bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical outcomes of different autografts used for all-epiphyseal, partial epiphyseal or transphyseal anterior cruciate ligament reconstruction in skeletally immature patients – a systematic review
Authors: Verhagen S , Dietvorst M , Delvaux EJLG , van der Steen MC , Janssen RPA
Published: August 2023

Background

Different types of grafts can be used for anterior cruciate ligament reconstruction (ACLR). There is little published data regarding skeletally immature patients. The purpose of this systematic review was to assess the clinical outcomes and complications for different autograft types used in all-epiphyseal, transphyseal and partial epiphyseal/hybrid ACLR in skeletally immature children and adolescents.

Methods

PubMed, Embase and Cochrane databases were systematically searched for literature regarding ACLR using hamstrings, quadriceps or bone-patellar-tendon-bone (BPTB) autografts in skeletally immature patients. Studies were included if they examined at least one of the following outcomes: graft failure, return to sport(s), growth disturbance, arthrofibrosis or patient reported outcomes and had a minimum follow-up of 1 year. Case reports, conference abstracts and studies examining allografts and extra-articular or over-the-top ACL reconstruction techniques were excluded. Graft failure rates were pooled for each graft type using the quality effects model of MetaXL. A qualitative synthesis of secondary outcomes was performed.

Results

The database search identified 242 studies. In total 31 studies were included in this review, comprising of 1358 patients. Most patients (81%) were treated using hamstring autograft. The most common used surgical technique was transphyseal. The weighted, pooled failure rate for each graft type was 12% for hamstring tendon autografts, 8% for quadriceps tendon autografts and 6% for BPTB autografts. Confidence intervals were overlapping. The variability in time to graft failure was high. The qualitative analysis of the secondary outcomes showed similar results with good clinical outcomes and low complication rates across all graft types.

Conclusions

Based on this review it is not possible to determine a superior graft type for ACLR in skeletally immature. Of the included studies, the most common graft type used was the hamstring tendon. Overall, graft failure rates are low, and most studies show good clinical outcomes with high return to sports rates.
Comparative effectiveness of aspirin for symptomatic venous thromboembolism prophylaxis in patients undergoing total joint arthroplasty, a cohort study
Authors: Sidhu Verinder , Badge Helen , Churches Timothy , Maree Naylor Justine , Adie Sam , A Harris Ian
Published: August 2023

Background

This study compares the symptomatic 90-day venous thromboembolism (VTE) rates in patients receiving aspirin to patients receiving low-molecular weight heparin (LMWH) or direct oral anticoagulants (DOACs), after total hip (THA) and total knee arthroplasty (TKA).

Methods

Data were collected from a multi-centre cohort study, including demographics, confounders and prophylaxis type (aspirin alone, LMWH alone, aspirin and LMWH, and DOACs). The primary outcome was symptomatic 90-day VTE. Secondary outcomes were major bleeding, joint related reoperation and mortality within 90 days. Data were analysed using logistic regression, the Student’s t and Fisher’s exact tests (unadjusted) and multivariable regression (adjusted).

Results

There were 1867 eligible patients; 365 (20%) received aspirin alone, 762 (41%) LMWH alone, 482 (26%) LMWH and aspirin and 170 (9%) DOAC. The 90-day VTE rate was 2.7%; lowest in the aspirin group (1.6%), compared to 3.6% for LMWH, 2.3% for LMWH and aspirin and 2.4% for DOACs. After adjusted analysis, predictors of VTE were prophylaxis duration < 14 days (OR = 6.7, 95% CI 3.5–13.1, p < 0.001) and history of previous VTE (OR = 2.4, 95% CI 1.1–5.8, p = 0.05). There were no significant differences in the primary or secondary outcomes between prophylaxis groups.

Conclusions

Aspirin may be suitable for VTE prophylaxis following THA and TKA. The comparatively low unadjusted 90-day VTE rate in the aspirin group may have been due to selective use in lower-risk patients.

Trial Registration

This study was registered at ClinicalTrials.gov, trial number NCT01899443 (15/07/2013).
An analysis of the associations of high-sensitivity C-reactive protein and uric acid with metabolic syndrome components in Korean adults by sex: a cross-sectional study using the Korea national health and nutrition examination survey 2016–2018
Authors: Kim Young Kyun , Yang Young-Mo
Published: August 2023

Background

Low-grade inflammation plays a role in the pathogenesis of metabolic syndrome (MetS), and measuring levels of inflammatory molecules, such as high-sensitivity C-reactive protein (hs-CRP), may indicate Mets progression. Serum uric acid (SUA) has also been identified as an independent risk factor for MetS. This study aimed to investigate the association between MetS components and levels of serum hs-CRP and SUA using representative and reliable data for the Korean population.

Methods

This study used the data of the Korea National Health and Nutrition Examination Survey 2016–2018, a cross-sectional and nationally representative survey performed by the Korean Centers for Disease Control and Prevention.

Results

We analysed the data of 13,454 individuals. High hs-CRP levels were observed in 1,164 (8.7%) subjects while 3,296 (24.5%) subjects had high SUA levels. Moreover, hs-CRP was negatively correlated with serum high-density lipoprotein (HDL) (OR, 1.703; 95% CI, 1.431–2.027). When stratified by sex, this trend remained, but the correlation was stronger in women than in men. Furthermore, high SUA levels were significantly associated with hypertension (HTN) (OR, 1.399; 95% CI, 1.210–1.616), hypertriglyceridemia (OR, 1.735; 95% CI, 1.486–2.026), and low HDL (OR, 1.257; 95% CI, 1.106–1.429), but not with diabetes mellitus (DM) (OR, 0.478; 95% CI, 0.382–0.597). When grouped by sex, this trend remained, however, all MetS components were found to be more prevalent in women with high SUA.

