bluuebunny/crossref_metadata_2025 huggingface dataset:
The dilemma of 12/14F ureteral access sheath (UAS) usage: a case control study
Authors: Ozimek Tomasz , Wiessmeyer Judith R. , Struck Julian P. , Roesch Marie C. , Gilbert Nils , Laturnus Jan M. , Merseburger Axel S. , Kramer Mario W.
Published: June 2022

Background

The insertion of a ureteral access sheath (UAS) is a frequent procedure during flexible ureteroscopy (fURS) to facilitate kidney stone treatment. The aim of this study was to investigate the influence of 12/14 French (F) UAS on fURS outcomes.

Methods

We performed a retrospective monocentric analysis of fURS procedures conducted at the Department of Urology (University Hospital Schleswig–Holstein, Lübeck, Germany) for kidney stone treatment via lithotripsy or basket stone retrieval between September 2013 and June 2017. Uni- and multivariate analyses were done with the help of RStudio (Version 1.0.136) software.

Results

In total, 283 consecutive fURS were analyzed. UAS was applied in 98 cases (34.63%). The insertion of UAS was preferred in cases with multiple kidney stones and larger median maximal stone diameter (p < 0.05). UAS usage correlated with elevated radiation exposure in seconds (94 vs. 61; p < 0.0001), prolonged operation time in minutes (99 vs. 66, p < 0.0001), length of hospital stay over 48 h (LOS, 22.49% vs. 10.81%; p = 0.015), more frequent postoperative systemic inflammatory response syndrome (SIRS, 13.27% vs. 4.32%; p = 0.013) and lower postoperative stone-free rates (60.20% vs. 78.92%; p = 0.0013). Moreover, we conducted uni- and multivariate subgroup analysis for cases with multiple kidney stones (≥ 2) and comparable stone burden; UAS was inserted in 48.3% of these cases (71/147). On multivariate logistic regression, UAS insertion was statistically associated with prolonged operation time in minutes (101 vs. 77; p = 0.004). No statistical differences regarding radiation exposure, stone-free rates, postoperative SIRS rates or LOS were noted between UAS and non-UAS patients with multiple kidney stones of similar size (p > 0.05).

Conclusions

12/14F UAS does not seem to improve overall outcomes in fURS for kidney stones. In patients with multiple kidney stones it may be associated with elevated operation time without a clear benefit in terms of improved stone-free status or reduced perioperative complication rate. Further prospective randomized studies to specify the indications for UAS usage are urgently needed.
Fluoroscopy-guided trans-urethral exchange of double-J ureteral stents
Authors: Kwak JungWon , Cho Sung Bum
Published: June 2022

Background

For patients with malignant ureteral obstruction or stricture who require long-term internal drainage, plastic double-J stents (DJ stents) represent the mainstay of therapeutic strategies. DJ stents should be replaced at least once every 6 months to avoid infection or obstruction. Although DJ stents are generally replaced under cystoscopy, successful fluoroscopy-guided retrograde replacement of DJ stents in the interventional suite has been described in the literature.

Methods

Between April 2004 and May 2020, we exchanged 143 DJ stents in 19 male and 22 female patients under fluoroscopic guidance using Nelaton catheters, snare catheters, and 8F DJ stents. All procedures were performed with patients under sedation and local anesthesia. There were 39 patients with malignant ureteral obstruction and two patients with benign ureteral strictures. This study was approved by the Institutional Review Board. Technical success, clinical success, complications, procedure time, and mean interval between two procedures were retrospectively reviewed, and the factors affecting the success rate of the procedure were analyzed.

Results

Obstruction was detected at the abdominal ureter in 4 patients, pelvic ureter in 29 patients, and intravesical ureter in 8 patients. Twenty-six patients underwent two or more sessions of the procedures, whereas 15 patients underwent single-session procedures. Total 34 outpatient-based procedures and 109 inpatient-based procedures were performed. Technical success and clinical success were achieved in 94.4% (135/143) and 93.3% (126/135) procedures, respectively. Mean procedure time was 21.5 min (range 9–192 min). Mean procedure interval was 101.8 days (range 5–306 days). Technical success was negatively affected by male sex and obstruction at the pelvic ureter and was positively affected by previous successful exchange. Left-sided ureteral stent placement and old age negatively influenced clinical success. Septic shock occurred in one patient and was treated with antibiotics.

Conclusion

Fluoroscopy-guided trans-urethral exchange of DJ stents is an effective and less painful procedure.
Use of a specialty endoscopy online platform for continuing medical education for clinical endoscopists during the COVID-19 pandemic
Authors: Li Guofu , Yu Tingting , Zhang Lichao , Du Haiming , Zhang Wei , Hou Senlin
Published: June 2022

Background

To explore the use of a digestive endoscopy professional online platform by domestic endoscopists and its application effect on endoscopists’ continuing medical education, analyse the related problems of continuing medical education using this method, and propose targeted improvement suggestions.

Methods

Based on the “Doctor’s Circle” app, a questionnaire was sent to all members who successfully registered on the Hebei Biliary and Pancreatic Endoscopy Diagnosis and Treatment Alliance online platform. The questionnaire was available for 30 days. The questionnaire survey results were collected and counted for a grouping comparison.

