bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating the coding accuracy of type 2 diabetes mellitus among patients with non-alcoholic fatty liver disease
Authors: Lee Seungwon , Shaheen Abdel Aziz , Campbell David J. T. , Naugler Christopher , Jiang Jason , Walker Robin L. , Quan Hude , Lee Joon
Published: February 2024

Background

Non-alcoholic fatty liver disease (NAFLD) describes a spectrum of chronic fattening of liver that can lead to fibrosis and cirrhosis. Diabetes has been identified as a major comorbidity that contributes to NAFLD progression. Health systems around the world make use of administrative data to conduct population-based prevalence studies. To that end, we sought to assess the accuracy of diabetes International Classification of Diseases (ICD) coding in administrative databases among a cohort of confirmed NAFLD patients in Calgary, Alberta, Canada.

Methods

The Calgary NAFLD Pathway Database was linked to the following databases: Physician Claims, Discharge Abstract Database, National Ambulatory Care Reporting System, Pharmaceutical Information Network database, Laboratory, and Electronic Medical Records. Hemoglobin A1c and diabetes medication details were used to classify diabetes groups into absent, prediabetes, meeting glycemic targets, and not meeting glycemic targets. The performance of ICD codes among these groups was compared to this standard. Within each group, the total numbers of true positives, false positives, false negatives, and true negatives were calculated. Descriptive statistics and bivariate analysis were conducted on identified covariates, including demographics and types of interacted physicians.

Results

A total of 12,012 NAFLD patients were registered through the Calgary NAFLD Pathway Database and 100% were successfully linked to the administrative databases. Overall, diabetes coding showed a sensitivity of 0.81 and a positive predictive value of 0.87. False negative rates in the absent and not meeting glycemic control groups were 4.5% and 6.4%, respectively, whereas the meeting glycemic control group had a 42.2% coding error. Visits to primary and outpatient services were associated with most encounters.

Conclusion

Diabetes ICD coding in administrative databases can accurately detect true diabetic cases. However, patients with diabetes who meets glycemic control targets are less likely to be coded in administrative databases. A detailed understanding of the clinical context will require additional data linkage from primary care settings.
Genome-wide comparative methylation analysis reveals the fate of germ stem cells after surrogate production in teleost
Authors: Nayak Rigolin , Franěk Roman , Laurent Audrey , Pšenička Martin
Published: February 2024

Background

Surrogate production by germline stem cell transplantation is a powerful method to produce donor-derived gametes via a host, a practice known as surrogacy. The gametes produced by surrogates are often analysed on the basis of their morphology and species-specific genotyping, which enables conclusion to be drawn about the donor’s characteristics. However, in-depth information, such as data on epigenetic changes, is rarely acquired. Germ cells develop in close contact with supporting somatic cells during gametogenesis in vertebrates, and we hypothesize that the recipient’s gonadal environment may cause epigenetic changes in produced gametes and progeny. Here, we extensively characterize the DNA methylome of donor-derived sperm and their intergenerational effects in both inter- and intraspecific surrogates.

Results

We found more than 3000 differentially methylated regions in both the sperm and progeny derived from inter- and intraspecific surrogates. Hypermethylation in the promoter regions of the protocadherin gamma gene in the intraspecific surrogates was found to be associated with germline transmission. On the contrary, gene expression level and the embryonic development of the offspring remained unaffected. We also discovered MAPK/p53 pathway disruption in interspecific surrogates due to promoter hypermethylation and identified that the inefficient removal of meiotic-arrested endogenous germ cells in hybrid gonads led to the production of infertile spermatozoa.

Conclusions

Donor-derived sperm and progeny from inter- and intraspecific surrogates were more globally hypermethylated than those of the donors. The observed changes in DNA methylation marks in the surrogates had no significant phenotypic effects in the offspring.
Higher-valency pneumococcal conjugate vaccines in older adults, taking into account indirect effects from childhood vaccination: a cost-effectiveness study for the Netherlands
Authors: de Boer Pieter T. , van Werkhoven Cornelis H. , van Hoek Albert Jan , Knol Mirjam J. , Sanders Elisabeth A. M. , Wallinga Jacco , de Melker Hester E. , Steens Anneke
Published: February 2024

Background

New 15- and 20-valent pneumococcal vaccines (PCV15, PCV20) are available for both children and adults, while PCV21 for adults is in development. However, their cost-effectiveness for older adults, taking into account indirect protection and serotype replacement from a switch to PCV15 and PCV20 in childhood vaccination, remains unexamined.

Methods

We used a static model for the Netherlands to assess the cost-effectiveness of different strategies with 23-valent pneumococcal polysaccharide vaccine (PPV23), PCV15, PCV20, and PCV21 for a 65-year-old cohort from a societal perspective, over a 15-year time horizon. Childhood vaccination was varied from PCV10 to PCV13, PCV15, and PCV20. Indirect protection was assumed to reduce the incidence of vaccine serotypes in older adults by 80% (except for serotype 3, no effect), completely offset by an increase in non-vaccine serotype incidence due to serotype replacement.