Conclusions

Our findings showed that low HDL was more prevalent in subjects with high hs-CRP, and high SUA levels were observed in subjects with HTN, hypertriglyceridemia, and low HDL. However, the prevalence of high SUA was lower in diabetic subjects.
Assessment of supportive care needs among cervical cancer patients under treatment in Nepal: a cross-sectional study
Authors: Dhakal Kamala , Wang Panpan , Mboineki Joanes Faustine , Getu Mikiyas Amare , Chen Changying
Published: August 2023

Backgrounds

The perceived supportive care needs (SCNs) of cancer patients are essential components of a care program. The first step in planning and intervening for supportive care is the proper identification of the SCNs of cancer patients. Cervical cancer (CC) is the most prevalent cancer among Nepali women. The authors assess SCNs and their predictors among CC patients under treatment by using a validated Nepali version supportive care need survey short form (SCNS- SF 34 N).

Methods

This descriptive cross-sectional study was conducted in 5 cancer treatment hospitals in Nepal. A culturally adapted and psychometrically validated Nepali version SCNS –SF- 34 N was completed by a convenience sample of 218 CC patients. Data were analyzed by using descriptive (frequency, percentage, mean, median) and inferential (Chi-square P-value and binary logistic regression analysis) statistics.

Results

The study showed that 99% of the respondents were in need of some level (low, moderate, high) of supportive care. The psychological domain, physical daily living, health system information, patient care support and sexuality domain ranked from first to fifth for SCNs with mean and standard deviations 70.29 ± 18.84, 63.25 ± 23.15, 57.90 ± 21.11, 56.46 ± 21.92 and 46.06 ± 34.16, respectively. Binary logistic regression found causal association between SCNs and variables “occupation (p-value = 0.007), and type of hospital (p-value = 0.000)” at a 95% confidence level.

Conclusion

Nepali CC patients perceive and experience many unmet SCNs, with psychological SCNs being the first priority. It is essential that the SCNs of patients may need to be known by their close family members, care providers, CC related program. so that they can offer intervention as per patients’ needs.
Non-canonical d-xylose and l-arabinose metabolism via d-arabitol in the oleaginous yeast Rhodosporidium toruloides
Authors: Adamczyk Paul A. , Coradetti Samuel T. , Gladden John M.
Published: August 2023

R. toruloides is an oleaginous yeast, with diverse metabolic capacities and high tolerance for inhibitory compounds abundant in plant biomass hydrolysates. While R. toruloides grows on several pentose sugars and alcohols, further engineering of the native pathway is required for efficient conversion of biomass-derived sugars to higher value bioproducts. A previous high-throughput study inferred that R. toruloides possesses a non-canonical l-arabinose and d-xylose metabolism proceeding through d-arabitol and d-ribulose. In this study, we present a combination of genetic and metabolite data that refine and extend that model. Chiral separations definitively illustrate that d-arabitol is the enantiomer that accumulates under pentose metabolism. Deletion of putative d-arabitol-2-dehydrogenase (RTO4_9990) results in > 75% conversion of d-xylose to d-arabitol, and is growth-complemented on pentoses by heterologous xylulose kinase expression. Deletion of putative d-ribulose kinase (RTO4_14368) arrests all growth on any pentose tested. Analysis of several pentose dehydrogenase mutants elucidates a complex pathway with multiple enzymes mediating multiple different reactions in differing combinations, from which we also inferred a putative l-ribulose utilization pathway. Our results suggest that we have identified enzymes responsible for the majority of pathway flux, with additional unknown enzymes providing accessory activity at multiple steps. Further biochemical characterization of the enzymes described here will enable a more complete and quantitative understanding of R. toruloides pentose metabolism. These findings add to a growing understanding of the diversity and complexity of microbial pentose metabolism.
Engineering transcriptional regulation of pentose metabolism in Rhodosporidium toruloides for improved conversion of xylose to bioproducts
Authors: Coradetti Samuel T. , Adamczyk Paul A. , Liu Di , Gao Yuqian , Otoupal Peter B. , Geiselman Gina M. , Webb-Robertson Bobbie-Jo M. , Burnet Meagan C. , Kim Young-Mo , Burnum-Johnson Kristin E. , Magnuson Jon , Gladden John M.
Published: August 2023