Results

By the deadline, 703 completed questionnaires had been received. After the registered doctors joined the platform, 469 (66.7%) experienced a significant influence on their own endoscopic operation ability level, and 354 (50.3%) felt a significant improvement in their ability to diagnose biliary- and pancreatic-related diseases. The application effect of the platform on members’ continuing medical education was affirmed by the vast majority of registered doctors. The clinical specialty of registered doctors, the length of time they joined the platform, the length of time they participated in the platform activities each time, and whether they played back course videos after the live broadcast of the course on the platform were the main factors affecting the application effect on continuing medical education (P < 0.05). Registered doctors who benefited significantly from the platform used it for 6–12 months, participated in activities for 1–2 hours each time, and often played back course videos.

Conclusion

The new model of continuing medical education based on an online platform breaks through the constraints of traditional models and meets the individualized needs of every medical worker to improve their comprehension level. At present, the global outbreak of COVID-19 makes this learning mode increasingly popular among medical workers. We should constantly improve the organization of the content and methods of continuing medical education courses, make the online platform better serve the majority of medical workers, and effectively improve the comprehension levels of clinicians.
Data quality and associated factors in the health management information system at health centers in Shashogo district, Hadiya zone, southern Ethiopia, 2021
Authors: Getachew Nigusu , Erkalo Bereket , Garedew Muluneh Getachew
Published: June 2022

Background

Poor quality routine data contributes to poor decision-making, inefficient resource allocation, loss of confidence in the health system, and may threaten the validity of impact evaluations. For several reasons in most developing countries, the routine health information systems in those countries are described as ineffective. Hence, the aim of this study is to determine the quality of data and associated factors in the routine health management information system in health centers of Shashogo district, Hadiya Zone.

Methods

A facility-based cross-sectional study was conducted from June 1, 2021, to July 1, 2021, and 300 participants were involved in the study through simple random sampling. The data was collected with a self-administered questionnaire by trained data collectors. After checking its completeness, the data was entered into EPI data version 3.1 and exported to SPSS version 25 for statistical analysis. Finally, variables with p < 0.05 during multivariable analysis were considered significant variables.

Result

A total of 300(100%) participant were included in the interview and HMIS data quality was 83% in Shashogo district health centers. The data quality in terms of accuracy, completeness, and timeliness was 79%, 86%, and 84%, respectively. Conducting supportive supervision [AOR 3.5 (1.4, 8.9)], checking accuracy [AOR 1.3 (1.5, 3.5)], filling registrations [AOR 2.7 (1.44, 7.7)], and confidence level [AOR 1.9 (1.55, 3.35)] were all rated positively found to be factors associated with data quality.

Conclusion

The overall level of data quality in Shashogo district health centers was found to be below the national expectation level. All dimensions of data quality in the district were below 90% in data accuracy, content completeness, and timeliness of data. Conducting supportive supervision, checking accuracy, filling registrations and confidence level were found to be factors associated with data quality. Hence, all stakeholders should give all necessary support to improve data quality in routine health information systems to truly attain the goal of providing good quality data for the decision-making process by considering the identified factors.
A neuromechanical model for Drosophila larval crawling based on physical measurements
Authors: Sun Xiyang , Liu Yingtao , Liu Chang , Mayumi Koichi , Ito Kohzo , Nose Akinao , Kohsaka Hiroshi
Published: June 2022

Background

Animal locomotion requires dynamic interactions between neural circuits, the body (typically muscles), and surrounding environments. While the neural circuitry of movement has been intensively studied, how these outputs are integrated with body mechanics (neuromechanics) is less clear, in part due to the lack of understanding of the biomechanical properties of animal bodies. Here, we propose an integrated neuromechanical model of movement based on physical measurements by taking Drosophila larvae as a model of soft-bodied animals.

Results

We first characterized the kinematics of forward crawling in Drosophila larvae at a segmental and whole-body level. We then characterized the biomechanical parameters of fly larvae, namely the contraction forces generated by neural activity, and passive elastic and viscosity of the larval body using a stress-relaxation test. We established a mathematical neuromechanical model based on the physical measurements described above, obtaining seven kinematic values characterizing crawling locomotion. By optimizing the parameters in the neural circuit, our neuromechanical model succeeded in quantitatively reproducing the kinematics of larval locomotion that were obtained experimentally. This model could reproduce the observation of optogenetic studies reported previously. The model predicted that peristaltic locomotion could be exhibited in a low-friction condition. Analysis of floating larvae provided results consistent with this prediction. Furthermore, the model predicted a significant contribution of intersegmental connections in the central nervous system, which contrasts with a previous study. This hypothesis allowed us to make a testable prediction for the variability in intersegmental connection in sister species of the genus Drosophila.

Conclusions

We generated a neurochemical model based on physical measurement to provide a new foundation to study locomotion in soft-bodied animals and soft robot engineering.
Hematopoietic differentiation persists in human iPSCs defective in de novo DNA methylation
Authors: Cypris Olivia , Franzen Julia , Frobel Joana , Glück Philipp , Kuo Chao-Chung , Schmitz Stephani , Nüchtern Selina , Zenke Martin , Wagner Wolfgang
Published: June 2022

Background

DNA methylation is involved in the epigenetic regulation of gene expression during developmental processes and is primarily established by the DNA methyltransferase 3A (DNMT3A) and 3B (DNMT3B). DNMT3A is one of the most frequently mutated genes in clonal hematopoiesis and leukemia, indicating that it plays a crucial role for hematopoietic differentiation. However, the functional relevance of Dnmt3a for hematopoietic differentiation and hematological malignancies has mostly been analyzed in mice, with the specific role for human hematopoiesis remaining elusive. In this study, we therefore investigated if DNMT3A is essential for hematopoietic differentiation of human induced pluripotent stem cells (iPSCs).