Results

Indirect effects from childhood vaccination reduced the cost-effectiveness of vaccination of older adults, depending on the serotype overlap between the vaccines. With PCV10, PCV13, or PCV15 in children, PCV20 was more effective and less costly for older adults than PPV23 and PCV15. PCV20 costs approximately €10,000 per quality-adjusted life year (QALY) gained compared to no pneumococcal vaccination, which falls below the conventional Dutch €20,000/QALY gained threshold. However, with PCV20 in children, PCV20 was no longer considered cost-effective for older adults, costing €22,550/QALY gained. As indirect effects progressed over time, the cost-effectiveness of PCV20 for older adults further diminished for newly vaccinated cohorts. PPV23 was more cost-effective than PCV20 for cohorts vaccinated 3 years after the switch to PCV20 in children. PCV21 offered the most QALY gains, and its cost-effectiveness was minimally affected by indirect effects due to its coverage of 11 different serotypes compared to PCV20.

Conclusions

For long-term cost-effectiveness in the Netherlands, the pneumococcal vaccine for older adults should either include invasive serotypes not covered by childhood vaccination or become more affordable than its current pricing for individual use.
COVID-19 induced shocks and its implications for human capital development
Authors: Omotayo Abiodun Olusola , Ogunniyi Adebayo Isaiah
Published: February 2024

Background

COVID-19 has delivered an enormous shock to the global economy, triggering the deepest recession in eight decades, almost three times as deep as the 2009 global recession. Of all the nations in Africa, Nigeria remains one of the nations with a huge and significant impact on the human capital.

Methods

Hence, here we employed the recent nationally representative data from Nigeria - the COVID-19 National Longitudinal Phone Survey 2020-World Bank Living Standards Measurement Study Integrated Agriculture Survey (LSMS-ISA), a harmonized dataset to explore how the COVID-19 induced shocks affected households’ human capital development (using health and education outcomes).

Results

The results indicate that the COVID-19 induced shocks impact on both health and education in Nigeria. Interestingly, access to social safety nets had a positive association with the health and education outcomes. The study concludes that households’ access to social safety nets, particularly during the COVID-19 pandemic aids in the development of the nation’s human capital. Therefore, effectively enhancing household’s resilience and strengthening human capital development require positive and considerable innovation, maybe over a period of years. Hence, just an access to the national social safety nets programs or social programs may not be as effective as expected. Therefore, it may not be as successful as intended to just have access to national social safety net programs or social programs that contribute or transfer negligible amounts to the vulnerable recipients over short time frames.
Association between prenatal exposure to alkylphenols and intelligence quotient among preschool children: sex-specific effects
Authors: Long Jinghua , Liang Jun , Liu Tao , Huang Huishen , Chen Jiehua , Liao Qian , Pang Lixiang , Yang Kaiqi , Chen Manlin , Chen Qian , Huang Xiaorong , Zhu Qihua , Zeng Xiaoyun , Huang Dongping , Qiu Xiaoqiang
Published: February 2024

Background

While prenatal exposure to alkylphenols (APs) has been demonstrated to be associated with neurodevelopmental impairments in animals, the evidence from epidemiological studies remains limited and inconclusive. This study aimed to explore the link between AP exposure during pregnancy and the intelligence quotient (IQ) of preschool children.

Methods

A total of 221 mother-child pairs from the Guangxi Zhuang Birth Cohort were recruited. Nonylphenol (NP), 4-tert-octylphenol (4-T-OP), 4-n-nonylphenol (4-N-NP), and 4-n-octylphenol were measured in maternal serum in early pregnancy. Childhood IQ was evaluated by the Fourth Edition of Wechsler Preschool and Primary Scale of the Intelligence at 3 to 6 years of age. The impact of APs on childhood IQ were evaluated by generalized linear models (GLMs), restricted cubic spline (RCS), and Bayesian kernel machine regression (BKMR).

Results

In GLMs, prenatal exposure to NP and the second tertile of 4-T-OP exhibited an inverse association with full-scale IQ (FSIQ) (β = -2.38; 95% CI: -4.59, -0.16) and working memory index (WMI) (β = -5.24; 95% CI: -9.58, -0.89), respectively. Prenatal exposure to the third tertile of 4-N-NP showed a positive association with the fluid reasoning index (β = 4.95; 95% CI: 1.14, 8.77) in total children, as well as in girls when stratified by sex. A U-shaped relationship between maternal 4-T-OP and WMI was noted in total children and girls by RCS (all P nonlinear < 0.05). The combined effect primarily driven by NP, of maternal AP mixtures at concentrations above the 50th percentile exhibited an inverse trend on FSIQ in total children and girls in BKMR.

Conclusions

Prenatal exposure to various APs affects IQ in preschool children, and there may be nonmonotonic and sex-specific effects. Further investigation across the population is required to elucidate the potential neurotoxic effects of APs.
A regulatory element associated to NAFLD in the promoter of DIO1 controls LDL-C, HDL-C and triglycerides in hepatic cells
Authors: Castillejo-López Casimiro , Bárcenas-Walls José Ramón , Cavalli Marco , Larsson Anders , Wadelius Claes
Published: February 2024

Background

Genome-wide association studies (GWAS) have identified genetic variants linked to fat metabolism and related traits, but rarely pinpoint causative variants. This limitation arises from GWAS not considering functional implications of noncoding variants that can affect transcription factor binding and potentially regulate gene expression. The aim of this study is to investigate a candidate noncoding functional variant within a genetic locus flagged by a GWAS SNP associated with non-alcoholic fatty liver disease (NAFLD), a condition characterized by liver fat accumulation in non-alcohol consumers.