Efficient conversion of pentose sugars remains a significant barrier to the replacement of petroleum-derived chemicals with plant biomass-derived bioproducts. While the oleaginous yeastRhodosporidiumtoruloides(also known asRhodotorulatoruloides) has a relatively robust native metabolism of pentose sugars compared to other wild yeasts, faster assimilation of those sugars will be required for industrial utilization of pentoses. To increase the rate of pentose assimilation inR.toruloides,we leveraged previously reported high-throughput fitness data to identify potential regulators of pentose catabolism. Two genes were selected for further investigation, a putative transcription factor (RTO4_12978, Pnt1) and a homolog of a glucose transceptor involved in carbon catabolite repression (RTO4_11990). Overexpression of Pnt1 increased the specific growth rate approximately twofold early in cultures on xylose and increased the maximum specific growth by 18% while decreasing accumulation of arabitol and xylitol in fast-growing cultures. Improved growth dynamics on xylose translated to a 120% increase in the overall rate of xylose conversion to fatty alcohols in batch culture. Proteomic analysis confirmed that Pnt1 is a major regulator of pentose catabolism inR.toruloides.Deletion of RTO4_11990 increased the growth rate on xylose, but did not relieve carbon catabolite repression in the presence of glucose. Carbon catabolite repression signaling networks remain poorly characterized inR.toruloidesand likely comprise a different set of proteins than those mainly characterized in ascomycete fungi.
Decoding the prognostic significance of integrator complex subunit 9 (INTS9) in glioma: links to TP53 mutations, E2F signaling, and inflammatory microenvironments
Authors: Lin Yu-Chieh , Chang Pei-Chi , Hueng Dueng-Yuan , Huang Shih-Ming , Li Yao-Feng
Published: August 2023

Introduction

Gliomas, a type of brain neoplasm, are prevalent and often fatal. Molecular diagnostics have improved understanding, but treatment options are limited. This study investigates the role of INTS9 in processing small nuclear RNA (snRNA), which is crucial to generating mature messenger RNA (mRNA). We aim to employ advanced bioinformatics analyses with large-scale databases and conduct functional experiments to elucidate its potential role in glioma therapeutics.

Materials and methods

We collected genomic, proteomic, and Whole-Exon-Sequencing data from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) for bioinformatic analyses. Then, we validated INTS9 protein expression through immunohistochemistry and assessed its correlation with P53 and KI67 protein expression. Gene Set Enrichment Analysis (GSEA) was performed to identify altered signaling pathways, and functional experiments were conducted on three cell lines treated with siINTS9. Then, we also investigate the impacts of tumor heterogeneity on INTS9 expression by integrating single-cell sequencing, 12-cell state prediction, and CIBERSORT analyses. Finally, we also observed longitudinal changes in INTS9 using the Glioma Longitudinal Analysis (GLASS) dataset.

Results

Our findings showed increased INTS9 levels in tumor tissue compared to non-neoplastic components, correlating with high tumor grading and proliferation index. TP53 mutation was the most notable factor associated with upregulated INTS9, along with other potential contributors, such as combined chromosome 7 gain/10 loss, TERT promoter mutation, and increased Tumor Mutational Burden (TMB). In GSEA analyses, we also linked INTS9 with enhanced cell proliferation and inflammation signaling. Downregulating INTS9 impacted cellular proliferation and cell cycle regulation during the function validation. In the context of the 12 cell states, INTS9 correlated with tumor-stem and tumor-proliferative-stem cells. CIBERSORT analyses revealed increased INTS9 associated with increased macrophage M0 and M2 but depletion of monocytes. Longitudinally, we also noticed that the INTS9 expression declined during recurrence in IDH wildtype.

Conclusion

This study assessed the role of INTS9 protein in glioma development and its potential as a therapeutic target. Results indicated elevated INTS9 levels were linked to increased proliferation capacity, higher tumor grading, and poorer prognosis, potentially resulting from TP53 mutations. This research highlights the potential of INTS9 as a promising target for glioma treatment.
Dysregulated lipid metabolism in TMZ-resistant glioblastoma: pathways, proteins, metabolites and therapeutic opportunities
Authors: Kao Tzu-Jen , Lin Chien-Liang , Yang Wen-Bin , Li Hao-Yi , Hsu Tsung-I
Published: August 2023

Glioblastoma (GBM) is a highly aggressive and lethal brain tumor with limited treatment options, such as the chemotherapeutic agent, temozolomide (TMZ). However, many GBM tumors develop resistance to TMZ, which is a major obstacle to effective therapy. Recently, dysregulated lipid metabolism has emerged as an important factor contributing to TMZ resistance in GBM. The dysregulation of lipid metabolism is a hallmark of cancer and alterations in lipid metabolism have been linked to multiple aspects of tumor biology, including proliferation, migration, and resistance to therapy. In this review, we aimed to summarize current knowledge on lipid metabolism in TMZ-resistant GBM, including key metabolites and proteins involved in lipid synthesis, uptake, and utilization, and recent advances in the application of metabolomics to study lipid metabolism in GBM. We also discussed the potential of lipid metabolism as a target for novel therapeutic interventions. Finally, we highlighted the challenges and opportunities associated with developing these interventions for clinical use, and the need for further research to fully understand the role of lipid metabolism in TMZ resistance in GBM. Our review suggests that targeting dysregulated lipid metabolism may be a promising approach to overcome TMZ resistance and improve outcomes in patients with GBM.
Role of different mechanisms in pro-inflammatory responses triggered by traffic-derived particulate matter in human bronchiolar epithelial cells
Authors: Refsnes Magne , Skuland Tonje , Jørgensen Rikke , Sæter-Grytting Vegard , Snilsberg Brynhild , Øvrevik Johan , Holme Jørn A. , Låg Marit
Published: August 2023

Background

Traffic-derived particles are important contributors to the adverse health effects of ambient particulate matter (PM). In Nordic countries, mineral particles from road pavement and diesel exhaust particles (DEP) are important constituents of traffic-derived PM. In the present study we compared the pro-inflammatory responses of mineral particles and DEP to PM from two road tunnels, and examined the mechanisms involved.