Results

We generated iPSC lines with knockout of either exon 2, 19, or 23 and analyzed the impact of different DNMT3A exon knockouts on directed differentiation toward mesenchymal and hematopoietic lineages. Exon 19−/− and 23−/− lines displayed an almost entire absence of de novo DNA methylation during mesenchymal and hematopoietic differentiation. Yet, differentiation efficiency was only slightly reduced in exon 19−/− and rather increased in exon 23−/− lines, while there was no significant impact on gene expression in hematopoietic progenitors (iHPCs). Notably, DNMT3A−/− iHPCs recapitulate some DNA methylation patterns of acute myeloid leukemia (AML) with DNMT3A mutations. Furthermore, multicolor genetic barcoding revealed growth advantage of exon 23−/− iHPCs in a syngeneic competitive differentiation assay.

Conclusions

Our results demonstrate that iPSCs with homozygous knockout of different exons of DNMT3A remain capable of mesenchymal and hematopoietic differentiation—and exon 23−/− iHPCs even gained growth advantage—despite loss of almost the entire de novo DNA methylation. Partial recapitulation of DNA methylation patterns of AML with DNMT3A mutations by our DNMT3A knockout iHPCs indicates that our model system can help to elucidate mechanisms of clonal hematopoiesis.
DEPDC1B collaborates with GABRD to regulate ESCC progression
Authors: Yuan Yunfeng , Ping Wei , Zhang Ruijie , Hao Zhipeng , Zhang Ni
Published: June 2022

Background

Esophageal squamous cell carcinoma (ESCC) is the leading cause of cancer-related death worldwide with a poor prognosis. Given that DEPDC1B plays a key role in multiple cancers, the role of this molecule in ESCC was explored to identify potential targets for ESCC patients.

Method

The expression level of DEPDC1B in ESCC was revealed based on the TCGA database and immunohistochemical experiments on clinical tissues. The correlation between DEPDC1B and survival of ESCC patients was analyzed by Kaplan–Meier method. Small hairpin RNA (shRNA)-mediated silencing of DEPDC1B expression in ESCC cells and performed a series of in vitro and in vivo functional validations.

Result

DEPDC1B was overexpressed in ESCC. High expression of DEPDC1B was significantly negatively correlated with overall survival in patients with ESCC. Moreover, knockdown of DEPDC1B inhibited ESCC cell proliferation, clone formation, migration, tumor formation and promoted apoptosis. Furthermore, knockdown of DEPDC1B leaded to significant downregulation of GABRD in ESCC cells. Meanwhile, GABRD expression was upregulated in ESCC, and its silencing can inhibit the proliferation and migration of the tumor cells. Interestingly, there was a protein interaction between DEPDC1B and GABRD. Functionally, GABRD knockdown partially reversed the contribution of DEPDC1B to ESCC progression. In addition, GABRD regulated ESCC progression may depend on PI3K/AKT/mTOR signaling pathway.

Conclusion

DEPDC1B collaborated with GABRD to regulate ESCC progression, and inhibition of this signaling axis may be a potential therapeutic target for ESCC.
A perspective on the diagnosis of cracked tooth: imaging modalities evolve to AI-based analysis
Authors: Guo Juncheng , Wu Yuyan , Chen Lizhi , Long Shangbin , Chen Daqi , Ouyang Haibing , Zhang Chunliang , Tang Yadong , Wang Wenlong
Published: June 2022

Despite numerous clinical trials and pre-clinical developments, the diagnosis of cracked tooth, especially in the early stages, remains a challenge. Cracked tooth syndrome is often accompanied by dramatic painful responses from occlusion and temperature stimulation, which has become one of the leading causes for tooth loss in adults. Current clinical diagnostical approaches for cracked tooth have been widely investigated based on X-rays, optical light, ultrasound wave, etc. Advances in artificial intelligence (AI) development have unlocked the possibility of detecting the crack in a more intellectual and automotive way. This may lead to the possibility of further enhancement of the diagnostic accuracy for cracked tooth disease. In this review, various medical imaging technologies for diagnosing cracked tooth are overviewed. In particular, the imaging modality, effect and the advantages of each diagnostic technique are discussed. What’s more, AI-based crack detection and classification methods, especially the convolutional neural network (CNN)-based algorithms, including image classification (AlexNet), object detection (YOLO, Faster-RCNN), semantic segmentation (U-Net, Segnet) are comprehensively reviewed. Finally, the future perspectives and challenges in the diagnosis of the cracked tooth are lighted.
Biomimetic and temporal-controlled nanocarriers with ileum transporter targeting for achieving oral administration of chemotherapeutic drugs
Authors: Liu Wei , Han Ying , Xin Xin , Chen Liqing , Liu Yanhong , Liu Chao , Zhang Xintong , Jin Mingji , Jin Jingzhe , Gao Zhonggao , Huang Wei
Published: June 2022

Background

Oral chemotherapy is preferred for patients with cancer owing to its multiple advantages, including convenience, better patient compliance, and improved safety. Nevertheless, various physical barriers exist in this route that hamper the development of oral chemotherapeutic formulations, including destruction of drugs in the gastrointestinal tract (GIT), low permeability in enterocytes, and short residence time in the intestine. To overcome these limitations, it is necessary to design an efficient oral drug delivery system with high efficacy and improved safety.