Methods

CRISPR-Cas9 gene editing in HepG2 cells was used to modify the regulatory element containing the candidate functional variant linked to NAFLD. Global gene expression in mutant cells was assessed through RT-qPCR and targeted transcriptomics. A phenotypic assay measured lipid droplet accumulation in the CRISPR-Cas9 mutants.

Results

The candidate functional variant, rs2294510, closely linked to the NAFLD-associated GWAS SNP rs11206226, resided in a regulatory element within the DIO1 gene's promoter region. Altering this element resulted in changes in transcription factor binding sites and differential expression of candidate target genes like DIO1, TMEM59, DHCR24, and LDLRAD1, potentially influencing the NAFLD phenotype. Mutant HepG2 cells exhibited increased lipid accumulation, a hallmark of NAFLD, along with reduced LDL-C, HDL-C and elevated triglycerides.

Conclusions

This comprehensive approach, that combines genome editing, transcriptomics, and phenotypic assays identified the DIO1 promoter region as a potential enhancer. Its activity could regulate multiple genes involved in the NAFLD phenotype or contribute to defining a polygenic risk score for enhanced risk assessment in NAFLD patients.
The dynamic role of nucleoprotein SHCBP1 in the cancer cell cycle and its potential as a synergistic target for DNA-damaging agents in cancer therapy
Authors: Zhou Mei , Duan Limin , Chen Jiangbin , Li Yumei , Yin Zhengrong , Song Siwei , Cao Yaqi , Luo Ping , Hu Fan , Yang Guanghai , Xu Juanjuan , Liao Tingting , Jin Yang
Published: February 2024

Background

Malignant tumours seriously threaten human life and health, and effective treatments for cancer are still being explored. The ability of SHC SH2 domain-binding protein 1 (SHCBP1) to induce cell cycle disturbance and inhibit tumour growth has been increasingly studied, but its dynamic role in the tumour cell cycle and corresponding effects leading to mitotic catastrophe and DNA damage have rarely been studied.

Results

In this paper, we found that the nucleoprotein SHCBP1 exhibits dynamic spatiotemporal expression during the tumour cell cycle, and SHCBP1 knockdown slowed cell cycle progression by inducing spindle disorder, as reflected by premature mitotic entry and multipolar spindle formation. This dysfunction was caused by G2/M checkpoint impairment mediated by downregulated WEE1 kinase and NEK7 (a member of the mammalian NIMA-related kinase family) expression and upregulated centromere/kinetochore protein Zeste White 10 (ZW10) expression. Moreover, both in vivo and in vitro experiments confirmed the significant inhibitory effects of SHCBP1 knockdown on tumour growth. Based on these findings, SHCBP1 knockdown in combination with low-dose DNA-damaging agents had synergistic tumouricidal effects on tumour cells. In response to this treatment, tumour cells were forced into the mitotic phase with considerable unrepaired DNA lesions, inducing mitotic catastrophe. These synergistic effects were attributed not only to the abrogation of the G2/M checkpoint and disrupted spindle function but also to the impairment of the DNA damage repair system, as demonstrated by mass spectrometry-based proteomic and western blotting analyses. Consistently, patients with low SHCBP1 expression in tumour tissue were more sensitive to radiotherapy. However, SHCBP1 knockdown combined with tubulin-toxic drugs weakened the killing effect of the drugs on tumour cells, which may guide the choice of chemotherapeutic agents in clinical practice.

Conclusion

In summary, we elucidated the role of the nucleoprotein SHCBP1 in tumour cell cycle progression and described a novel mechanism by which SHCBP1 regulates tumour progression and through which targeting SHCBP1 increases sensitivity to DNA-damaging agent therapy, indicating its potential as a cancer treatment.

Graphical Abstract
Technological Vanguard: the outstanding performance of the LTY-CNN model for the early prediction of epileptic seizures
Authors: Yang Yang , Luan Tianyun , Yu Zhangjun , Zhang Min , Li Fengtian , Chen Xing , Gao Fei , Zhang Zhijun
Published: February 2024

Background:

Epilepsy is a common neurological disorder that affects approximately 60 million people worldwide. Characterized by unpredictable neural electrical activity abnormalities, it results in seizures with varying intensity levels. Electroencephalography (EEG), as a crucial technology for monitoring and predicting epileptic seizures, plays an essential role in improving the quality of life for people with epilepsy.

Method:

This study introduces an innovative deep learning model, a lightweight triscale yielding convolutional neural network” (LTY-CNN), that is specifically designed for EEG signal analysis. The model integrates a parallel convolutional structure with a multihead attention mechanism to capture complex EEG signal features across multiple scales and enhance the efficiency achieved when processing time series data. The lightweight design of the LTY-CNN enables it to maintain high performance in environments with limited computational resources while preserving the interpretability and maintainability of the model.

