bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional targeted therapy for glioma based on platelet membrane-coated nanogels
Authors: Li Qin , Shen Jinglan , Wu Lingling , Lei Siyun , Yang Yimin , Xu Weide , Hao Ke , Zhang Yi , Kong Fei , Yang Wei , Wang Yaling , Peng Lina , Li Kaiqiang , Wang Zhen
Published: February 2023

Glioma treatment remains a challenge owing to unsatisfactory targeted chemotherapy, where the blood–brain barrier (BBB) hinders the efficient uptake of therapeutics into the brain. Vasculogenic mimicry (VM) formed by invasive glioma cells negatively affects the treatment of glioma. Herein, we developed a targeted biomimetic drug delivery system comprising a doxorubicin-loaded platelet membrane-coated nanogel (DOX@PNGs). The nanogels provide great redox/pH dual responsiveness, while the platelet membrane (PLTM) promotes stability and circulation time. In vitro cellular uptake and in vivo imaging experiments demonstrated that the DOX@PNGs delivery system could penetrate the BBB, target gliomas, and destruct VM. DOX@PNGs increased drug penetration and prolonged mouse survival time during the treatment of orthotopic gliomas. These results indicate this biomimetic drug delivery system to be promising for glioma treatment and may be clinically translated in the future.
Designing multi-epitope vaccine against important colorectal cancer (CRC) associated pathogens based on immunoinformatics approach
Authors: Motamedi Hamid , Ari Marzie Mahdizade , Shahlaei Mohsen , Moradi Sajad , Farhadikia Parisa , Alvandi Amirhoushang , Abiri Ramin
Published: February 2023

Background

It seems that several members of intestinal gut microbiota like Streptococcus bovis, Bacteroides fragilis, Helicobacter pylori, Fusobacterium nucleatum, Enterococcus faecalis, Escherichia coli, Peptostreptococcus anaerobius may be considered as the causative agents of Colorectal Cancer (CRC). The present study used bioinformatics and immunoinformatics approaches to design a potential epitope-based multi-epitope vaccine to prevent CRC with optimal population coverage.

Methods

In this study, ten amino acid sequences of CRC-related pathogens were retrieved from the NCBI database. Three ABCpred, BCPREDS and LBtope online servers were considered for B cells prediction and the IEDB server for T cells (CD4+ and CD8+) prediction. Then, validation, allergenicity, toxicity and physicochemical analysis of all sequences were performed using web servers. A total of three linkers, AAY, GPGPG, and KK were used to bind CTL, HTL and BCL epitopes, respectively. In addition, the final construct was subjected to disulfide engineering, molecular docking, immune simulation and codon adaptation to design an effective vaccine production strategy.

Results

A total of 19 sequences of different lengths for linear B-cell epitopes, 19 and 18 sequences were considered as epitopes of CD4+ T and CD8+ cells, respectively. The predicted epitopes were joined by appropriate linkers because they play an important role in producing an extended conformation and protein folding. The final multi-epitope construct and Toll-like receptor 4 (TLR4) were evaluated by molecular docking, which revealed stable and strong binding interactions. Immunity simulation of the vaccine showed significantly high levels of immunoglobulins, helper T cells, cytotoxic T cells and INF-γ.

Conclusion

Finally, the results showed that the designed multi-epitope vaccine could serve as an excellent prophylactic candidate against CRC-associated pathogens, but in vitro and animal studies are needed to justify our findings for its use as a possible preventive measure.
Draft genomes of three closely related low light-adapted Prochlorococcus
Authors: Berta-Thompson Jessie W. , Thomas Elaina , Cubillos-Ruiz Andrés , Hackl Thomas , Becker Jamie W. , Coe Allison , Biller Steven J. , Berube Paul M. , Chisholm Sallie W.
Published: February 2023

Objectives

The marine cyanobacterium Prochlorococcus is a critical part of warm ocean ecosystems and a model for studying microbial evolution and ecology. To expand the representation of this organism’s vast wild diversity in sequence collections, we performed a set of isolation efforts targeting low light-adapted Prochlorococcus. Three genomes resulting from this larger body of work are described here.

Data description

We present draft-quality Prochlorococcus genomes from enrichment cultures P1344, P1361, and P1363, sampled in the North Pacific. The genomes were built from Illumina paired reads assembled de novo. Supporting datasets of raw reads, assessments, and sequences from co-enriched heterotrophic marine bacteria are also provided. These three genomes represent members of the low light-adapted LLIV Prochlorococcus clade that are closely related, with 99.9% average nucleotide identity between pairs, yet vary in gene content. Expanding the powerful toolkit of Prochlorococcus genomes, these sequences provide an opportunity to study fine-scale variation and microevolutionary processes.
Endovascular repair of aortic pathologies involving the aortic arch using castor stent-graft combined with in-vitro fenestration technology
Authors: Luo Zeng-Rong , Zhang Jia-Xin , Huang Zhong-Yao , Chen Liang-Wan
Published: February 2023

Background

Aortic arch pathologies are concerning clinical conditions with poor prognoses. The use of thoracic endovascular aortic repair (TEVAR) has been investigated to treat aortic arch pathologies. Nonetheless, cerebral blood flow regulation during endovascular aortic arch repair therapy remains challenging. Castor, a unique single-branched stent graft, has been proven effective for retaining the left subclavian artery (LSA). This study aimed to determine whether endovascular therapy for pathologies involving the aortic arch using Castor in combination with the in-vitro fenestration technique is promising, effective, and safe.