Results

Herein, we designed novel glycocholic acid (GCA)-functionalized double layer nanoparticles (GCA-NPs), which can act via an endogenous pathway and in a temporally controlled manner in the intestine, to enhance the oral bioavailability of hydrophobic chemotherapeutic drugs such as paclitaxel (PTX). GCA-NPs were composed of quercetin (Qu)-modified liposomes (QL) coated with GCA-chitosan oligosaccharide conjugate (GCOS). The GCA-NPs thus prepared showed prolonged intestinal retention time and good GIT stability due to the presence of chitosan oligosaccharide (COS) and enhanced active transportation via intestinal apical sodium-dependent bile acid transporter (ASBT) due to the presence of GCA. GCA-NPs also efficiently inhibited intestinal P-gp induced by Qu. PTX-loaded GCA-NPs (PTX@GCA-NPs) had a particle size of 84 nm and an entrapment efficiency of 98% with good stability. As a result, the oral bioavailability of PTX was increased 19-fold compared to that of oral Taxol® at the same dose. Oral PTX@GCA-NPs displayed superior antitumor efficacy and better safety than Taxol® when administered intravenously.

Conclusions

Our novel drug delivery system showed remarkable efficacy in overcoming multiple limitations and is a promising carrier for oral delivery of multiple drugs, which addresses several challenges in oral delivery in the clinical context.

Graphical Abstract
NEK2 promotes the migration and proliferation of ESCC via stabilization of YAP1 by phosphorylation at Thr-143
Authors: Su Wei , Hu Hao , Ding Qiurong , Wang Min , Zhu Yan , Zhang Zhaochao , Geng Zihan , Lin Shengli , Zhou Pinghong
Published: June 2022

Background

Esophageal Squamous Cell Carcinoma (ESCC) was characterized as a regional-prevalent and aggressive tumor with high morbidity and mortality. NIMA-related kinase 2 (NEK2) is an interesting oncogene, the alteration of which leads to patients-beneficial outcomes. We aimed to explore the role of NEK2 in ESCC and excavate its mechanism.

Methods

RNA-seq data were downloaded from TCGA and GEO and analyzed by R software. The protein levels were detected by immunohistochemistry (IHC) or western blot (WB), and mRNA expression was detected by qRT-PCR. The in vitro role of proliferation and migration was detected by Transwell migration assay and by colony formation assay, respectively. The in vivo roles were explored using a subcutaneous xenograft tumor model, where immunofluorescence (IF) and IHC were employed to investigate expression and localization. The interaction between proteins was detected by immunoprecipitation. The stability of proteins was measured by WB in the presence of cycloheximide.

Results

A higher level of NEK2 was found in ESCC than normal esophageal epithelia in GEO, TCGA, and tissue microarray, which was associated with worse prognoses. The NEK2 knockdown impaired the proliferation and migration of ESCC, which also downregulated YAP1 and EMT markers like N-cadherin and Vimentin in vitro. On the contrary, NEK2 overexpression enhanced the migration of ESCC and elevated the levels of YAP1, N-cadherin, and Vimentin. Additionally, the overexpression of YAP1 in NEK2 knocked down ESCCs partly rescued the corresponding decrease in migration. The knockdown of NEK2 played an anti-tumor role in vivo and was accompanied by a lower level and nucleus shuffling of YAP1. In mechanism, NEK2 interacted with YAP1 and increased the stability of both endogenous and exogenous YAP1 by preventing ubiquitination. Moreover, the computer-predicted phosphorylation site of YAP1, Thr-143, reduced the ubiquitination of HA-YAP1, strengthened its stability, and thus influenced the migration in vitro.

Conclusions

NEK2 is a prognostic oncogene highly expressed in ESCC and promotes the progression of ESCC in vitro and in vivo. Mechanistically, NEK2-mediated phosphorylation of YAP1 at Thr-143 protects it from proteasome degradation and might serve as a promising therapeutic target in ESCC.
Rationale and design of interleukin-1 blockade in recently decompensated heart failure (REDHART2): a randomized, double blind, placebo controlled, single center, phase 2 study
Authors: Van Tassell Benjamin , Mihalick Virginia , Thomas Georgia , Marawan Amr , Talasaz Azita H. , Lu Juan , Kang Le , Ladd Amy , Damonte Juan Ignacio , Dixon Dave L. , Markley Roshanak , Turlington Jeremy , Federmann Emily , Del Buono Marco Giuseppe , Biondi-Zoccai Giuseppe , Canada Justin M. , Arena Ross , Abbate Antonio
Published: June 2022

Background

Heart failure (HF) is a global leading cause of mortality despite implementation of guideline directed therapy which warrants a need for novel treatment strategies. Proof-of-concept clinical trials of anakinra, a recombinant human Interleukin-1 (IL-1) receptor antagonist, have shown promising results in patients with HF.

Method

We designed a single center, randomized, placebo controlled, double-blind phase II randomized clinical trial. One hundred and two adult patients hospitalized within 2 weeks of discharge due to acute decompensated HF with reduced ejection fraction (HFrEF) and systemic inflammation (high sensitivity of C-reactive protein > 2 mg/L) will be randomized in 2:1 ratio to receive anakinra or placebo for 24 weeks. The primary objective is to determine the effect of anakinra on peak oxygen consumption (VO2) measured at cardiopulmonary exercise testing (CPX) after 24 weeks of treatment, with placebo-corrected changes in peak VO2 at CPX after 24 weeks (or longest available follow up). Secondary exploratory endpoints will assess the effects of anakinra on additional CPX parameters, structural and functional echocardiographic data, noninvasive hemodynamic, quality of life questionnaires, biomarkers, and HF outcomes.