Results:

In tests conducted on the SWEC-ETHZ and CHB-MIT datasets, the LTY-CNN demonstrated outstanding performance. On the SWEC-ETHZ dataset, the LTY-CNN achieved an accuracy of 99.9%, an area under the receiver operating characteristic curve (AUROC) of 0.99, a sensitivity of 99.9%, and a specificity of 98.8%. Furthermore, on the CHB-MIT dataset, it recorded an accuracy of 99%, an AUROC of 0.932, a sensitivity of 99.1%, and a specificity of 93.2%. These results signify the remarkable ability of the LTY-CNN to distinguish between epileptic seizures and nonseizure events. Compared to other existing epilepsy detection classifiers, the LTY-CNN attained higher accuracy and sensitivity.

Conclusion:

The high accuracy and sensitivity of the LTY-CNN model demonstrate its significant potential for epilepsy management, particularly in terms of predicting and mitigating epileptic seizures. Its value in personalized treatments and widespread clinical applications reflects the broad prospects of deep learning in the health care sector. This also highlights the crucial role of technological innovation in enhancing the quality of life experienced by patients.
Endothelium-specific deletion of p62 causes organ fibrosis and cardiac dysfunction
Authors: Feng Jing , Li Yan , Zhang Yu , Sun Shengnan , Sun Jian , Xu Quanlin , Ji Xingzhao , Liu Yi , Wan Qiang
Published: February 2024

Background

The autophagy adapter SQSTM1/p62 is crucial for maintaining homeostasis in various organs and cells due to its protein–protein interaction domains and involvement in diverse physiological and pathological processes. Vascular endothelium cells play a unique role in vascular biology and contribute to vascular health.

Methods

Using the Cre-loxP system, we generated mice with endothelium cell-specific knockout of p62 mediated by Tek (Tek receptor tyrosine kinase)-cre to investigate the essential role of p62 in the endothelium. In vitro, we employed protein mass spectrometry and IPA to identify differentially expressed proteins upon knockdown of p62. Immunoprecipitation assays were conducted to demonstrate the interaction between p62 and FN1 or LAMC2 in human umbilical vein endothelium cells (HUVECs). Additionally, we identified the degradation pathway of FN1 and LAMC2 using the autophagy inhibitor 3-methyladenine (3-MA) or proteasome inhibitor MG132. Finally, the results of immunoprecipitation demonstrated that the interaction between p62 and LAMC2 was abolished in the PB1 truncation group of p62, while the interaction between p62 and FN1 was abolished in the UBA truncation group of p62.

Results

Our findings revealed that p62 Endo mice exhibited heart, lung, and kidney fibrosis compared to littermate controls, accompanied by severe cardiac dysfunction. Immunoprecipitation assays provided evidence of p62 acting as an autophagy adapter in the autophagy-lysosome pathway for FN1 and LAMC2 degradation respectively through PB1 and UBA domain with these proteins rather than proteasome system.

Conclusions

Our study demonstrates that defects in p62 within endothelium cells induce multi-organ fibrosis and cardiac dysfunction in mice. Our findings indicate that FN1 and LAMC2, as markers of (EndoMT), have detrimental effects on HUVECs and elucidate the autophagy-lysosome degradation mechanism of FN1 and LAMC2.
High CD133 expression in proximal tubular cells in diabetic kidney disease: good or bad?
Authors: Zhang Yuhan , Xu Lusi , Guo Congcong , Li Xianzhi , Tian Yutian , Liao Lin , Dong Jianjun
Published: February 2024

Background

Proximal tubular cells (PTCs) play a critical role in the progression of diabetic kidney disease (DKD). As one of important progenitor markers, CD133 was reported to indicate the regeneration of dedifferentiated PTCs in acute kidney disease. However, its role in chronic DKD is unclear. Therefore, we aimed to investigate the expression patterns and elucidate its functional significance of CD133 in DKD.

Methods

Data mining was employed to illustrate the expression and molecular function of CD133 in PTCs in human DKD. Subsequently, rat models representing various stages of DKD progression were established. The expression of CD133 was confirmed in DKD rats, as well as in human PTCs (HK-2 cells) and rat PTCs (NRK-52E cells) exposed to high glucose. The immunofluorescence and flow cytometry techniques were utilized to determine the expression patterns of CD133, utilizing proliferative and injury indicators. After overexpression or knockdown of CD133 in HK-2 cells, the cell proliferation and apoptosis were detected by EdU assay, real-time cell analysis and flow analysis. Additionally, the evaluation of epithelial, progenitor cell, and apoptotic indices was performed through western blot and quantitative RT-PCR analyses.

Results

The expression of CD133 was notably elevated in both human and rat PTCs in DKD, and this expression increased as DKD progressed. CD133 was found to be co-expressed with CD24, KIM-1, SOX9, and PCNA, suggesting that CD133+ cells were damaged and associated with proliferation. In terms of functionality, the knockdown of CD133 resulted in a significant reduction in proliferation and an increase in apoptosis in HK-2 cells compared to the high glucose stimulus group. Conversely, the overexpression of CD133 significantly mitigated high glucose-induced cell apoptosis, but had no impact on cellular proliferation. Furthermore, the Nephroseq database provided additional evidence to support the correlation between CD133 expression and the progression of DKD. Analysis of single-cell RNA-sequencing data revealed that CD133+ PTCs potentially play a role in the advancement of DKD through multiple mechanisms, including heat damage, cell microtubule stabilization, cell growth inhibition and tumor necrosis factor-mediated signaling pathway.