Methods

Eligible patients were enrolled between June 2018 and December 2021. All patients underwent TEVAR with an evaluated proximal landing zone for “Castor” located in Ishimaru zones 0–1. Moreover, the supra-aortic branches (SABs) were reconstructed using the Castor in combination with the in-vitro fenestration technique.

Results

Herein, 57 patients with aortic arch lesions were treated with Castor in combination with the in-vitro fenestration technique. Innominate artery and the left carotid artery (LCA) were reconstructed in 5 patients, LCA and left subclavian artery (LSA) were reconstructed in 22 patients, and the total SABs were effectively reconstructed in 30 patients (including a hybrid arch repair case). Among them (excluding a hybrid arch repair case) were in-vitro fenestration methodologies for LCA in 32 of 34 cases (2 switched to in-situ fenestration) and LSA in 51 of 56 cases (3 switched to in-situ fenestration and 2 converted to spring coil caulking); furthermore, LCA and LSA in-vitro fenestration were simultaneously successfully performed in 27 of 34 cases. There were no surgical-related neurological complications, and early mortality was estimated at 5.26%. At a mean follow-up of 3.75 months, computed tomography (CTA) images confirmed that each branch stent remained patent. There were no signs of endoleaks, migrative manifestations, or the need for secondary endovascular intervention or conversion to open surgical procedures.

Conclusion

Castor, in combination with in-vitro fenestration, reflects a feasible, efficient procedure for re-developing SABs.
Unexplained visual loss after primary pars-plana-vitrectomy with silicone oil tamponade in fovea-sparing retinal detachment
Authors: Barth T. , Helbig H. , Maerker D. , Gamulescu M.-A. , Radeck V.
Published: February 2023

Background

To investigate the incidence and clinical characteristics of unexplained visual loss in patients with fovea-sparing rhegmatogenous retinal detachment (RRD) during or after silicone oil (SO) tamponade.

Methods

The medical charts of all patients with macula-on RRDs, who underwent pars-plana-vitrectomy (ppV) with SO tamponade were retrospectively assessed regarding unexplained visual loss (UVL) of ≥ 3 Snellen lines and alterations on optical coherence tomography (OCT) during or after SO tamponade. The clinical data analysed included visual acuity, surgical parameters, OCT images, duration of SO tamponade and the time point of visual decline. Cases with re-detachment or secondary causes of visual loss such as SO emulsification, epiretinal membranes or macular edema were excluded.

Results

Over a 15-year-period, 22 cases with macula-on RRD, which had primarily been treated with ppV and SO tamponade, met the inclusion criteria. In most eyes (n = 20; 91%), the RRD was caused by a giant retinal tear (GRT). In 11 of these 22 cases (50%), best-corrected visual acuity (BCVA) had dropped by at least 3 lines for no apparent reason. In these 11 cases, mean preoperative logMAR BCVA was 0.2 (SD 0.13; range 0-0.5), equal to Snellen’s VA of 0.63, and mean postoperative logMAR BCVA 1.0 (SD 0.24; range 0.5–1.3), equal to Snellen’s VA of 0.10. Visual decline occurred about 12 weeks postoperatively (SD 6.2; range 3–20 ) and comprised 8 lines (SD 2.3; range -11 to -4). SO was removed on average 139 (SD 50.0; range 88–271) days after the first ppV. In 9 cases visual decline occurred while the SO was in-situ. In 2 patients, BCVA decline was noted 2 weeks after SO removal. In all eyes, preoperative central foveal thickness (CFT) was 254 μm (SD 24.2), which decreased to 224 μm (SD 29.6) during SO tamponade and increased to 247 μm (SD 29.2) after SO removal, irrespective of the presence of UVL. The mean follow-up time was 20 months (SD 30.6) after SO removal.

Conclusion

UVL after SO tamponade for macula-on RRD is more frequent than expected. The incidence in our case series was 50%. The mechanism of this phenomenon is still unknown. In general, vitreoretinal surgeons should thoroughly question the need for SO tamponade, inform their patients of possible UVL and remove SO as early as possible.

Trial registration

The study was approved by the local ethics committee on 6th of May 2022 (Ethikkommission der Universität Regensburg, Votum 22-2925-104) and was conducted in accordance with the ethical standards of the Declaration of Helsinki.
Bioinformatic analysis of underlying mechanisms of Kawasaki disease via Weighted Gene Correlation Network Analysis (WGCNA) and the Least Absolute Shrinkage and Selection Operator method (LASSO) regression model
Authors: Xie Yaxue , Shi Hongshuo , Han Bo
Published: February 2023

Background

Kawasaki disease (KD) is a febrile systemic vasculitis involvingchildren younger than five years old. However, the specific biomarkers and precise mechanisms of this disease are not fully understood, which can delay the best treatment time, hence, this study aimed to detect the potential biomarkers and pathophysiological process of KD through bioinformatic analysis.

Methods

The Gene Expression Omnibus database (GEO) was the source of the RNA sequencing data from KD patients. Differential expressed genes (DEGs) were screened between KD patients and healthy controls (HCs) with the “limma” R package. Weighted gene correlation network analysis (WGCNA) was performed to discover the most corresponding module and hub genes of KD. The node genes were obtained by the combination of the least absolute shrinkage and selection operator (LASSO) regression model with the top 5 genes from five algorithms in CytoHubba, which were further validated with the receiver operating characteristic curve (ROC curve). CIBERSORTx was employed to discover the constitution of immune cells in KDs and HCs. Functional enrichment analysis was performed to understand the biological implications of the modular genes. Finally, competing endogenous RNAs (ceRNA) networks of node genes were predicted using online databases.

