
The triglyceride glucose (TyG) index serves as a surrogate indicator of insulin resistance. However, there is limited evidence on the association between the TyG index and carotid artery plaque (CAP) in patients with coronary heart disease (CHD).

Methods
The 10,535 CHD patients were divided according to TyG index quartiles (Q1: TyG index < 8.52; Q2: 8.52 ≤ TyG index < 8.93; Q3: 8.93 ≤ TyG index ≤ 9.40; Q4: TyG index > 9.40). The presence or absence of CAP was determined by carotid ultrasonography. Logistic regression was used to analyze the relationship between the TyG index and CAP in CHD patients. The relationship between the TyG index and CAP in according to sex, age groups, and glucose metabolism states were also assessed.

Results
The baseline analysis showed that there were significant differences in related parameters among CHD patients divided into four groups according to the quartile of the TyG index. In the multi-adjusted modles, compared to Q1 of the TyG index, the odds ratios (OR) for Q4 of the TyG index for CAP were 1.37 (95% confidence interval [CI] 1.28–1.47) in CHD patients. The association between the TyG index and CAP in female (OR: 1.35; 95% CI 1.29–1.43) was higher than that in male (OR: 1.20; 95% CI 1.13–1.27). The OR value of middle-aged (≤ 60 years old) patients (OR: 1.34; 95% CI 1.26–1.42) was higher than that in elderly (> 60 years old) patients (OR: 1.16; 95% CI 1.11–1.22). In different glucose metabolism states, the TyG index of CHD patients was significantly related to the risk of CAP, with the highest OR value observed for diabetes (OR: 1.36; 95% CI 1.26–1.46).

Conclusions
The TyG index and CAP showed a significant association in CHD patients. This association between TyG index and CAP in CHD patients is higher in female than in male, and the association in middle-aged and elderly patients is higher than that in elderly patients. In the condition of DM, the association between TyG index and carotid artery plaque in CHD patients is higher.

Graphical abstract
High PPT1 expression predicts poor clinical outcome and PPT1 inhibitor DC661 enhances sorafenib sensitivity in hepatocellular carcinoma
Authors: Xu Jianjun , Su Zhe , Cheng Xiang , Hu Shaobo , Wang Wenjie , Zou Tianhao , Zhou Xing , Song Zifang , Xia Yun , Gao Yang , Zheng Qichang 
Published: March 2022

Abstract
Background
Adaptive resistance and side effects of sorafenib treatment result in unsatisfied survival of patients with hepatocellular carcinoma (HCC). Palmitoyl-protein thioesterase 1 (PPT1) plays a critical role in progression of various cancers. However, its role on prognosis and immune infiltrates in HCC remains unclarified.

Methods
By data mining in the Cancer Genome Atlas databases, the role of PPT1 in HCC were initially investigated. Furthermore, HCC cell lines Hep 3B and Hep 1-6 were treated with DC661 or siRNA against PPT1. The biological function of PPT1 was determined by CCK-8 test, colony formation assay, TUNEL staining, immunofluorescence staining, Western blot test, and PI-Annexin V apoptosis assays in vitro. Animal models of subcutaneous injection were applied to investigate the therapeutic role of targeting PPT1.

Results
We found that PPT1 levels were significantly upregulated in HCC tissues compared with normal tissues and were significantly associated with a poor prognosis. Multivariate analysis further confirmed that high expression of PPT1 was an independent risk factor for poor overall survival of HCC patients. We initially found that PPT1 was significantly upregulated in sorafenib-resistant cell lines established in this study. Upon sorafenib treatment, HCC cells acquired adaptive resistance by inducing autophagy. We found that DC661, a selective and potent small-molecule PPT1-inhibitor, induced lysosomal membrane permeability, caused lysosomal deacidification, inhibited autophagy and enhanced sorafenib sensitivity in HCC cells. Interestingly, this sensitization effect was also mediated by the induction mitochondrial pathway apoptosis. In addition, the expression level of PPT1 was associated with the immune infiltration in the HCC tumor microenvironment, and PPT1 inhibitor DC661 significantly enhanced the anti-tumor immune response by promoting dendritic cell maturation and further promoting CD8+ T cell activation. Moreover, DC661 combined with sorafenib was also very effective at treating tumor models in immunized mice.