Conclusion

Our study demonstrates that the upregulation of CD133 is linked to cellular proliferation and protects PTC from apoptosis in DKD and high glucose induced PTC injury. We propose that heightened CD133 expression may facilitate cellular self-protective responses during the initial stages of high glucose exposure. However, its sustained increase is associated with the pathological progression of DKD. In conclusion, CD133 exhibits dual roles in the advancement of DKD, necessitating further investigation.
Association between modifiable lifestyle factors and telomere length: a univariable and multivariable Mendelian randomization study
Authors: Chen Miao , Wang Zhen , Xu Hongfei , Teng Peng , Li Weidong , Ma Liang
Published: February 2024

Background

Telomere length has long been recognized as a valuable biomarker of aging and is inversely correlated with chronological age. Various lifestyle factors have been implicated in telomere shortening or preservation; however, the association between lifestyle factors and telomere length remains controversial. To address this issue, we conducted a Mendelian randomization (MR) analysis to investigate the potential causal associations between multiple lifestyle factors and telomere length.

Methods

Independent genetic variants strongly associated with lifestyle factors (tobacco smoking, sleep duration, insomnia, and physical activity) were selected as instrumental variables from corresponding genome-wide association studies (GWASs). Summary-level data for telomere length was obtained from a GWAS comprising 472,174 European ancestries. Univariable and multivariable MR analyses were performed to assess the relationships.

Results

The genetic liability to lifetime smoking was robustly associated with shorter telomere length (odd ratio [OR]: 0.882; 95% confidence interval [CI]: 0.847–0.918). Genetically predicted insomnia was also linked to shorter telomere length (OR: 0.972; 95% CI: 0.959–0.985), while no significant association was observed between sleep duration and telomere length. Furthermore, a suggestive association was found between moderate-to-vigorous physical activity and longer telomere length (OR: 1.680; 95% CI: 1.115–2.531). In multivariable MR analyses, adjusting for potential mediators such as body mass index, type 2 diabetes, alcohol consumption, and alcohol use disorder, the associations of lifetime smoking and insomnia with telomere length remained robust.

Conclusion

Our findings suggest that smoking and insomnia may contribute to telomere shortening, while physical activity may play a role in telomere length maintenance. These findings underscore the importance of managing positive risk factors and adopting a healthy lifestyle to promote telomere health.
Epstein-Barr virus-positive inflammatory follicular dendritic cell sarcoma with significant granuloma: case report and literature review
Authors: Nie Chenchen , Xie Xun , Li Hangyan , Li Yangcan , Chen Zhihong , Li Yanchun , Li Zhenfeng
Published: February 2024

Background

Epstein-Barr virus-positive inflammatory follicular dendritic cell sarcoma (EBV+IFDCS) is a rare disease characterized by mild clinical symptoms and non-specific imaging findings. The diagnosis of the disease depends on pathological diagnosis. However, EBV+IFDCS has a very broad spectrum of histological morphology and immune phenotypes, and its histopathological features have not been fully described by pathologists.

Case presentation

A 59-year-old female, with no significant discomfort, was found to have a splenic mass during a routine physical examination. Microscopic examination at low magnification revealed numerous epithelioid granulomas, amidst which a substantial inflammatory response was observed. Interspersed among the dense inflammatory cells were spindle or oval-shaped cells, distributed sporadically with indistinct boundaries. Under high magnification, these spindle cells had subtle features: smooth and clear nuclear membranes, inconspicuous small nucleoli, and infrequent mitotic figures. Immunophenotypically, the spindle cells expressed CD21 and CD23, and Epstein-Barr encoding region (EBER) in situ hybridization yielded positive results. The inflammatory milieu predominantly consisted of T cells, with a minority of plasma cells expressing IgG4. The confluence of morphological and immunohistochemical findings led to the final pathological diagnosis of EBV+IFDCS in this case.

Conclusions

The presentation of EBV+IFDCS with pronounced granulomatous changes is rare. This morphological variant poses a high risk of misdiagnosis, frequently leading to confusion with other granulomatous diseases. Accurate diagnosis necessitates a comprehensive analysis, integrating immunohistochemistry and in situ hybridization. The case presented here is instrumental in raising awareness and understanding of EBV+IFDCS, with the goal of reducing misdiagnoses and unrecognized cases.
Implementation of state health insurance benefit mandates for cancer-related fertility preservation: following policy through a complex system
Authors: Su H. Irene , Kaiser Bonnie N. , Crable Erika L. , Ortega Ricardo Flores , Yoeun Sara W. , Economou Melina A. , Fernandez Estefania , Romero Sally A. D. , Aarons Gregory A. , McMenamin Sara B.
Published: February 2024

Background

A myriad of federal, state, and organizational policies are designed to improve access to evidence-based healthcare, but the impact of these policies likely varies due to contextual determinants of, reinterpretations of, and poor compliance with policy requirements throughout implementation. Strategies enhancing implementation and compliance with policy intent can improve population health. Critically assessing the multi-level environments where health policies and their related health services are implemented is essential to designing effective policy-level implementation strategies. California passed a 2019 health insurance benefit mandate requiring coverage of fertility preservation services for individuals at risk of infertility due to medical treatments, in order to improve access to services that are otherwise cost prohibitive. Our objective was to document and understand the multi-level environment, relationships, and activities involved in using state benefit mandates to facilitate patient access to fertility preservation services.