Discussion

The current trial will assess the effects of IL-1 blockade with anakinra for 24 weeks on cardiorespiratory fitness in patients with recent hospitalization due to acute decompensated HFrEF.

Trial registration: The trial was registered prospectively with ClinicalTrials.gov on Jan 8, 2019, identifier NCT03797001.
Neoadjuvant immunotherapy across cancers: meeting report from the Immunotherapy Bridge—December 1st–2nd, 2021
Authors: Burton Elizabeth M. , Amaria Rodabe N. , Cascone Tina , Chalabi Myriam , Gross Neil D. , Mittendorf Elizabeth A. , Scolyer Richard A. , Sharma Padmanee , Ascierto Paolo A.
Published: June 2022

After the success of immunotherapy in the treatment of advanced metastatic cancer, further evaluation in earlier settings, including high-risk, surgically-resectable disease is underway. Potential benefits of a neoadjuvant immunotherapeutic approach include presurgical tumor shrinkage, reduced surgical morbidity, early eradication of micrometastases and prevention of distant disease, and greater antigen-specific T cell response. For some cancers, pathologic response has been established as a surrogate measure for long-term outcomes, therefore offering the ability for early and objective assessment of treatment efficacy and the potential to inform and personalize adjuvant treatment clinical decision-making. Leveraging the neoadjuvant treatment setting offers the ability to deeply interrogate longitudinal tissue in order to gain translatable, pan-malignancy insights into response and mechanisms of resistance to immunotherapy. Neoadjuvant immunotherapy across cancers was a focus of discussion at the virtual Immunotherapy Bridge meeting (December 1–2, 2021). Clinical, biomarker, and pathologic insights from prostate, breast, colon, and non-small-cell lung cancers, melanoma and non-melanoma skin cancers were discussed and are summarized in this report.
Microglial amyloid beta clearance is driven by PIEZO1 channels
Authors: Jäntti Henna , Sitnikova Valeriia , Ishchenko Yevheniia , Shakirzyanova Anastasia , Giudice Luca , Ugidos Irene F. , Gómez-Budia Mireia , Korvenlaita Nea , Ohtonen Sohvi , Belaya Irina , Fazaludeen Feroze , Mikhailov Nikita , Gotkiewicz Maria , Ketola Kirsi , Lehtonen Šárka , Koistinaho Jari , Kanninen Katja M. , Hernández Damian , Pébay Alice , Giugno Rosalba , Korhonen Paula , Giniatullin Rashid , Malm Tarja
Published: June 2022

Background

Microglia are the endogenous immune cells of the brain and act as sensors of pathology to maintain brain homeostasis and eliminate potential threats. In Alzheimer's disease (AD), toxic amyloid beta (Aβ) accumulates in the brain and forms stiff plaques. In late-onset AD accounting for 95% of all cases, this is thought to be due to reduced clearance of Aβ. Human genome-wide association studies and animal models suggest that reduced clearance results from aberrant function of microglia. While the impact of neurochemical pathways on microglia had been broadly studied, mechanical receptors regulating microglial functions remain largely unexplored.

Methods

Here we showed that a mechanotransduction ion channel, PIEZO1, is expressed and functional in human and mouse microglia. We used a small molecule agonist, Yoda1, to study how activation of PIEZO1 affects AD-related functions in human induced pluripotent stem cell (iPSC)-derived microglia-like cells (iMGL) under controlled laboratory experiments. Cell survival, metabolism, phagocytosis and lysosomal activity were assessed using real-time functional assays. To evaluate the effect of activation of PIEZO1 in vivo, 5-month-old 5xFAD male mice were infused daily with Yoda1 for two weeks through intracranial cannulas. Microglial Iba1 expression and Aβ pathology were quantified with immunohistochemistry and confocal microscopy. Published human and mouse AD datasets were used for in-depth analysis of PIEZO1 gene expression and related pathways in microglial subpopulations.

Results

We show that PIEZO1 orchestrates Aβ clearance by enhancing microglial survival, phagocytosis, and lysosomal activity. Aβ inhibited PIEZO1-mediated calcium transients, whereas activation of PIEZO1 with a selective agonist, Yoda1, improved microglial phagocytosis resulting in Aβ clearance both in human and mouse models of AD. Moreover, PIEZO1 expression was associated with a unique microglial transcriptional phenotype in AD as indicated by assessment of cellular metabolism, and human and mouse single-cell datasets.

Conclusion

These results indicate that the compromised function of microglia in AD could be improved by controlled activation of PIEZO1 channels resulting in alleviated Aβ burden. Pharmacological regulation of these mechanoreceptors in microglia could represent a novel therapeutic paradigm for AD.
Reduced microglia activation following metformin administration or microglia ablation is sufficient to prevent functional deficits in a mouse model of neonatal stroke
Authors: Bourget Clara , Adams Kelsey V. , Morshead Cindi M.
Published: June 2022

Background

Neonatal stroke is a devastating insult that can lead to life-long impairments. In response to hypoxic–ischaemic injury, there is loss of neurons and glia as well as a neuroinflammatory response mediated by resident immune cells, including microglia and astrocytes, which can exacerbate damage. Administration of the antidiabetic drug metformin has been shown to improve functional outcomes in preclinical models of brain injury and the cellular basis for metformin-mediated recovery is unknown. Given metformin’s demonstrated anti-inflammatory properties, we investigated its role in regulating the microglia activation and used a microglia ablation strategy to investigate the microglia-mediated outcomes in a mouse model of neonatal stroke.