Methods

The pro-inflammatory potential of 100 µg/mL coarse (PM10-2.5), fine (PM2.5-0.18) and ultrafine PM (PM0.18) sampled in two road tunnels paved with different stone materials was assessed in human bronchial epithelial cells (HBEC3-KT), and compared to DEP and particles derived from the respective stone materials. Release of pro-inflammatory cytokines (CXCL8, IL-1α, IL-1β) was measured by ELISA, while the expression of genes related to inflammation (COX2, CXCL8, IL-1α, IL-1β, TNF-α), redox responses (HO-1) and metabolism (CYP1A1, CYP1B1, PAI-2) was determined by qPCR. The roles of the aryl hydrocarbon receptor (AhR) and reactive oxygen species (ROS) were examined by treatment with the AhR-inhibitor CH223191 and the anti-oxidant N-acetyl cysteine (NAC).

Results

Road tunnel PM caused time-dependent increases in expression of CXCL8, COX2, IL-1α, IL-1β, TNF-α, COX2, PAI-2, CYP1A1, CYP1B1 and HO-1, with fine PM as more potent than coarse PM at early time-points. The stone particle samples and DEP induced lower cytokine release than all size-fractionated PM samples for one tunnel, and versus fine PM for the other tunnel. CH223191 partially reduced release and expression of IL-1α and CXCL8, and expression of COX2, for fine and coarse PM, depending on tunnel, response and time-point. Whereas expression of CYP1A1 was markedly reduced by CH223191, HO-1 expression was not affected. NAC reduced the release and expression of IL-1α and CXCL8, and COX2 expression, but augmented expression of CYP1A1 and HO-1.

Conclusions

The results indicate that the pro-inflammatory responses of road tunnel PM in HBEC3-KT cells are not attributed to the mineral particles or DEP alone. The pro-inflammatory responses seem to involve AhR-dependent mechanisms, suggesting a role for organic constituents. ROS-mediated mechanisms were also involved, probably through AhR-independent pathways. DEP may be a contributor to the AhR-dependent responses, although other sources may be of importance.
16S rRNA gene sequencing reveals the effect of fluoxetine on gut microbiota in chronic unpredictable stress-induced depressive-like rats
Authors: Dong Hui , Tang Xiaowei , Ye Jie , Xiao Wenhuan
Published: August 2023

Objectives

Gut microbiota is relevant to the pathogenesis of mental disorders including depression. This study aimed to investigate the influence of fluoxetine (FLX) on the gut microbiota in rats with Chronic Unpredictable Mild Stresses (CUMS)-induced depression.

Results

We confirmed that the 28-day CUMS-induced depression rat model. Chronic FLX administration weakly improved depressive-like behaviors in rats. Illumina 16S rRNA gene sequencing on rat feces showed CUMS increased the relative abundance of Firmicutes (60.31% vs. 48.09% in Control, p < 0.05) and Lactobacillus genus (21.06% vs. 6.82% in control, p < 0.05); FLX and CUMS increased Bacilli class (20.00% ~ 24.08% vs. 10.31% in control, p < 0.05).

Conclusion

Collectively, our study showed that both CUMS and FLX changed the compositions of gut microbiota in rats. FLX and CUMS distinctly regulated the gut microbiota in depressed rats.
China nationwide landscape of 16 types inherited metabolic disorders: a retrospective analysis on 372,255 clinical cases
Authors: Zhao Beibei , Chen Peichun , She Xuhui , Chen Xiuru , Ni Zhou , Zhou Duo , Yu Zinan , Liu Chang , Huang Xinwen
Published: August 2023

Background

Inherited metabolic disorders (IMDs) usually occurs at young age and hence it severely threatening the health and life of young people. While so far there lacks a comprehensive study which can reveals China’s nationwide landscape of IMDs. This study aimed to evaluate IMDs incidence and regional distributions in China at a national and province level to guide clinicians and policy makers.

Methods

The retrospective study conducted from January 2012 to March 2021, we analyzed and characterized 372255 cases’ clinical test information and diagnostic data from KingMed Diagnostics Laboratory. The samples were from 32 provincial regions of China, the urine organic acids were detected by gas chromatography-mass spectrometry (GC–MS), amino acids and acylcarnitines in dried blood spots were detected by liquid chromatography-tandem mass spectrometry (LC–MS/MS). We did a statistical analysis of the distribution of the 16 most common IMDs in amino acid disorders and organic acidemias, and then paid special attention to analyze the age and regional distributions of different IMDs. The statistical analyses and visualization analysis were performed with the programming language R (version 4.2.1).

Results

There were 4911 positive cases diagnosed, which was 1.32% of the total sample during the ten-year study period. Most diseases tended to occur at ages younger than 18 year-old. The Ornithine Transcarbamylase Deficiency tended to progress on male infants who were less than 28 days old. While the peak of the positive case number of Citrin Deficiency disease (CD) was at 1–6 months. Different IMDs’ had different distribution patterns in China’s provinces. Methylmalonic Acidemias and Hyperphenylalaninemia had an imbalanced distribution pattern in China and its positive rate was significantly higher in North China than South China. Conversely, the positive rate of CD was significantly higher in South China than North China.