Methods

We conducted a mixed-methods study and used the policy-optimized exploration, preparation, implementation, and sustainment (EPIS) framework to analyze the implementation of California’s fertility preservation benefit mandate (SB 600) at and between the state insurance regulator, insurer, and clinic levels.

Results

Seventeen publicly available fertility preservation benefit mandate-relevant documents were reviewed. Interviews were conducted with four insurers; 25 financial, administrative, and provider participants from 16 oncology and fertility clinics; three fertility pharmaceutical representatives; and two patient advocates. The mandate and insurance regulator guidance represented two “Big P” (system level) policies that gave rise to a host of “little p” (organizational) policies by and between the regulator, insurers, clinics, and patients. Many little p policies were bridging factors to support implementation across levels and fertility preservation service access. Characterizing the mandate’s functions (i.e., policy goals) and forms (i.e., ways that policies were enacted) led to identification of (1) intended and unintended implementation, service, and patient outcomes, (2) implementation processes by level and EPIS phase, (3) actor-delineated key processes and heterogeneity among them, and (4) inner and outer context determinants that drove adaptations.

Conclusions

Following the midstream and downstream implementation of a state health insurance benefit mandate, data generated will enable development of policy-level implementation strategies, evaluation of determinants and important outcomes of effective implementation, and design of future mandates to improve fit and fidelity.
PLK4 as a potential target to enhance radiosensitivity in triple-negative breast cancer
Authors: Pellizzari Sierra , Bhat Vasudeva , Athwal Harjot , Cescon David W. , Allan Alison L. , Parsyan Armen
Published: February 2024

Radioresistance is one of the barriers to developing more effective therapies against the most aggressive, triple-negative, breast cancer (TNBC) subtype. In our previous studies, we showed that inhibition of Polo-like Kinase 4 (PLK4) by a novel drug, CFI-400945 significantly enhances the anticancer effects of radiotherapy (RT) compared to single treatment alone. Here we further investigate the role of PLK4 in enhancing radiation effects in TNBC and explore mechanisms of PLK4 inhibition and radiation combinatorial antiproliferative effects. To assess cellular proliferation in response to treatments, we used colony formation assays in TNBC cell lines and patient-derived organoids (PDOs). Downregulation of PLK4 expression was achieved using siRNA silencing in TNBC cell lines. Immunofluorescence against centrin was used to assess the alteration of centriole amplification in response to treatments. We observed that inhibition of PLK4 by CFI-400945 or Centrinone B or its downregulation by siRNA, when combined with RT, resulted in a significant increase in antiproliferative effect in TNBC cells lines and PDOs compared to untreated or single-treated cells. Anticancer synergy was observed using a response matrix in PDOs treated with CFI-400945 and RT. We show that the overamplification of centrioles might be involved in the combined antiproliferative action of RT and PLK4 inhibition. Our data suggest that PLK4 is a promising target for enhancing the anticancer effects of RT in TNBC that, at least in part, is modulated by the overamplification of centrioles. These results support further mechanistic and translational studies of anti-PLK4 agents and RT as an anticancer combination treatment strategy.
Impact of model-informed precision dosing in adults receiving vancomycin via continuous infusion: a randomized, controlled clinical trial
Authors: Van Wynsberge Glenn , Grootaert Veerle , Buyle Franky , Van Praet Jens , Colman Roos , Moors Ine , Somers Annemie , Veld Diana Huis in ‘t , De Cock Pieter ,   on behalf of the VANC-DOS Consortium, Bigler Kim , Capiau Andreas , Claus Barbara , Degroote Laure , De Keulenaer Julie , Deryckere Sabine , Deschepper Lotte , De Smet Sanne , De Smet Veronique , Heus Astrid , Huys Liesbeth , Langui Jolien , Lodewyck Tom , Mertens Sarah , Neyt Jeroen , Schauwvlieghe Alexander , Snauwaert Sylvia , Van Butsele Katleen , Vandecasteele Stefaan , Van Laethem Kevin , Vermis Karen , Verstraete Barbara
Published: February 2024

Background

Vancomycin is a commonly prescribed antibiotic to treat gram-positive infections. The efficacy of vancomycin is known to be directly related to the pharmacokinetic/pharmacodynamic (PK/PD) index of the area under the concentration-time curve (AUC) divided by the minimal inhibitory concentration (MIC) of the pathogen. However, in most countries, steady-state plasma concentrations are used as a surrogate parameter of target AUC/MIC, but this practice has some drawbacks. Hence, direct AUC-guided monitoring of vancomycin using model-informed precision dosing (MIPD) tools has been proposed for earlier attainment of target concentrations and reducing vancomycin-related nephrotoxicity. However, solid scientific evidence for these benefits in clinical practice is still lacking. This randomized controlled trial (RCT) aims to investigate the clinical utility of MIPD dosing of vancomycin administered via continuous infusion in hospitalized adults.