Methods

Hypoxia-ischaemia (H-I) was performed on post-natal day 8. Metformin was administered for one week, starting one day after injury. Immunohistochemistry was used to examine the spatiotemporal response of microglia and astrocytes after hypoxia-ischaemia, with or without metformin treatment. To evaluate the effects of microglia depletion after hypoxia-ischaemia, we delivered Plexxikon 5622 for 1 or 2 weeks post-injury. The regional pattern of microglia and astrocyte depletion was assessed through immunohistochemistry. Motor behaviour was assessed with the righting reflex, hindlimb suspension, grip strength and cylinder tests.

Results

Herein, we revealed a spatiotemporally regulated response of microglia and astrocytes after hypoxia-ischaemia. Metformin treatment after hypoxia-ischaemia had no effect on microglia number and proliferation, but significantly reduced microglia activation in all regions examined, concomitant with improved behavioural outcomes in injured mice. Plexxikon 5622 treatment successfully ablated microglia, resulting in a > 90% depletion in microglia in the neonatal brain. Microglia rapidly repopulated upon treatment cessation of Plexxikon. Most interesting, microglia ablation was sufficient to reduce functional deficits after hypoxia-ischaemia, mimicking the effects of 1 week of metformin treatment post-injury.

Conclusion

These results highlight the importance of regulating the neuroinflammatory response after neonatal stroke to promote recovery.
Superior control of inflammatory pain by corticotropin-releasing factor receptor 1 via opioid peptides in distinct pain-relevant brain areas
Authors: Mousa Shaaban A. , Khalefa Baled I. , Shaqura Mohammed , Al-Madol Mohammed , Treskatsch Sascha , Schäfer Michael
Published: June 2022

Background

Under inflammatory conditions, the activation of corticotropin-releasing factor (CRF) receptor has been shown to inhibit pain through opioid peptide release from immune cells or neurons. CRF’s effects on human and animal pain modulation depend, however, on the distribution of its receptor subtypes 1 and 2 (CRF-R1 and CRF-R2) along the neuraxis of pain transmission. The objective of this study is to investigate the respective role of each CRF receptor subtype on centrally administered CRF-induced antinociception during inflammatory pain.

Methods

The present study investigated the role of intracerebroventricular (i.c.v.) CRF receptor agonists on nociception and the contribution of cerebral CRF-R1 and/or CRF-R2 subtypes in an animal model of Freund’s complete adjuvant (FCA)-induced hind paw inflammation. Methods used included behavioral experiments, immunofluorescence confocal analysis, and reverse transcriptase-polymerase chain reaction.

Results

Intracerebroventricular, but systemically inactive, doses of CRF elicited potent, dose-dependent antinociceptive effects in inflammatory pain which were significantly antagonized by i.c.v. CRF-R1-selective antagonist NBI 27914 (by approximately 60%) but less by CRF-R2-selective antagonist K41498 (by only 20%). In line with these findings, i.c.v. administration of CRF-R1 agonist stressin I produced superior control of inflammatory pain over CRF-R2 agonist urocortin-2. Intriguingly, i.c.v. opioid antagonist naloxone significantly reversed the CRF as well as CRF-R1 agonist-elicited pain inhibition. Consistent with existing evidence of high CRF concentrations in brain areas such as the thalamus, hypothalamus, locus coeruleus, and periaqueductal gray following its i.c.v. administration, double-immunofluorescence confocal microscopy demonstrated primarily CRF-R1-positive neurons that expressed opioid peptides in these pain-relevant brain areas. Finally, PCR analysis confirmed the predominant expression of the CRF-R1 over CRF-R2 in representative brain areas such as the hypothalamus.

Conclusion

Taken together, these findings suggest that CRF-R1 in opioid-peptide-containing brain areas plays an important role in the modulation of inflammatory pain and may be a useful therapeutic target for inflammatory pain control.
Individual experience influences reconstruction of division of labour under colony disturbance in a queenless ant species
Authors: Tanaka Yasunari , Hojo Masaru K. , Shimoji Hiroyuki
Published: June 2022

Background

Division of labour (DOL) is ubiquitous across biological hierarchies. In eusocial insects, DOL is often characterized by age-related task allocation, but workers can flexibly change their tasks, allowing for DOL reconstruction in fluctuating environments. Behavioural change driven by individual experience is regarded as a key to understanding this task flexibility. However, experimental evidence for the influence of individual experience is remains sparse. Here we tested the effect of individual experience on task choice in the queenless ponerine ant, Diacamma cf. indicum from Japan.

Results

We confirmed that both nurses and foragers shifted to vacant tasks when the colony composition was biased to one or the other. We also found that nurses which are induced to forage readily revert to nursing when reintroduced into balanced colonies. In contrast, foragers which are induced to revert to nursing very rarely return to a foraging role, even 19 days post reintroduction to their original colony.