Conclusions

Results of this work, such as the differences in distribution pattern of different diseases in terms of age, region, etc. provide important insights and references for clinicians, researchers and healthcare policy makers. The policy makers could optimize the better health screening programs for covering children and infants in specific ages and regions based on our findings.
Diversity of several estimates transformed on time scales
Authors: Sahir Muhammad Jibril Shahab , Afzal Deeba , Inc Mustafa , Alshomrani Ali Saleh
Published: August 2023

In this research article, we prove several generalizations of reverse Callebaut, Rogers–Hölder, and Cauchy–Schwarz inequalities via reverses of Young inequalities on time scales. Discrete, continuous, and quantum versions of the results are unified and extended on time scales.
Factors that influence modern contraceptive use among women aged 35 to 49 years and their male partners in Gomoa West District, Ghana: a qualitative study
Authors: Takyi Amy , Sato Miho , Adjabeng Michael , Smith Chris
Published: August 2023

Background

Fertility declines with age, but it remains important to protect women from unplanned pregnancies throughout their reproductive lives. The objective of this study was to describe factors that influence modern contraceptive use among women aged 35 to 49 years and their male partners in Gomoa West District of Ghana.

Methods

In-depth interviews were conducted remotely for 22 women, 15 male partners of the women interviewed and seven family planning (FP) providers. In all, a total of 44 participants took part in the study. Seven refusals were recorded, four females and three males. Four focus group discussions were organized for 21 participants who took part in the in-depth interviews. Data collected were transcribed and coded after exporting to Nvivo12 qualitative analysis software. Thematic analysis was undertaken using an abductive approach.

Results

Factors that influenced the use of modern contraceptives included: achieved desired family size, providing for the family, counselling by health professionals, influence of the male partner, and health reasons. Barriers cited included: religious or socio-cultural reasons, experience or fear of side effects, rumors or misconceptions, declining fertility, and the belief that contraceptive use is a matter for women. Within the study group, roughly half of women used modern contraceptives, while the majority of male partners were non-users.

Conclusion

Contraception among women aged 35 to 49 years and their male partners is influenced by several factors such as achieved desired family size, influence of the male partner, rumors or misconceptions, and declining fertility. Strengthening male involvement in family planning activities and health educational activities could alleviate fear and reduce misconceptions about using modern contraceptives.
A microCT-based platform to quantify drug targeting
Authors: Ausk Brandon J. , Tucker Adam N. , Huber Philippe , Firoozabadi Reza , Gross Jeffrey M. , Gross Ted S. , Bain Steven D.
Published: August 2023

Background

Heterotopic ossification (HO) is a frequent and debilitating complication of traumatic musculoskeletal injuries and orthopedic procedures. Prophylactic dosing of botulinum toxin type A (BTxA) holds potential as a novel treatment option if accurately distributed throughout soft-tissue volumes where protection is clinically desired. We developed a high-resolution, microcomputed tomography (microCT)-based imaging strategy to assess drug distribution and validated this platform by quantifying distribution achieved via a prototype delivery system versus a single-bolus injection.

Methods

We injected an iodine-containing contrast agent (iodixanol 320 mg I/mL) into dissected rabbit musculature followed by microCT imaging and analysis. To contrast the performance of distributed versus bolus injections, a three-dimensional (3D) 64-cm3-printed soft-tissue holder was developed. A centered 2-cm3 volume of interest (VOI) was targeted with a single-bolus injection or an equal volume distributed injection delivered via a 3D-printed prototype. VOI drug coverage was quantified as a percentage of the VOI volume that was < 1.0 mm from the injected fluid.

Results

The microCT-based approach enabled high-resolution quantification of injection distribution within soft tissue. The distributed dosing prototype provided significantly greater tissue coverage of the targeted VOI (72 ± 3%, mean ± standard deviation) when compared to an equal volume bolus dose (43 ± 5%, p = 0.031) while also enhancing the precision of injection targeting.

Conclusions

A microCT-based imaging technique precisely quantifies drug distribution within a soft-tissue VOI, providing a path to overcome a barrier for clinical translation of prophylactic inhibition of HO by BTxA.

Relevance statement

This platform will facilitate rapid optimization of injection parameters for clinical devices used to effectively and safely inhibit the formation of heterotopic ossification.

Key points

• MicroCT provides high-resolution quantification of soft-tissue drug distribution.

• Distributed dosing is required to maximize soft-tissue drug coverage.

• Imaging platform will enable rapid screening of 3D-printed drug distribution prototypes.

Graphical Abstract
Lactiplantibacillus plantarum, lactiplantibacillus pentosus and inulin meal inclusion boost the metagenomic function of broiler chickens
Authors: Ferrocino Ilario , Biasato Ilaria , Dabbou Sihem , Colombino Elena , Rantsiou Kalliopi , Squara Simone , Gariglio Marta , Capucchio Maria Teresa , Gasco Laura , Cordero Chiara Emilia , Liberto Erica , Schiavone Achille , Cocolin Luca
Published: August 2023

Background

The inclusion of alternative ingredients in poultry feed is foreseen to impact poultry gut microbiota. New feeding strategies (probiotics/prebiotics) must be adopted to allow sustainable productions. Therefore, the current study aimed to use metagenomics approaches to determine how dietary inclusion of prebiotic (inulin) plus a multi-strain probiotic mixture of Lactiplantibacillus plantarum and Lactiplantibacillus pentosus affected microbiota composition and functions of the gastro-intestinal tract of the broilers during production. Fecal samples were collected at the beginning of the trial and after 5, 11 and 32 days for metataxonomic analysis. At the end of the trial, broilers were submitted to anatomo-pathological investigations and caecal content was subjected to volatilome analysis and DNAseq.