Methods

Participants from 11 wards at two Belgian hospitals are randomly allocated to the intervention group or the standard-of-care comparator group. In the intervention group, clinical pharmacists perform dose calculations using CE-labeled MIPD software and target an AUC24h of 400 to 600 mg × h/L, whereas patients in the comparator group receive standard-of-care dosing and monitoring according to the institutional guidelines. The primary endpoint is the proportion of patients reaching the target AUC24h/MIC of 400–600 between 48 and 72 h after start of vancomycin treatment. Secondary endpoints are the proportion of patients with (worsening) acute kidney injury (AKI) during and until 48 h after stop of vancomycin treatment, the proportion of patients reaching target AUC24h/MIC of 400–600 between 72 and 96 h after start of vancomycin treatment, and the proportion of time within the target AUC24h/MIC of 400–600.

Discussion

This trial will clarify the propagated benefits and provide new insights into how to optimally monitor vancomycin treatment.

Trial registration

EudraCT number: 2021-003670-31. Registered June 28, 2021. ClinicalTrials.gov identifier: NCT05535075. Registered September 10, 2022. Protocol version 3, protocol date: April 21, 2023.
High-resolution mapping of age- and gender-specific risk of Clonorchis sinensis infection risk in Guangdong, China: a geostatistical modeling study
Authors: Huang Si-Yue , Chen Jing-Diao , Zeng Qing-Sheng , Lai Ying-Si
Published: February 2024

Background

The latest national survey on the distribution of human parasites in China demonstrated that Guangdong was among the endemic provinces with the highest Clonorchis sinensis infection rates. High-resolution, age- and gender-specific risk maps of the temporal and spatial distributions are essential for the targeted control work.

Methods

Disease data on the prevalence of C.sinensis infection from 1990 onwards, either age- and gender-specific or aggregated across age and gender, were collected through systematic review and four large-scale surveys in Guangdong Province. Environmental and socioeconomic variables were obtained from open-access databases and employed as potential predictors. A Bayesian geostatistical model was developed to estimate the C.sinensis infection risk at high spatial resolution.

Results

The final dataset included 606 surveys at 463 unique locations for C.sinensis infection. Our findings suggested that following an initial increase and stabilization, the overall population-adjusted prevalence had declined to 2.2% (95% Bayesian credible interval: 1.7–3.0%) in the period of 2015 onwards. From 2015 onwards, moderate and high infection risks were found in the northern regions (e.g. Heyuan and Shaoguan cities) and the southern Pearl River Delta (e.g. Foshan, Zhongshan, Zhuhai and Jiangmen cities), respectively. Age- and gender-specific risk maps revealed that males had a higher infection risk than females, and the infection risk was higher in adults compared to children.

Conclusions

Our high-resolution risk maps of C. sinensis infection in Guangdong Province identified the spatial, temporal, age and gender heterogeneities, which can provide useful information assisting tailored control strategies.

Graphical Abstract
Curation of myeloma observational study MALIMAR using XNAT: solving the challenges posed by real-world data
Authors: Doran Simon J. , Barfoot Theo , Wedlake Linda , Winfield Jessica M. , Petts James , Glocker Ben , Li Xingfeng , Leach Martin , Kaiser Martin , Barwick Tara D. , Chaidos Aristeidis , Satchwell Laura , Soneji Neil , Elgendy Khalil , Sheeka Alexander , Wallitt Kathryn , Koh Dow-Mu , Messiou Christina , Rockall Andrea
Published: February 2024

Objectives

MAchine Learning In MyelomA Response (MALIMAR) is an observational clinical study combining “real-world” and clinical trial data, both retrospective and prospective. Images were acquired on three MRI scanners over a 10-year window at two institutions, leading to a need for extensive curation.

Methods

Curation involved image aggregation, pseudonymisation, allocation between project phases, data cleaning, upload to an XNAT repository visible from multiple sites, annotation, incorporation of machine learning research outputs and quality assurance using programmatic methods.

Results

A total of 796 whole-body MR imaging sessions from 462 subjects were curated. A major change in scan protocol part way through the retrospective window meant that approximately 30% of available imaging sessions had properties that differed significantly from the remainder of the data. Issues were found with a vendor-supplied clinical algorithm for “composing” whole-body images from multiple imaging stations. Historic weaknesses in a digital video disk (DVD) research archive (already addressed by the mid-2010s) were highlighted by incomplete datasets, some of which could not be completely recovered. The final dataset contained 736 imaging sessions for 432 subjects. Software was written to clean and harmonise data. Implications for the subsequent machine learning activity are considered.

Conclusions

MALIMAR exemplifies the vital role that curation plays in machine learning studies that use real-world data. A research repository such as XNAT facilitates day-to-day management, ensures robustness and consistency and enhances the value of the final dataset. The types of process described here will be vital for future large-scale multi-institutional and multi-national imaging projects.