Conclusions

Taken together, our results suggest that individual experience decreases the response threshold of original foragers, as they continue to be specialist nurses in a disturbed colony. However, original nurses do not appear strongly affected by having forager experience and revert to being nurses. Therefore, while individual experience does have an effect, other factors, such as reproductive ability, are clearly required to understand DOL maintenance in fluctuating environments.
Murine in utero exposure to simulated complex urban air pollution disturbs offspring gut maturation and microbiota during intestinal suckling-to-weaning transition in a sex-dependent manner
Authors: Guilloteau Eva , Coll Patrice , Lu Zhuyi , Djouina Madjid , Cazaunau Mathieu , Waxin Christophe , Bergé Antonin , Caboche Ségolène , Gratien Aline , Al Marj Elie , Hot David , Dubuquoy Laurent , Launay David , Vignal Cécile , Lanone Sophie , Body-Malapel Mathilde
Published: June 2022

Background

Emerging data indicate that prenatal exposure to air pollution may lead to higher susceptibility to several non-communicable diseases. Limited research has been conducted due to difficulties in modelling realistic air pollution exposure. In this study, pregnant mice were exposed from gestational day 10–17 to an atmosphere representative of a 2017 pollution event in Beijing, China. Intestinal homeostasis and microbiota were assessed in both male and female offspring during the suckling-to-weaning transition.

Results

Sex-specific differences were observed in progeny of gestationally-exposed mice. In utero exposed males exhibited decreased villus and crypt length, vacuolation abnormalities, and lower levels of tight junction protein ZO-1 in ileum. They showed an upregulation of absorptive cell markers and a downregulation of neonatal markers in colon. Cecum of in utero exposed male mice also presented a deeply unbalanced inflammatory pattern. By contrast, in utero exposed female mice displayed less severe intestinal alterations, but included dysregulated expression of Lgr5 in colon, Tjp1 in cecum, and Epcam, Car2 and Sis in ileum. Moreover, exposed female mice showed dysbiosis characterized by a decreased weighted UniFrac β-diversity index, a higher abundance of Bacteroidales and Coriobacteriales orders, and a reduced Firmicutes/Bacteroidetes ratio.

Conclusion

Prenatal realistic modelling of an urban air pollution event induced sex-specific precocious alterations of structural and immune intestinal development in mice.
The impact of neoliberal generative mechanisms on Indigenous health: a critical realist scoping review
Authors: Poirier Brianna , Sethi Sneha , Haag Dandara , Hedges Joanne , Jamieson Lisa
Published: June 2022

The pervasive nature and colonial foundations of neoliberalism has significant ramifications for Indigenous health, globally. Not only does neoliberalism undermine Indigenous collectivist values by emphasising personal autonomy, but the exploitation of natural resources has unique implications for Indigenous wellbeing. Therefore, this scoping review aims to synthesise evidence that articulates the impacts of neoliberalism on global Indigenous health inequities. Two reviewers searched PubMed, Embase, Scopus, Web of Science, and ProQuest Central to identify records eligible for inclusion. The search was not restricted by geographic location or language. Using principles of qualitative meta-aggregation, generative mechanism summaries and illustrations were extracted from each of the included articles, synthesised into broader categories, then considered in the context of neoliberal ideologies. The systematic search identified 9952 unique records, of which 38 fully satisfied the inclusion criteria. Findings represented 23 Indigenous communities across 12 countries and considered the impacts of neoliberalism across 16 health outcomes. Eighty-eight generative mechanisms of neoliberalism and 12 generative mechanisms of resistance were extracted from the included articles and mapped against four core principles of neoliberalism: competitive and private markets, reduced public expenditure on infrastructure, personal autonomy, and deregulation that facilitates economic activity. Overwhelmingly, neoliberalism has manifest impacts, through various pathways, on poor health outcomes and experiences for Indigenous communities included in this review. Importantly, Indigenous communities continue to resist the impacts of neoliberalism through advocacy, reclamation of traditional practices, and opposition to industrial development. Consideration and investigation of neoliberal structures and ideologies must become common practice in health equity scholarship. Actors within neoliberal societies must resist dominant epistemological, ontological, and praxiological stances that reinforce the supremacy of colonial values and subalternation of Indigenous ways of knowing, being, and doing to begin effectively addressing Indigenous health inequities.
Breastfeeding and humanitarian emergencies: the experiences of pregnant and lactating women during the earthquake in Abruzzo, Italy
Authors: Giusti Angela , Marchetti Francesca , Zambri Francesca , Pro Elide , Brillo Eleonora , Colaceci Sofia
Published: June 2022

Background

Emergencies have a great impact on infant and young child feeding. Despite the evidence, the recommended feeding practices are often not implemented in the emergency response, undermining infant and maternal health. The aim of this study was to explore the experiences of pregnant and lactating women during the earthquake emergency that occurred in L’Aquila on 6 April 2009.

Methods

The study design was qualitative descriptive. Data were collected by individual semi-structured interviews, investigating the mother’s experiences of pregnancy, childbirth, breastfeeding, infant formula or complementary feeding during the emergency and the post emergency phase. Data analysis was categorical and was performed by using N-Vivo software.

Results

Six women who were pregnant at the time of the earthquake were interviewed in January 2010. In addition to the essential needs of pregnant and lactating women, such as those related to the emergency shelters conditions, the main findings emerged from this study were: the reconfiguration of relationships and the central role of partners and family support; the need of spaces for sharing experiences and practices with other mothers; the lack of breastfeeding support after the hospital discharge; the inappropriate donations and distribution of Breast Milk Substitutes.