Results

A total of 267 DEGs were analyzed between 153 KD patients and 92 HCs in the training set, spanning two modules according to WGCNA. The turquoise module was identified as the hub module, which was mainly enriched in cell activation involved in immune response, myeloid leukocyte activation, myeloid leukocyte mediated immunity, secretion and leukocyte mediated immunity biological processes; included type II diabetes mellitus, nicotinate and nicotinamide metabolism, O-glycan biosynthesis, glycerolipid and glutathione metabolism pathways. The node genes included ADM, ALPL, HK3, MMP9 and S100A12, and there was good performance in the validation studies. Immune cell infiltration analysis revealed that gamma delta T cells, monocytes, M0 macrophage, activated dendritic cells, activated mast cells and neutrophils were elevated in KD patients. Regarding the ceRNA networks, three intact networks were constructed: NEAT1/NORAD/XIST-hsa-miR-524-5p-ADM, NEAT1/NORAD/XIST-hsa-miR-204-5p-ALPL, NEAT1/NORAD/XIST-hsa-miR-524-5p/hsa-miR-204-5p-MMP9.

Conclusion

To conclude, the five-gene signature and three ceRNA networks constructed in our study are of great value in the early diagnosis of KD and might help to elucidate our understanding of KD at the RNA regulatory level.
Undernutrition among the children below five years of age in Uganda: a spatial analysis approach
Authors: Maniragaba Vallence Ngabo , Atuhaire Leonard K. , Rutayisire Pierre Claver
Published: February 2023

Background

Undernutrition is a health condition caused by a lack of enough food intake, not having enough of the right combination of food nutrients, or the body’s failure to utilize the food eaten resulting in either, stunting, being underweight, or wasting. Globally, undernutrition affects more than 149 million under-five children, while in Uganda about 3 in every 10 children suffer from undernutrition. Undernutrition and its risk factors among under-five children in Uganda were unevenly distributed across the country and a study that focused on spatial distribution was prudent to examine the nature of the problem and salient factors associated with it. The current study addressed the issues of spatial heterogeneity of undernutrition and its determinants with the goal to identify hot spots and advise policymakers on the best actions to be taken to address the problem.

Methods

Data were obtained from the 2016 Uganda Demographic and Health Survey. Prevalence rates and percentages of risk factors were combined with the Uganda district shape file to allow spatial analysis. Moran’s I, Getis-Ord (GI*), and Geographically Weighted Regressions were respectively used to establish the local, global, and geographically weighted regressions across the country. Stata 15 and ArcGIS 10. 7 soft wares were used.

Results

The results indicate that undernutrition in Uganda shows varies spatially across regions. Evidence of hot spots exists in the Karamoja and Arua regions, cold spot areas exist around the central part of the country while the greatest part of Western Uganda, Northern, and Eastern were not significant.

Conclusion

The study reveals that a variation in the distribution of undernutrition throughout the country. Significant spatial patterns associated with undernutrition as identified through the hotspot and cold spot analysis do exist in Uganda. Programs targeting to reduce the undernutrition of under-five children in Uganda should consider the spatial distribution of undernutrition and its determinants whereby priority should be given to hotspot areas. The spatial intensity of undernutrition and its determinants indicate that focus should be tailored to meet the local needs as opposed to a holistic national approach.
Partial breast reconstruction of 30 cases with peri-mammary artery perforator flaps
Authors: Shen Meiying , Xu Yuhang , Wu Zongyuan , Wang Jiaming , Pan Huawen , Xu Bo
Published: February 2023

Background

Volume replacement is one of the vital techniques of oncoplastic surgery (OPS) when applying breast-conserving surgery. The clinical application of peri-mammary artery perforator flaps for this indication is uneven in China. Here, we describe the results of our clinical experience with peri-mammary artery flaps for partial breast reconstruction.

Methods

In this study, 30 patients underwent partial breast resection for quadrant breast cancer followed by partial breast reconstruction with peri-mammary artery perforator flaps, which included the thoracodorsal artery perforator flap (TDAP), anterior intercostal artery perforator flap (AICAP), lateral intercostal artery perforator flap (LICAP), and lateral thoracic artery perforator flap (LTAP). All the patients’ operation plans were discussed comprehensively and were performed by sticking to every step. The satisfaction outcome was assessed with the extracted version of the BREAST-Q version 2.0, Breast Conserving Therapy Module Preoperative and Postoperative Scales both preoperatively and postoperatively.

Results

According to the study outcomes, the mean flap size was 5.3*4.2*2.8 cm (3.0–7.0*3.0–5.0*1.0–3.5 cm). The mean surgical time was 142 min (100–250 min). No partial flap failure was detected, and no severe complications were observed. Most patients were satisfied with the outcomes regarding the dressing, sexual life, and breast shape postoperation. Furthermore, the sensation of the surgical area, scar satisfaction, and recovery state gradually improved. Overall, LICAP and AICAP had higher scores when different flaps were compared.