Results

Probiotic plus prebiotic inclusion did not significantly influence bird performance and did not produce histopathological alterations or changes in blood measurements, which indicates that the probiotic did not impair the overall health status of the birds. The multi-strain probiotic plus inulin inclusion in broilers increased the abundance of Blautia, Faecalibacterium and Lachnospiraceae and as a consequence an increased level of butyric acid was observed. In addition, the administration of probiotics plus inulin modified the gut microbiota composition also at strain level since probiotics alone or in combination with inulin select specific Faecalibacterium prausnitzi strain populations. The metagenomic analysis showed in probiotic plus prebiotic fed broilers a higher number of genes required for branched-chain amino acid biosynthesis belonging to selected F. prausnitzi strains, which are crucial in increasing immune function resistance to pathogens. In the presence of the probiotic/prebiotic a reduction in the occurrence of antibiotic resistance genes belonging to aminoglycoside, beta-lactamase and lincosamide family was observed.

Conclusions

The positive microbiome modulation observed is particularly relevant, since the use of these alternative ingredients could promote a healthier status of the broiler’s gut.
Crystal structures of main protease (Mpro) mutants of SARS-CoV-2 variants bound to PF-07304814
Authors: Jiang Haihai , Zou Xiaofang , Zeng Pei , Zeng Xiangyi , Zhou Xuelan , Wang Jie , Zhang Jin , Li Jian
Published: August 2023

There is an urgent need to develop effective antiviral drugs to prevent the viral infection caused by constantly circulating SARS-CoV-2 as well as its variants. The main protease (Mpro) of SARS-CoV-2 is a salient enzyme that plays a vital role in viral replication and serves as a fascinating therapeutic target. PF-07304814 is a covalent inhibitor targeting SARS-CoV-2 Mpro with favorable inhibition potency and drug-like properties, thus making it a promising drug candidate for the treatment of COVID-19. We previously solved the structure of PF-07304814 in complex with SARS-CoV-2 Mpro. However, the binding modes of PF-07304814 with Mpros from evolving SARS-CoV-2 variants is under-determined. In the current study, we expressed six Mpro mutants (G15S, K90R, M49I, S46F, V186F, and Y54C) that have been identified in Omicron variants including the recently emerged XBB.1.16 subvariant and solved the crystal structures of PF-07304814 bound to Mpro mutants. Structural analysis provided insight into the key molecular determinants responsible for the interaction between PF-07304814 and these mutant Mpros. Patterns for PF-07304814 to bind with these investigated Mpro mutants and the wild-type Mpro are generally similar but with some differences as revealed by detailed structural comparison. Structural insights presented in this study will inform the development of novel drugs against SARS-CoV-2 and the possible conformation changes of Mpro mutants when bound to an inhibitor.
Simultaneous waveform inversion of seismic-while-drilling data for P-wave velocity, density, and source parameters
Authors: Li Jinji , Keating Scott D. , Innanen Kristopher A. , Shor Roman , Kazemi Nasser
Published: August 2023

Full-waveform inversion (FWI), as an optimization-based approach to estimating subsurface models, is limited by incomplete acquisition and illumination of the subsurface. The incorporation of additional data from new and independent raypaths should be expected to result in significant increase in the accuracy of FWI models. In principle, seismic-while-drilling (SWD) technology can supply these additional raypaths; however, it introduces a new suite of unknowns, namely precise source locations (i.e., drilling path), source signature, and radiation characteristics. A new FWI algorithm is formulated in which the source radiation patterns and positions join the velocity and density values of the grid cells as unknowns to be determined. Several numerical inversion experiments are then conducted with different source settings using a synthetic model. The SWD sources are supplemented by explosive sources and multicomponent receivers at the surface, simulating a conventional surface acquisition geometry. The subsurface model and SWD source properties are recovered and analyzed. The analysis is suggestive that SWD involvement can enhance the accuracy of FWI models, with varying degrees of enhancement depending on factors such as trajectory inclination, source density, and drill path extension. The impact of SWD-FWI over standard FWI is reduced when low-frequency data are missing, but improvements over the models constructed with no subsurface sources remain. This formulation permits general source information, such as position and moment tensor components, to be independently obtained. This inversion scheme may lead to a range of potential applications for which medium properties and source information are required.
Creating a cancer advocacy program in Indonesia.
Authors: Lee David Dai-Wee , Tane Kaori , Permata Tiara Bunga Mayang , Su Yu-Li , Malik Monica , Stockler Martin R. ,   ASCO Leadership Development Program Asia Pacific 2021 - 2022
Published: August 2023