Critical relevance statement

This article showcases innovative data curation methods using a state-of-the-art image repository platform; such tools will be vital for managing the large multi-institutional datasets required to train and validate generalisable ML algorithms and future foundation models in medical imaging.

Key points

• Heterogeneous data in the MALIMAR study required the development of novel curation strategies.

• Correction of multiple problems affecting the real-world data was successful, but implications for machine learning are still being evaluated.

• Modern image repositories have rich application programming interfaces enabling data enrichment and programmatic QA, making them much more than simple “image marts”.

Graphical Abstract
Dramatic response of synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome to tofacitinib monotherapy: a case report
Authors: Dierckx Stéphanie , Nisolle Jean-François , Boutsen Yves
Published: February 2024

Introduction

The synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is a rare condition. Its treatment remains a challenge for clinicians, and often yields mixed results.

Case

We report the case of a 51-year-old Caucasian woman who presented with SAPHO syndrome with mainly axial involvement. She had been treated with sulfasalazine and anti-inflammatory drugs for many years without any success. A few weeks after starting treatment with tofacitinib, both clinical and biological parameters dramatically improved. Imaging also showed considerable regression of the vertebral and pelvic lesions. However, tofacitinib had to be discontinued due to the occurrence of pulmonary embolism. Consequently, recurrence of bone pain and biologic inflammation was rapidly observed.

Conclusions

Anti-JAKs are an interesting treatment option in the management of SAPHO syndrome that need further clinical trials and assessment for validating response.
Simultaneously improving accuracy and computational cost under parametric constraints in materials property prediction tasks
Authors: Gupta Vishu , Li Youjia , Peltekian Alec , Kilic Muhammed Nur Talha , Liao Wei-keng , Choudhary Alok , Agrawal Ankit
Published: February 2024

Modern data mining techniques using machine learning (ML) and deep learning (DL) algorithms have been shown to excel in the regression-based task of materials property prediction using various materials representations. In an attempt to improve the predictive performance of the deep neural network model, researchers have tried to add more layers as well as develop new architectural components to create sophisticated and deep neural network models that can aid in the training process and improve the predictive ability of the final model. However, usually, these modifications require a lot of computational resources, thereby further increasing the already large model training time, which is often not feasible, thereby limiting usage for most researchers. In this paper, we study and propose a deep neural network framework for regression-based problems comprising of fully connected layers that can work with any numerical vector-based materials representations as model input. We present a novel deep regression neural network, iBRNet, with branched skip connections and multiple schedulers, which can reduce the number of parameters used to construct the model, improve the accuracy, and decrease the training time of the predictive model. We perform the model training using composition-based numerical vectors representing the elemental fractions of the respective materials and compare their performance against other traditional ML and several known DL architectures. Using multiple datasets with varying data sizes for training and testing, We show that the proposed iBRNet models outperform the state-of-the-art ML and DL models for all data sizes. We also show that the branched structure and usage of multiple schedulers lead to fewer parameters and faster model training time with better convergence than other neural networks. Scientific contribution: The combination of multiple callback functions in deep neural networks minimizes training time and maximizes accuracy in a controlled computational environment with parametric constraints for the task of materials property prediction.
Cost-utility and cost-effectiveness analysis of disease-modifying drugs of relapsing–remitting multiple sclerosis: a systematic review
Authors: Gallehzan Nasrin Abulhasanbeigi , Khosravi Majid , Jamebozorgi Khosro , Mir Nazanin , Jalilian Habib , Soleimanpour Samira , Hoseini Saeed , Rezapour Aziz , Eshraghi Abbas
Published: February 2024

Background

Multiple sclerosis (MS) is a chronic, autoimmune, and inflammatory disease. The economic burden of MS is substantial, and the high cost of Disease-modifying drugs (DMDs) prices are the main drivers of healthcare expenditures. We conducted a systematic review of studies evaluating the cost-utility and cost-effectiveness of DMDs for relapsing–remitting multiple sclerosis (RRMS).

Materials and method

Searches were conducted in PubMed, Web of Science, Scopus, and Embase. The search covered articles published between May 2001 and May 2023. Studies that were written in English and Persian and examined the cost-utility and cost-effectiveness of DMDs in patients with MS were included in our review. Data extraction was guided by the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist, and the quality of economic evaluations was assessed using the Quality of Health Economics Studies Instrument (QHES). All costs were converted to 2020 U.S. dollars using Purchasing Power Parity (PPP).

Results

The search yielded 1589 studies, and 49 studies were eligible for inclusion. The studies were mainly based on a European setting. Most studies employed Markov model to assess the cost–effectiveness. The lowest and highest numerical value of outcome measures were -1,623,918 and 2,297,141.53, respectively. Furthermore, the lowest and highest numerical value of the cost of DMDs of RRMS were $180.67, and $1474840.19, respectively.

Conclusions

Based on the results of all studies, it can be concluded that for the treatment of patients with MS, care-oriented strategies should be preferred to drug strategies. Also, among the drug strategies with different prescribing methods, oral disease-modifying drugs of RRMS should be preferred to injectable drugs and intravenous infusions.