Conclusions

Based on this study, we found that peri-mammary artery flaps had significant value in breast-conserving surgery, especially in patients with small or medium-sized breasts. Perforators could be detected by vascular ultrasound before the operation. More than one perforator could be found most of the time. No severe complications occurred when performing a suitable plan, including discussing and recording the operation procedure; the focus of care, the choice for precise and proper perforators, and the mechanism for hiding the scars were all considered and recorded in a specific chart. Patients were satisfied with the reconstruction technique of peri-mammary artery perforator flaps after breast-conserving, and the satisfaction of AICAP and LICAP was higher. In general, this technique is suitable for partial breast reconstruction and has no negative impact on patient satisfaction.
Comparison of the efficacy of dienogest and GnRH-a after endometriosis surgery
Authors: Tang Mingjun , Yang Wenhui , Zhang Haiyan
Published: February 2023

Objective

To compare the efficacy of dienogest and GnRH-a after endometriosis surgery.

Methods

Patients with endometriosis who were admitted to our hospital from December 2020 to March 2022 were randomly collected. A total of 81 patients were collected and divided into 40 cases in the control group and 41 cases in the observation group. Among them, the control group was treated with GnRH-a drug, and the observation group was treated with dienogest (DNG).

Results

The study found that the therapeutic effects of the two drugs were basically the same in patients with endometriosis. The VAS and Kupperman scores of the control group were 0.78 ± 0.8, 3.9 ± 1.84, P < 0.05, respectively; the VAS and Kupperman scores of the observation group were 0.73 ± 0.78, 1.55, respectively ± 1.24, P < 0.05, the difference was statistically significant.In the case of postoperative recurrence, the observation group was better than the control group, with 8 cases of recurrence in the control group and 2 cases of recurrence in the observation group, P < 0.05.

Conclusion

In the comparison of postoperative efficacy of the two drugs on patients with endometriosis, dienogest is better than GnRH-a adjuvant drug in postoperative recurrence, and has a good improvement and application, which is worthy of further promotion in clinical practice.
Why do women walk away from maternal health services in Southwest Ethiopia? A qualitative study of caregivers' and clients' perspectives
Authors: Kitila Sena Belina , Feyissa Garumma Tolu , Wordofa Muluemebet Abera
Published: February 2023

Background

Continuum of care for Maternal Health Care is continuity of care through pregnancy, childbirth, and after birth as a key strategy in reaching mothers and babies at a crucial time. Despite the widespread drop out from the continuum of care, there is limited understanding of perspectives of providers and clients about factors leading to drop out from care among women in Ethiopia.

Objective

The aim of this study is to explore the underlying reasons for which women walk away from maternal health services in Ethiopia care providers' and clients' perspectives.

Methods

The population for the study were comprised of all purposefully selected district health department deputy heads, MCH coordinators, primary health center unit directors, midwives and nurses in charge of maternity department and who have been rendering maternal health services and chosen women among those attending the MCH clinic for maternal health services in order to identify reasons for dropout from the perspective of the service users based on the established criteria. The final sample size was determined based on the level of information saturation and a total of 20 in-depth interviewees were conducted. The unstructured key informant interview (KII) guide was used to collect data to gain an in-depth understanding of the context in which continuum of care for maternal health care takes place and existing barriers.

Result

The main themes were identified and compared across all the transcripts to determine similarities and variations in the views of respondents. The major reasons for which women walk away from maternal health services were categorized under three main themes: healthcare system related reasons, community level barriers and individual level barriers. Interpretive analysis was conducted, and elucidations of the results follow the respective themes and verbatim that capture dominant views were considered wherever appropriate to substantiate the findings.

Conclusion and recommendations

Women were walk away from maternal health services because of health system, community level and individual level factors. Hence, implementing initiatives to improve both providers and clients side barriers are essential. Furthermore, we recommend more large-scale studies to digging out more context specific barriers.
Decreasing reproductive and abortion care barriers: findings on the student health center's role from a student survey
Authors: Rohrer Cynthia D. , Modrek Sepideh
Published: February 2023

Background

College-aged young adults in the US have low utilization and high need for reproductive healthcare. Multiple barriers to reproductive care exist. University Student Health Centers (SHCs) provide varying degrees of reproductive products and services. Recently, California legislated that public university SHCs add medication abortion to their care.

Methods

To examine existing attitudes and barriers to reproductive healthcare for public university students, we conducted an anonymous online survey at a large, diverse, urban coastal California State University. Students were asked about numerous barriers accessing reproductive services in general and at the SHC, which we categorized into three groups: stigma, access and system. Respondents were also asked about knowledge and preferences for accessing and recommending various services. To understand the extent to which inequities exist, we compared differences across racialized/ethnic identity, gender identity, anticipated degree, and living distance from campus using chi-squared tests.

Results

The majority of survey (n = 273) respondents experienced stigma and access barriers in general healthcare settings which made obtaining reproductive healthcare for themselves or their partners difficult (stigma barriers 55%; 95% CI 49%–61%; access barriers 68%; 95% CI 62–73%). Notably, students reported statistically significant lower rates of access barriers at the SHC, 50%, than in general reproductive healthcare settings, 68%. There were limited differences by student demographics. Students also reported a high willingness to use or recommend the SHC for pregnancy tests (73%; 95% CI 67–78%), emergency contraception pills (72%; 95% CI 66–78%) and medication abortion (60%; 95% CI 54–66%). Students were less likely to know where to access medication abortion compared to other services, suggesting unmet need.