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Background: Political will is crucial for successful cancer control. The ASCO Asia-Pacific Leadership Development Program tasked our group to address this issue. We identified the development of cancer advocacy in the Asia-Pacific as a key enabler, and Indonesia as ideal to develop and pilot a generalisable program. Indonesia has 270M citizens spread over 17,000 islands and 38 provinces posing major challenges for cancer control. There are no established cancer advocacy platforms in Indonesia with limited advocacy knowledge and readiness in the oncology community. Methods: Our vision is to establish a sustainable home for cancer control networks, with wide outreach throughout Indonesia. Our missions are to bridge the gap between cancer experts, patients, and policy makers; establish a network of cancer control platforms widely reaching to local districts, and empower cancer advocacy. This project proposes 2 main objectives. Firstly to cultivate cancer advocacy with a two-tier approach. We plan to collaborate with ASCO advocacy experts to develop a curriculum for cancer advocacy training, which would be conducted at an Indonesian cancer society meeting for oncologists. Thereafter, to create a web-based on-demand advocacy training for the wider community including nurses, patients, carers, and others using interactive e-learning activities. The second objective is to set up provincial cancer control platforms. These will be established by oncologists who have completed cancer advocacy training, to reach out to their local stakeholders. These provincial platforms will identify local cancer care gaps, and develop strategies to improve cancer control locally. The target is for these groups to hold at least one cancer awareness activity each year. At the national level, we plan to hold annual national cancer forums focusing on cancer advocacy, to congregate local advocacy champions and policy makers. This meeting will help cancer experts, advocates, and other stakeholders to meet with decision makers. Results: We plan for at least one oncologist from each Indonesian province to attend the advocacy training program in the first year. This will be expanded in the second year to include at least 2 participants per province in the on-demand cancer advocacy program. The national cancer control forum is planned for year 2. Conclusions: We aspire to build a sustainable, provincial training program for cancer advocacy, and to develop provincial cancer control networks in Indonesia. Once implemented, this model can be modified for application in other Asia Pacific countries.
Heart rate variability and the quality of life of patients receiving chemotherapy against gynecologic malignancies.
Authors: Higashiyama Nozomi , Yamaguchi Ken , Inayama Yoshihide , Koike Ayami , Ueda Akihiko , Kitamura Sachiko , Taki Mana , Yamanoi Koji , Murakami Ryusuke , Egawa Miho , Hamanishi Junzo , Mandai Masaki
Published: August 2023

106

Background: Improving quality of life (QOL) of patients with cancer is essential. However, evaluating QOL requires completing QOL questionnaires consisting of 30–40 questions, which is too burdensome for the patients to continue. Therefore, development of the methodology which does not dependent on the adherence of the patients is urgent to evaluate QOL. Recently, heart rate variability (HRV) has been reported to be associated with the autonomic nervous system. This study aims to develop and validate a machine-learning model to predict QOL from HRV. Methods: Fifty patients with gynecological cancers from our hospital were used as test data, and 15 patients with gynecological cancer from other hospitals were used as validation data. Using a mobile application, they recorded daily HRV and weekly QOL questionnaires (EORTC qlq-C30, FACT-G, PHQ9, PRO-CTCAE). A binary classification model was developed using the XgBoost Classifier to predict whether patients experienced at least one of severe numbness, insomnia, depression, and fatigue using their HRV. SHAP values of the HRV used for prediction were clustered into three groups using unsupervised learning (Parametric Umap). QOL indices for each group were compared. Metabolites in serums that contribute to HRV variation were identified using metabolome analysis. Results: Clustering using the SHAP values indicated high, middle, and low QOL groups (Group A, B, and C, respectively). The total score of FACT-G, an index of overall QOL, was 82.4, 72.7, and 67.3 out of 108 (Group A, B, and C, respectively). Global health status, another index of overall QOL was also highest in Group A and lowest in Group C. The score of fatigue was 27.2, 46.3, and 54.9 out of 100; the score of pain was 17.6, 27.2, and 35.8 out of 100; the score of depression was 1.8, 4.5, and 6.6 out of 27 (Group A, B, and C, respectively). The scores of numbness, diarrhea, appetite loss, insomnia and nausea were also highest in the Group C and lowest in the Group A. The HRV of validation datasets also showed a similar classification with total scores of FACT-G as 76.0, 67.8, and 62.1 and the score of depression as 3.8, 5.7 and 8.0 (Group A, B, and C, respectively). Metabolites in serum contributing to HRV variation are Arachidonic acid and Dopamine, which are associated with inflammation and depression. Conclusions: Measuring HRV is a simple way to evaluate the QOL of patients with gynecologic cancers. Monitoring QOL over time using HRV possibly allows early detection of deterioration in QOL, such as complications and side effects of chemotherapy. Clinical trial information: UMIN000038937 .
Improving treatment adherence in patients with cancer in low and middle-income countries, through digital health self-care interventions.
Authors: Akinjiola Kolawole , Ogboye Ayoposi
Published: August 2023

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Background: The WHO notes that adherence to treatment for people living with chronic conditions, including cancer is of global concern. This poor adherence is brought about in low- and middle-income countries like Nigeria, by patient factors such as poor health literacy, overshadowing religious beliefs, and forgetfulness, as well as systemic factors like fragmented patient care due to physician burnout. The aim of this study was to evaluate the effectiveness of digital self-care interventions via CompleteHealth in improving treatment adherence in people living with cancer. Methods: This was a retrospective study done on 63 patients on treatment for metastatic castrate-resistant prostate cancer, enrolled on mDoc’s digital CompleteHealth platform between January to December 2022. Each patient was assigned a virtual health coach who provided self-care support, monitored their health metrics, encouraged regular physical activity, and maintained normal body weight. Synchronous and asynchronous digital nudges were provided via the multiple channels of the digital CompleteHealth platform such as the web app, SMS, and phone calls. The patients also had access to virtual fitness, nutrition, and emotional wellness coaches as required. Results: 56/63 patients (88%) completed their full course of 6 months of treatment. The adherence was at 78.4%, which represents the average percentage of members who refilled medication as at when due, allowing for 30 days or less between fillings. Allowing for 90 days in between fillings, adherence was at 90.5%. Conclusions: The use of digital health interventions via virtual health coaching for self-care support has been demonstrated through CompleteHealth to improve treatment adherence in patients living with cancer significantly. There is therefore a place to scale up the use of digital health coaching to further improve this statistic, as it is likely to impact treatment outcomes positively.
VPAC targeted optical imaging assay (VPAC assay) of voided urine for management of patients with persistently elevated PSA.
Authors: Thakur Mathew L. , Trabulsi Edouard John , Dale Emma , Singh Vivek , Chhabra Anupriya , Dahlgren Olivia , Kolesnikov Oleksandr , Wang Kerith , Gomella Leonard G.
Published: August 2023