Conclusions
Our findings suggest that targeting PPT1 with DC661 in combination with sorafenib might be a novel and effective alternative therapeutic strategy for HCC.
MT5-MMP promotes neuroinflammation, neuronal excitability and Aβ production in primary neuron/astrocyte cultures from the 5xFAD mouse model of Alzheimer’s disease
Authors: Pilat Dominika , Paumier Jean-Michel , García-González Laura , Louis Laurence , Stephan Delphine , Manrique Christine , Khrestchatisky Michel , Di Pasquale Eric , Baranger Kévin , Rivera Santiago 
Published: March 2022

AbstractBackgroundMembrane-type matrix metalloproteinase 5 (MT5-MMP) deficiency in the 5xFAD mouse model of Alzheimer's disease (AD) reduces brain neuroinflammation and amyloidosis, and prevents deficits in synaptic activity and cognition in prodromal stages of the disease. In addition, MT5-MMP deficiency prevents interleukin-1 beta (IL-1β)-mediated inflammation in the peripheral nervous system. In this context, we hypothesized that the MT5-MMP/IL-1β tandem could regulate nascent AD pathogenic events in developing neural cells shortly after the onset of transgene activation.MethodsTo test this hypothesis, we used 11–14 day in vitro primary cortical cultures from wild type, MT5-MMP−/−, 5xFAD and 5xFAD/MT5-MMP−/−mice, and evaluated the impact of MT5-MMP deficiency and IL-1β treatment for 24 h, by performing whole cell patch-clamp recordings, RT-qPCR, western blot, gel zymography, ELISA, immunocytochemistry and adeno-associated virus (AAV)-mediated transduction.Results5xFAD cells showed higher levels of MT5-MMP than wild type, concomitant with higher basal levels of inflammatory mediators. Moreover, MT5-MMP-deficient cultures had strong decrease of the inflammatory response to IL-1β, as well as decreased stability of recombinant IL-1β. The levels of amyloid beta peptide (Aβ) were similar in 5xFAD and wild-type cultures, and IL-1β treatment did not affect Aβ levels. Instead, the absence of MT5-MMP significantly reduced Aβ by more than 40% while sparing APP metabolism, suggesting altogether no functional crosstalk between IL-1β and APP/Aβ, as well as independent control of their levels by MT5-MMP. The lack of MT5-MMP strongly downregulated the AAV-induced neuronal accumulation of the C-terminal APP fragment, C99, and subsequently that of Aβ. Finally, MT5-MMP deficiency prevented basal hyperexcitability observed in 5xFAD neurons, but not hyperexcitability induced by IL-1β treatment.ConclusionsNeuroinflammation and hyperexcitability precede Aβ accumulation in developing neural cells with nascent expression of AD transgenes. MT5-MMP deletion is able to tune down basal neuronal inflammation and hyperexcitability, as well as APP/Aβ metabolism. In addition, MT5-MMP deficiency prevents IL-1β-mediated effects in brain cells, except hyperexcitability. Overall, this work reinforces the idea that MT5-MMP is at the crossroads of pathogenic AD pathways that are already incipiently activated in developing neural cells, and that targeting MT5-MMP opens interesting therapeutic prospects.
Esophageal cancer with a double aortic arch: a case report and literature review
Authors: Kang Kai , Wang Sheng , Xiong Fei , Kai Jindan , Wang Jianjian , Li Binfeng 
Published: March 2022

Abstract
Background
Double aortic arch (DAA) is an extremely rare vascular malformation, even more so when coexisting with esophageal cancer.