Conclusions

Our study provides evidence that students face barriers accessing reproductive healthcare and that SHCs are a trusted and accessible source of this care. SHCs have a key role in increasing health, academic and gender equity in the post-Roe era. Attention and financial support must be paid to SHCs to ensure success as state legislatures mandate them to expand reproductive and abortion care access.
Reliability and validity of the Chinese version of the self-directed learning instrument in Chinese nursing students
Authors: Gao Ziyun , Zhang Lin , Ma Jianing , Sun Hong , Hu Mengya , Wang Meiding , Liu Haiyang , Guo Leilei
Published: February 2023

Background

In a rapidly changing healthcare environment, Self-directed learning (SDL) ability is recognized as a crucial condition for nursing students and nurse to deal with severe challenges positively. Developing SDL ability is becoming more and more important among nursing students. SDL is related to nursing students enhancing their own knowledge, skills and maintaining lifelong learning. This study is aim at translating the Self-directed Learning Instrument (SDLI) into Chinese and verify its reliability and validity among nursing students.

Methods

The study adopted a cross-sectional design and the multistage sampling design. The SDLI was translated into Chinese, and the reliability and validity of the scale were tested among 975 nursing students.

Results

The Cronbach’s α value of the Chinese version of SDLI was 0.916. The split-half reliability coefficient was 0.829, and the retest coefficient was 0.884. The content validity index of the scale was 0.95. Furthermore, the four-factors model was obtained by using exploratory factor analysis, explaining 55.418% variance, and the communalities of the items ranged from 0.401 to 0.664. With modified confirmatory factor analysis, the fit indices were chi-square/degree of freedom (CMIN/DF) = 2.285, the comparative fit index (CFI) = 0.947, and the tucker lewis index (TLI) was 0.938. And, the model fitting indexes were all in the acceptable range and confirmatory factor analysis indicated that the model fit the SDLI well.

Conclusion

The Chinese version of SDLI has good validity and reliability among nursing students. It can be used to measure the SDL ability of nursing students in China.
Consensus recommendations on the role of nurses in the care of headache patients: protocol for a european e-delphi study
Authors: Rasmussen Annette Vangaa , Jensen Rigmor Hoejland , Karlsson Leena Eklund , Mose Louise Schlosser
Published: February 2023

Background

Nurses play an important role in the treatment of headache patients at the specialized headache centers in Europe, however, a unified definition of nursing tasks and conduction of tasks is lacking. The objective of this e-Delphi study is twofold. Initially, to obtain healthcare professional headache experts’ opinions on which tasks are associated with nurses’ care in migraine treatment. Then, through an iterative multi-staged process, to combine the opinions into group consensus statements and develop evident European nursing recommendations for migraine treatment.

Methods

In Delphi studies there are no unambiguous methodological guidelines and this protocol is being published to ensure transparency and quality in the study process. We invite nurses working in specialized headache centers and neurologists co-working with nurses in Finland, Denmark, Norway, Sweden, United Kingdom, Netherlands, Germany, Ireland, Estonia and Switzerland to participate anonymously in the expert panel. This e-Delphi study consists of three rounds of online questionnaires. We use Open-ended questions to capture the essentials of nurse tasks as understood by the expert panel members. Data are analyzed using content analysis. Predefined statements are applied for the experts to rate the importance of nurses’ tasks synthesized from a systematic examination of the existing literature. Consensus is measured using descriptive statistics; median, Interquartile range (IQR) and percentage agreement. Measurement of agreement between participants will be analyzed using inferential statistics; Kendall’s coefficient and stability between rounds; Wilcoxon rank-sum test. Statements, which receive consensus in the third round, are included in the final compilation of European recommendations for nurse care for migraine patients.

Discussion

The e-Delphi study will provide European recommendations on nurse care in migraine treatment, which could not be created on the basis of the existing literature. The recommendations can open for the conduction of further research including measurement of efficacy of clinical implementation of the recommended tasks.

Trial registration

The study is registered at The Region of Southern Denmark (21/52,885). According to The Regional Ethical Committee and Danish law, no additional approval is relevant (20212000-145). A written informed consent is obtained from all participants before inclusion in the study.
Structural and DNA end resection study of the bacterial NurA-HerA complex
Authors: Yang Jieyu , Sun Yiyang , Wang Ying , Hao Wanshan , Cheng Kaiying
Published: February 2023

Background

The nuclease NurA and the ATPase/translocase HerA play a vital role in repair of double-strand breaks (DSB) during the homologous recombination in archaea. A NurA-HerA complex is known to mediate DSB DNA end resection, leading to formation of a free 3′ end used to search for the homologous sequence. Despite the structures of individual archaeal types of NurA and HerA having been reported, there is limited information regarding the molecular mechanisms underlying this process. Some bacteria also possess homologs of NurA and HerA; however, the bacterial type of this complex, as well as the detailed mechanisms underlying the joining of NurA-HerA in DSB DNA end resection, remains unclear.

Results

We report for the first time the crystal structures of Deinococcus radiodurans HerA (drHerA) in the nucleotide-free and ADP-binding modes. A D. radiodurans NurA-HerA complex structure was constructed according to a low-resolution cryo-electron microscopy map. We performed site-directed mutagenesis to map the drNurA-HerA interaction sites, suggesting that their interaction is mainly mediated by ionic links, in contrast to previously characterized archaeal NurA-HerA interactions. The key residues responsible for the DNA translocation activity, DNA unwinding activity, and catalytic activities of the drNurA-HerA complex were identified. A HerA/FtsK-specific translocation-related motif (TR motif) that guarantees the processivity of double-stranded DNA (dsDNA) translocation was identified. Moreover, a mechanism for the translocation-regulated resection of the 5′ tail of broken dsDNA and the corresponding generation of a recombinogenic 3′ single-stranded DNA tail by the drNurA-HerA complex was elucidated.