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Background: Nearly 50% of patients with persistently elevated PSA (PEP) have prostate cancer (PCa) despite previous negative biopsy. However not all patients agree to undergo repeat, invasive trans rectal or trans perineal prostate biopsy (PB). To identify men at high risk of PCa, the need is unmet of other reliable diagnostic methods. The goal of this investigation was to determine if the VPAC assay, which is being developed in our laboratory and detects PCa efficiently, by imaging PCa cells shed in voided urine, collected without digital rectal examination (DRE), can address the common clinical dilemma of when or if to repeat biopsy on PEP subjects. Methods: PEP patients (N=21, 55-75 yr. PSA 2.8 – 42 ng/ml), scheduled for PB and signed informed consent form were enrolled. They provided pre and clinically required, post DRE urine. VPAC assay was performed on both urine samples from each patient. VPAC, a genomic receptor, encodes G protein and expresses in high density on all malignant PCa cells, was targeted with TP4303, a biomolecule with fluorophore, designed in our laboratory with high affinity (Kd, 3.1x10-9M) for VPAC. Urine was centrifuged, cells on a glass slide fixed, incubated with TP4303 and excess was washed. Cells were then examined under a microscope. TP4303 fluorescence around cell nucleus allowed to identify malignant PCa cells. For urine collected post DRE, MDx Health assay, approved by FDA and determines mRNA levels of DXL1 and HOXC6 biomarkers and indicates risk of PCa, was also performed. Results were compared with gold standard histopathology of tissues acquired through PB, and evaluated statistically. Results: Of 21 PEP patients, who underwent PB, three (14%) had histopathologically proven, clinically significant PCa with Grade Group 2. All three (100%) patients were correctly identified as positive for PCa by the VPAC assay, while MDx reported low risk for two (9.5%) and high risk for one (53%). Of the remaining 18, histologically negative subjects, VPAC assay was disconcordant in five (28%), with positive for PCa. In these five patients, MDx also reported moderate to high risk (40%-59%). Of the remaining 13 histologically negative PCa patient, all (100%) had concordant results with VPAC assay while MDx reported low risk in 2 patients and moderate to high risk (range 30% to 90%) in other eleven. Results with sensitivity and specificity of the assays are given in the table. Conclusions: The VPAC assay data, in this small exploratory cohort, appear promising as an additional diagnostic in the clinical management of PEP patients, minimizing the number of unnecessary invasive PBs and eliminating possible overtreatment. Work is in progress. Support: NIH 5R01CA249921. [Table: see text]
The challenge of colorectal cancer (CRC) screening in low and middle-income countries (LMIC): The Brazilian ten year long experience.
Authors: Filogonio Victor , Maia Yara Rafaela , Maia Lucas Henrique
Published: August 2023

129

Background: The increasing incidence of CRC seen in LMIC and the high mortality rates compared to high-income countries points towards the difficult implementation of an effective screening strategy in LMIC. Brazil is one of the few Latin American countries and LMIC that have a population-based CRC screening program, targeting ages 50 to 74 and performing a fecal occult blood test (FT) every 2 years and colonoscopy/sigmoidoscopy as a confirmatory test. Methods: We performed a cross-sectional study, which evaluated the prevalence of every stage of CRC/carcinoma in situ (CIS) at the time of its diagnosis from 2013 to 2022. Similar data regarding the Brazilian breast and cervical cancer screening programs was obtained. Each stage was evaluated by age targeted by their respective screening program using the national database (DATASUS). Results: In the analyzed decade there was a total of 87507 CRC/CIS cases in the overall studied population, which only 11% was of Stage I or less and 70% was of stage III or IV at the time of diagnosis. In the subdivided age groups, the prevalence of each stage remained somewhat constant through all groups (In situ/Stage 0 = 8-9%; Stage I = 3%; Stage II = 20-21%; Stage III = 35-36%; Stage IV = 32-34%) and the majority of cases occurred from age 60 to 64 (20549 cases). In 2022, a total of 2128168 RT was performed - corresponding to only 4,6% of the targeted population - and 408489 colonoscopies. When compared to other cancer screening programs, CRC presents indifferent to age group, sustaining constant rate of regional/distant stages, with at least 32% of patients presenting a <17% 5-year survival rate (5-YSR), whereas cervical cancer presents approximately 80% of cases at >91% 5-YSR at the first age group, and breast cancer with 89% of cases at >86% 5-YSR at the first age group. Conclusions: Data suggests the inefficacy of CRC screening implementation, and literature sustains to be due to its poor acceptance by the population and the unavailability of confirmatory imaging tests due to long-waiting times and high cost, reducing its ability to detect early stage lesions, in contrast with the overall acceptance and high effectivity of cervical/breast cancer screening. The discrepancy between the guidelines and their implementation as a screening program in LMIC are in consonant. This study aims to be a launching point for new research and interventional studies evaluating the impact of better locally adjusted actions in the prevention of CRC such as screening invitations, in-community health education, and the developing of better cost-benefit confirmatory methods might hinder the advance of CRC in LMIC.[Table: see text]