Methods
We report a new case of DAA with esophageal cancer recently seen at our Thoracic Tumor Clinic and review cases of DAA coexisting with esophageal cancer reported in the literature of English language from 2010 to 2020. The purposes of our literature review were to explore how to best achieve radical esophagectomy while reducing postoperative complications. The clinical manifestations, diagnostic method, surgical approach, reconstruction route, and the extent of lymphadenectomy of esophageal cancer with DAA were analyzed in detail.

Results and conclusion
For such patients, 3D computed tomography is necessary for preoperative diagnosis. The surgical approach should consider factors such as the location of the tumor in the esophagus and whether the tumor is surrounded by DAA, as well as the position of the descending aorta and the requirements for the surgical field for lymphadenectomy. If esophageal reconstruction is required, the retrosternal route is preferred. We recommend that only patients with positive results of intraoperative frozen biopsy of recurrent laryngeal nerve lymph nodes should undergo three-field lymphadenectomy, which may be the best method to achieve radical esophagectomy for middle and lower esophageal cancers with DAA while minimizing postoperative complications.
Recent advances in the developmental origin of neuroblastoma: an overview
Authors: Ponzoni Mirco , Bachetti Tiziana , Corrias Maria Valeria , Brignole Chiara , Pastorino Fabio , Calarco Enzo , Bensa Veronica , Giusto Elena , Ceccherini Isabella , Perri Patrizia 
Published: March 2022

AbstractNeuroblastoma (NB) is a pediatric tumor that originates from neural crest-derived cells undergoing a defective differentiation due to genomic and epigenetic impairments. Therefore, NB may arise at any final site reached by migrating neural crest cells (NCCs) and their progeny, preferentially in the adrenal medulla or in the para-spinal ganglia.NB shows a remarkable genetic heterogeneity including several chromosome/gene alterations and deregulated expression of key oncogenes that drive tumor initiation and promote disease progression.NB substantially contributes to childhood cancer mortality, with a survival rate of only 40% for high-risk patients suffering chemo-resistant relapse. Hence, NB remains a challenge in pediatric oncology and the need of designing new therapies targeted to specific genetic/epigenetic alterations become imperative to improve the outcome of high-risk NB patients with refractory disease or chemo-resistant relapse.In this review, we give a broad overview of the latest advances that have unraveled the developmental origin of NB and its complex epigenetic landscape.Single-cell RNA sequencing with spatial transcriptomics and lineage tracing have identified the NCC progeny involved in normal development and in NB oncogenesis, revealing that adrenal NB cells transcriptionally resemble immature neuroblasts or their closest progenitors. The comparison of adrenal NB cells from patients classified into risk subgroups with normal sympatho-adrenal cells has highlighted that tumor phenotype severity correlates with neuroblast differentiation grade.Transcriptional profiling of NB tumors has identified two cell identities that represent divergent differentiation states, i.e. undifferentiated mesenchymal (MES) and committed adrenergic (ADRN), able to interconvert by epigenetic reprogramming and to confer intra-tumoral heterogeneity and high plasticity to NB.Chromatin immunoprecipitation sequencing has disclosed the existence of two super-enhancers and their associated transcription factor networks underlying MES and ADRN identities and controlling NB gene expression programs.The discovery of NB-specific regulatory circuitries driving oncogenic transformation and maintaining the malignant state opens new perspectives on the design of innovative therapies targeted to the genetic and epigenetic determinants of NB. Remodeling the disrupted regulatory networks from a dysregulated expression, which blocks differentiation and enhances proliferation, toward a controlled expression that prompts the most differentiated state may represent a promising therapeutic strategy for NB.
Preventive efficacy of six monthly oral doses of Simparica Trio®, Heartgard® Plus, and Interceptor® Plus against a macrocyclic lactone-resistant strain (ZoeLA) of heartworm (Dirofilaria immitis) in dogs
Authors: Myers Jamie A. E. , Holzmer Susan , McCall John W. , Mahabir Sean P. , McTier Tom L. , Maeder Steven J. , Kryda Kristina 
Published: March 2022