Conclusions

Our work provides new insights into the mechanism underlying bacterial NurA-HerA-mediated DSB DNA end resection, and the way this complex digests the 5′ tail of a DNA duplex and provides long 3′ free end for strand invasion in the bacterial homologous recombination process.
SGLT-2 inhibitors and in-stent restenosis-related events after acute myocardial infarction: an observational study in patients with type 2 diabetes
Authors: Marfella Raffaele , Sardu Celestino , D’Onofrio Nunzia , Fumagalli Carlo , Scisciola Lucia , Sasso Ferdinando Carlo , Siniscalchi Mario , Marfella Ludovica Vittoria , D’Andrea Davide , Minicucci Fabio , Signoriello Giuseppe , Cesaro Arturo , Trotta Maria Consiglia , Frigé Chiara , Prattichizzo Francesco , Balestrieri Maria Luisa , Ceriello Antonio , Calabrò Paolo , Mauro Ciro , del Viscovo Luca , Paolisso Giuseppe
Published: February 2023

Background

No study evaluated the incidence of intra-stent restenosis (ISR)-related events in patients with type 2 diabetes (T2DM) and acute myocardial infarction (AMI) treated or not with sodium/glucose cotransporter 2 inhibitors (SGLT2i).

Methods

We recruited 377 patients with T2DM and AMI undergoing percutaneous coronary intervention (PCI). Among them, 177 T2DM were treated with SGLT2 inhibitors before PCI. The primary outcome was major adverse cardiovascular events (MACE) defined as cardiac death, re-infarction, and heart failure related to ISR. In patients without ISR, minimal lumen area and minimal lumen diameter were assessed by coronary CT-angiography at 1-year follow-up.

Results

Glycemic control was similar in SGLT2i-treated patients and never SGLT2i-users. The incidence of ISR-related MACE was higher in never SGLT2i-users compared with SGLT2i-treated patients, an effect independent of glycemic status (HR = 0.418, 95% CI = 0.241–0.725, P = 0.002) and observed also in the subgroup of patients with HbA1c < 7% (HR = 0.393, 95% CI = 0.157–0.984, P = 0.027). In patients without the event, the stent patency was greater in SGLT2i-treated patients compared with never SGLT2i-users at 1-year follow-up.

Conclusions

SGLT2i treatment in T2DM is associated with a reduced incidence of ISR-related events, independently of glycemic control.
Women attending antenatal care as a sentinel surveillance population for malaria in Geita region, Tanzania: feasibility and acceptability to women and providers
Authors: Emerson Courtney , Ulimboka Stephen , Lemwayi Ruth , Kinyina Alen , Nhiga Samwel L. , Aaron Sijenunu , Simeo Japhet , Kitojo Chonge , Reaves Erik J. , Drake Mary , Hussein Yahaya , Bungire Leila , Gutman Julie R. , Winch Peter J.
Published: February 2023

Background

Measurement of malaria prevalence is conventionally estimated through infrequent cross-sectional household surveys that do not provide continuous information regarding malaria parasitaemia. Recent studies have suggested that malaria parasitaemia prevalence among women attending antenatal care (ANC) correlates with prevalence among children under 5 years old and that pregnant women could be a sentinel population for tracking malaria prevalence. In mainland Tanzania, 97% of women are tested for malaria parasitaemia during first ANC visits. However, acceptability among pregnant women and healthcare providers of collecting malaria risk factor data during ANC visits is limited.

Methods

A tablet-based questionnaire including 15 questions on insecticide-treated net ownership and use and care-seeking for febrile children was introduced at 40 healthcare facilities in Geita Region, Tanzania. Facilities were randomly selected from among those with 15–120 first ANC visits per month. To assess perspectives regarding introduction of the questionnaire, 21 semi-structured interviews were held with providers and facility in-charges at 12 facilities. Thirty pregnant and recently delivered women participated in focus group discussions at seven facilities to assess the acceptability of spending additional time answering questions about malaria risk.

Results

All pregnant women reported that introduction of ANC surveillance and spending 10 more minutes with providers answering questions about their health would be neutral or beneficial. They perceived being asked about their health as standard of care. Providers and in-charges reported that introduction of ANC surveillance was within their scope of practice. Nine of 21 indicated it could potentially benefit women’s health. Six providers expressed concern about staffing shortages and need for reimbursement for extra time and noted that data management occurs after hours.