Conclusions

During and after L’Aquila earthquake, several aspects of infant and young child feeding did not comply with standard practices and recommendations. The response system appeared not always able to address the specific needs of pregnant and lactating women. It is urgent to develop management plans, policies and procedures and provide communication, sensitization, and training on infant and young child feeding at all levels and sectors of the emergency response.
Healing of joint capsule after hip arthroscopy using interportal capsulotomy and capsular closure influences clinical outcomes
Authors: Gao Guanying , Jiao Chenbo , Liu Jiayang , Zhou Chang , Liu Yuhao , Ao Yingfang , Xu Yan
Published: June 2022

Background

Hip arthroscopy for treatment of femoroacetabular impingement (FAI) has developed rapidly and has been shown to significantly decrease pain and improve hip function. However, the relationship between hip capsule characteristics and healing after arthroscopic surgery and changes in patient-reported outcomes scores (PROs) for postoperative pain, function, and symptoms is still uncertain.

Methods

We retrospectively evaluated consecutive patients who were diagnosed with FAI and underwent hip arthroscopy for treatment in our hospital between May 2018 and November 2020. All patients had preoperative MRI and postoperative MRI at least 6 months after arthroscopy. Hip capsular thickness was measured at the proximal, middle, and distal site of the capsule. PROs and PROs at final follow-up were obtained, including visual analog scale (VAS) for pain and modified Harris Hip Score (mHHS).

Results

A total of 194 patients were included in this study. The mean MRI follow-up time was 14.3 (range, 6–37) months, and the mean clinical follow-up time was 26.1 (range, 12–43) months. Postoperative capsular thickness or net change were not correlated with postoperative PROs and VAS (P > .05). Capsular defect was observed in 17 (8.8%) patients. Patients with capsular defect had a relatively higher BMI (P < .05). Patients with capsular defect had a significant lower mHHS and higher VAS compared with patients with continuous capsule (P < .05). Ninety-one percentage of patients with continuous capsule surpassed minimal clinically important difference (MCID) and 80.8% achieved PASS, but only 58.8% of patients with capsular defect surpassed MCID and 47.1% achieved patient acceptable symptom state (PASS).

Conclusions

Postoperative capsular thickness may not have influence on the clinical outcomes of hip arthroscopy for treatment of FAI. Some capsule of patients who underwent arthroscopic interportal capsulotomy and repair could not heal. Postoperative capsular continuity had a great impact on the clinical outcomes of hip arthroscopy for FAI. Patients with higher BMI may be more likely to have capsule failure to heal.
Templated freezing: a simple method may increase gripping force of the clamp on the tendon
Authors: Wang T. , Yu H.
Published: June 2022

Purpose

To evaluate the effectiveness of combining a customized mold with frozen conventional clamps against other freezing and non-freezing methods.

Methods

Forty-five porcine and 45 chicken tendons were evenly divided into five groups (n = 9 + 9/group): control group, non-freezing with gauze placed between tendon and clamp (gauze), non-freezing with suture fixation at tendon ends (suture), freezing with dry ice pocket placed at the clamps (pocket), and freezing using a templated liquid nitrogen clamp with a customized mold (mold). Tension tests were used to measure failure modes and loads.

Result

Slippage and avulsion were observed in non-freezing groups with significantly lower failure loads compared to freezing methods. With freezing, rupture occurred near the central point only in the mold group. The failure loads for porcine tendons in the mold group were higher (2121.651 ± 73.101 N) than the pocket group (1746.337 ± 68.849 N). The failure loads of chicken tendons in the mold (243.552 ± 15.881 N) and pocket groups (260.647 ± 22.161 N) were not statistically different.

Conclusion

Freezing clamps represent the better choice for soft tissue clamping. The customized mold method could improve gripping effectiveness.
Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4
Authors: Wang Shaowei , Li Boyang , Solomon Victoria , Fonteh Alfred , Rapoport Stanley I. , Bennett David A. , Arvanitakis Zoe , Chui Helena C. , Sullivan Patrick M. , Yassine Hussein N.
Published: June 2022

Background

Apolipoprotein E4 (APOE4) is associated with a greater response to neuroinflammation and the risk of developing late-onset Alzheimer’s disease (AD), but the mechanisms for this association are not clear. The activation of calcium-dependent cytosolic phospholipase A2 (cPLA2) is involved in inflammatory signaling and is elevated within the plaques of AD brains. The relation between APOE4 genotype and cPLA2 activity is not known.

Methods

Mouse primary astrocytes, mouse and human brain samples differing by APOE genotypes were collected for measuring cPLA2 expression, phosphorylation, and activity in relation to measures of inflammation and oxidative stress.

Results

Greater cPLA2 phosphorylation, cPLA2 activity and leukotriene B4 (LTB4) levels were identified in ApoE4 compared to ApoE3 in primary astrocytes, brains of ApoE-targeted replacement (ApoE-TR) mice, and in human brain homogenates from the inferior frontal cortex of persons with AD dementia carrying APOE3/4 compared to APOE3/3. Higher phosphorylated p38 MAPK but not ERK1/2 was found in ApoE4 primary astrocytes and mouse brains than that in ApoE3. Greater cPLA2 translocation to cytosol was observed in human postmortem frontal cortical synaptosomes with recombinant ApoE4 than ApoE3 ex vivo. In ApoE4 astrocytes, the greater levels of LTB4, reactive oxygen species (ROS), and inducible nitric oxide synthase (iNOS) were reduced after cPLA2 inhibition.

Conclusions

Our findings implicate greater activation of cPLA2 signaling system with APOE4, which could represent a potential drug target for mitigating the increased neuroinflammation with APOE4 and AD.