Abstract
Background
Administration of four to six consecutive monthly doses of 24 µg/kg moxidectin alone shows high effectiveness in preventing the maturation of macrocyclic lactone (ML)-resistant heartworm strains, Dirofilaria immitis JYD-34 and ZoeLA. This laboratory study evaluated the efficacy of six consecutive monthly oral doses of Simparica Trio® (moxidectin/sarolaner/pyrantel) compared to six monthly doses of either Heartgard® Plus (ivermectin/pyrantel) or Interceptor® Plus (milbemycin oxime/praziquantel) against ML-resistant D. immitis ZoeLA strain.

Methods
Beagle dogs were inoculated with 50 third-stage (L3) D. immitis larvae (ZoeLA) 30 days prior to the first treatment. Dogs were randomized to treatment (six animals in each group) with six monthly oral doses of placebo, Simparica Trio, Heartgard Plus, or Interceptor Plus at their respective label doses. Microfilaria (MF) and antigen tests were conducted periodically, and efficacy was evaluated by necropsy for adult heartworms approximately 9 months after L3 inoculation.

Results
Adult heartworms were recovered from all six placebo dogs, with a geometric mean of 35.5 worms (range, 23–48). Five of the six dogs treated with Simparica Trio were infected with a geometric mean of 1.0 worms (range, 0–3), and all remained MF-negative. All Heartgard Plus-treated dogs (six) were infected with a geometric mean of 32.5 worms (range, 22–38); five of these dogs were MF-positive at day 236. All Interceptor Plus-treated dogs (six) were infected with a geometric mean of 22.8 worms (range, 10–34); five of these dogs were MF-positive at day 236. The efficacy of six consecutive doses with Simparica Trio, Heartgard Plus, and Interceptor Plus against ZoeLA was 97.2, 8.5, and 35.9%, respectively. Adult worm counts for the Simparica Trio-treated group were significantly lower (P < 0.0001) than placebo control, Heartgard Plus, and Interceptor Plus-treated groups. Adult worm counts for Heartgard Plus and Interceptor Plus were not significantly different from placebo (P > 0.05).

Conclusions
Simparica Trio prevented microfilaremia in all dogs and was highly effective (97.2%) and significantly better than either Heartgard Plus (8.5%) or Interceptor Plus (35.9%) in preventing the development of the ZoeLA ML-resistant heartworm strain when administered for six consecutive months in this comparative laboratory efficacy study.

Graphical Abstract
Computational pathology for musculoskeletal conditions using machine learning: advances, trends, and challenges
Authors: Konnaris Maxwell A. , Brendel Matthew , Fontana Mark Alan , Otero Miguel , Ivashkiv Lionel B. , Wang Fei , Bell Richard D. 
Published: March 2022

AbstractHistopathology is widely used to analyze clinical biopsy specimens and tissues from pre-clinical models of a variety of musculoskeletal conditions. Histological assessment relies on scoring systems that require expertise, time, and resources, which can lead to an analysis bottleneck. Recent advancements in digital imaging and image processing provide an opportunity to automate histological analyses by implementing advanced statistical models such as machine learning and deep learning, which would greatly benefit the musculoskeletal field. This review provides a high-level overview of machine learning applications, a general pipeline of tissue collection to model selection, and highlights the development of image analysis methods, including some machine learning applications, to solve musculoskeletal problems. We discuss the optimization steps for tissue processing, sectioning, staining, and imaging that are critical for the successful generalizability of an automated image analysis model. We also commenting on the considerations that should be taken into account during model selection and the considerable advances in the field of computer vision outside of histopathology, which can be leveraged for image analysis. Finally, we provide a historic perspective of the previously used histopathological image analysis applications for musculoskeletal diseases, and we contrast it with the advantages of implementing state-of-the-art computational pathology approaches. While some deep learning approaches have been used, there is a significant opportunity to expand the use of such approaches to solve musculoskeletal problems.