Conclusions

Pregnant women and providers generally perceived ANC surveillance for malaria as acceptable and positive. Pregnant and recently delivered women saw this as a reasonable and even helpful intervention. To be seen as a part of standard practice, efforts are needed to ensure providers perceive a benefit for ANC clients and that staffing concerns are addressed. In addition, staff should receive feedback related to data submissions regarding malaria prevalence and risk factors among women at their facility, with actions to take.
Mesenchymal stem cell-released oncolytic virus: an innovative strategy for cancer treatment
Authors: Ghasemi Darestani Nadia , Gilmanova Anna I. , Al-Gazally Moaed E. , Zekiy Angelina O. , Ansari Mohammad Javed , Zabibah Rahman S. , Jawad Mohammed Abed , Al-Shalah Saif A. J. , Rizaev Jasur Alimdjanovich , Alnassar Yasir S. , Mohammed Naseer Mihdi , Mustafa Yasser Fakri , Darvishi Mohammad , Akhavan-Sigari Reza
Published: February 2023

Oncolytic viruses (OVs) infect, multiply, and finally remove tumor cells selectively, causing no damage to normal cells in the process. Because of their specific features, such as, the ability to induce immunogenic cell death and to contain curative transgenes in their genomes, OVs have attracted attention as candidates to be utilized in cooperation with immunotherapies for cancer treatment. This treatment takes advantage of most tumor cells' inherent tendency to be infected by certain OVs and both innate and adaptive immune responses are elicited by OV infection and oncolysis. OVs can also modulate tumor microenvironment and boost anti-tumor immune responses. Mesenchymal stem cells (MSC) are gathering interest as promising anti-cancer treatments with the ability to address a wide range of cancers.
MSCs exhibit tumor-trophic migration characteristics, allowing them to be used as delivery vehicles for successful, targeted treatment of isolated tumors and metastatic malignancies. Preclinical and clinical research were reviewed in this study to discuss using MSC-released OVs as a novel method for the treatment of cancer.
Efficacy and safety of TNF inhibitors in the treatment of juvenile idiopathic arthritis: a systematic literature review
Authors: Horneff Gerd , Minden Kirsten , Rolland Catherine , Daly Ana C. Hernandez , Borlenghi Cecilia , Ruperto Nicolino
Published: February 2023

Objective

A systematic literature review was conducted to summarize efficacy and safety data from studies that evaluated tumor necrosis factor inhibitors in patients with juvenile idiopathic arthritis (JIA).

Methods

Relevant publications were identified via online searches (cutoff: March 16, 2021). After screening search results, outcome data were extracted if the treatment arm included ≥ 30 patients. Outcomes were described narratively, with efficacy assessed by JIA-American College of Rheumatology (ACR) response criteria and safety assessed by the incidence of serious adverse events (SAEs) per 100 patient-years (100PY).

Results

Among 87 relevant publications included in the qualitative synthesis, 19 publications described 13 clinical trials. Across the 13 trials, the percentages of patients who achieved JIA-ACR30/50/70/90 responses at Week 12 with adalimumab ranged 71–94%, 68–90%, 55–61%, and 39–42%, respectively; with etanercept (Week 12), 73–94%, 53–78%, 36–59%, and 28%; with golimumab (Week 16), 89%, 79%, 66%, and 36%; and with infliximab (Week 14), 64%, 50%, and 22% (JIA-ACR90 not reported). SAE incidence across all time points ranged 0–13.7 SAE/100PY for adalimumab, 0–20.0 SAE/100PY for etanercept, and 10.4–24.3 SAE/100PY for golimumab (1 study). SAE incidence could not be estimated from the 2 infliximab publications.

Conclusion

Tumor necrosis factor inhibitors are effective and well tolerated in the treatment of JIA, but additional evidence from head-to-head studies and over longer periods of time, especially in the context of the transition from pediatric to adult care, would be useful.
Old age promotes retinal fibrosis in choroidal neovascularization through circulating fibrocytes and profibrotic macrophages
Authors: Yi Caijiao , Liu Jian , Deng Wen , Luo Chang , Qi Jinyan , Chen Mei , Xu Heping
Published: February 2023

Background

Retinal fibrosis affects 40–70% of neovascular age-related macular degeneration patients. This study investigated the effect of ageing on subretinal fibrosis secondary to choroidal neovascularization and the mechanism of action.

Methods

Subretinal fibrosis was induced in young (2.5-month) and aged (15–16-month) C57BL/6J mice using the two-stage laser protocol. Five and 30 days later, eyes were collected and stained for CD45 and collagen-1 and observed by confocal microscopy. Fibrocytes (CD45+collagen-1+) were detected in the bone marrow (BM), blood and fibrotic lesions by flow cytometry and confocal microscopy, respectively. BM-derived macrophages (BMDMs) were cultured from young and aged mice with or without TGF-β1 (10 ng/mL) treatment. The expression of mesenchymal marker αSMA (Acta2), fibronectin (Fn1) and collagen-1 (Col1a1) was examined by qPCR and immunocytochemistry, whereas cytokine/chemokine production was measured using the Luminex multiplex cytokine assay. BM were transplanted from 22-month (Ly5.2) aged mice into 2.5-month (Ly5.1) young mice and vice versa. Six weeks later, subretinal fibrosis was induced in recipient mice and eyes were collected for evaluation of fibrotic lesion size.

Results

Under normal conditions, the number of circulating fibrocytes (CD45+collagen-1+) and the expression levels of Tgfb1, Col1a1, Acta2 and Fn1 in BMDMs were significantly higher in aged mice compared to young mice. Induction of subretinal fibrosis significantly increased the number of circulating fibrocytes, enhanced the expression of Col1a1, Acta2 and Fn1 and the production of soluble urokinase plasminogen activator surface receptor (suPAR) but decreased the production of CXCL10 in BMDMs. BMDMs from aged subretinal fibrosis mice produced significantly higher levels of VEGF, angiopoietin-2 and osteopontin than cells from young subretinal fibrosis mice. The subretinal fibrotic lesion in 15–16-month aged mice was 62% larger than that in 2.5-month young mice. The lesion in aged mice contained a significantly higher number of fibrocytes compared to that in young mice. The number of circulating fibrocytes positively correlated with the size of subretinal fibrotic lesion. Transplantation of BM from aged mice significantly increased subretinal fibrosis in young mice.

Conclusions

A retina–BM–blood–retina pathway of fibrocyte/macrophage recruitment exists during retinal injury. Ageing promotes subretinal fibrosis through higher numbers of circulating fibrocytes and profibrotic potential of BM-derived macrophages.
Carotid body paraganglioma metastatic to spine causing cord compression: a case report
Authors: Tabb Jazmyne N. , Maas Jared A. , Earla Bhargav P. , Fallon Kenneth B. , McDonald Andrew M. , Dobelbower Michael C.
Published: February 2023

Background

Carotid body tumors (CBTs) are rare neuroendocrine neoplasms arising near the carotid bifurcation with a reported incidence of 1 to 2 cases in 100,000 patients. Most CBTs are sporadic, benign, slow-growing, and non-secreting, but untreated CBTs can grow locally to compress the nearby blood vessels, esophagus, and airway. Regional metastases can occur in 5% to 10% of cases, but distant metastases are exceedingly rare, occurring in roughly 1–2% of cases. As such, the optimal treatment for metastatic CBTs is not well-defined. We report a rare case of a patient with CBT distant metastases causing spinal cord compression.

Case presentation

A 40-year-old African American female presented with a right neck mass, headaches, vertigo, tinnitus, hoarseness, and dysphagia. Imaging demonstrated a Shamblin II right neck mass; subsequent transcervical resection and pathology showed a carotid body paraganglioma. The patient recurred locally near the carotid bifurcation, so she underwent Stereotactic Body Radiation Therapy to the recurrent right neck disease. She later re-presented with new onset bilateral lower extremity weakness, dysmetria, and numbness. She was found to have metastatic disease to the thoracic spine causing spinal cord compression. She underwent laminectomy, tumor resection, and posterior fixation followed by adjuvant radiation therapy. She was started on systemic therapy with sunitinib. She eventually progressed with metastatic disease to the right iliac bone, which was treated with palliative radiotherapy. Second line systemic therapy with capecitabine and temozolomide was started. At last follow up, the patient was asymptomatic with stable persistent disease.

Conclusions

Paragangliomas often exhibit a prolonged interval to the development of progression; locoregional recurrences or rare distant metastases have been reported to occur as many as 20 years from diagnosis. The natural course of CBTs in other cases as well as the present case call into question the idea that CBTs are truly benign; instead CBTs may be indolent tumors with metastatic potential. Treatment choices for CBTs include surgical resection, radiation therapy, and systemic therapy, though the optimal treatment regimen for metastatic CBTs is not well-defined. A more advanced understanding of CBT pathophysiology, disease classification, risk stratification, and treatment options is needed to improve outcomes for patients.
A randomized, double-blind trial comparing the effect of two blood pressure targets on global brain metabolism after out-of-hospital cardiac arrest
Authors: Mølstrøm Simon , Nielsen Troels Halfeld , Nordstrøm Carl-Henrik , Forsse Axel , Møller Søren , Venø Søren , Mamaev Dmitry , Tencer Tomas , Theódórsdóttir Ásta , Krøigård Thomas , Møller Jacob , Hassager Christian , Kjærgaard Jesper , Schmidt Henrik , Toft Palle
Published: February 2023

Purpose

This study aimed to assess the effect of different blood pressure levels on global cerebral metabolism in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA).

Methods

In a double-blinded trial, we randomly assigned 60 comatose patients following OHCA to low (63 mmHg) or high (77 mmHg) mean arterial blood pressure (MAP). The trial was a sub-study in the Blood Pressure and Oxygenation Targets after Out-of-Hospital Cardiac Arrest-trial (BOX). Global cerebral metabolism utilizing jugular bulb microdialysis (JBM) and cerebral oxygenation (rSO2) was monitored continuously for 96 h. The lactate-to-pyruvate (LP) ratio is a marker of cellular redox status and increases during deficient oxygen delivery (ischemia, hypoxia) and mitochondrial dysfunction. The primary outcome was to compare time-averaged means of cerebral energy metabolites between MAP groups during post-resuscitation care. Secondary outcomes included metabolic patterns of cerebral ischemia, rSO2, plasma neuron-specific enolase level at 48 h and neurological outcome at hospital discharge (cerebral performance category).

Results

We found a clear separation in MAP between the groups (15 mmHg, p < 0.001). Cerebral biochemical variables were not significantly different between MAP groups (LPR low MAP 19 (16–31) vs. high MAP 23 (16–33), p = 0.64). However, the LP ratio remained high (> 16) in both groups during the first 30 h. During the first 24 h, cerebral lactate > 2.5 mM, pyruvate levels > 110 µM, LP ratio > 30, and glycerol > 260 µM were highly predictive for poor neurological outcome and death with AUC 0.80. The median (IQR) rSO2 during the first 48 h was 69.5% (62.0–75.0%) in the low MAP group and 69.0% (61.3–75.5%) in the high MAP group, p = 0.16.

Conclusions

Among comatose patients resuscitated from OHCA, targeting a higher MAP 180 min after ROSC did not significantly improve cerebral energy metabolism within 96 h of post-resuscitation care. Patients with a poor clinical outcome exhibited significantly worse biochemical patterns, probably illustrating that insufficient tissue oxygenation and recirculation during the initial hours after ROSC were essential factors determining neurological outcome.