Ocular SurfacePub Date : 2024-08-29DOI: 10.1016/j.jtos.2024.08.015
Lina Sprogyte, Mijeong Park, Lamia Nureen, Nicodemus Tedla, Alexander Richardson, Nick Di Girolamo
{"title":"Development and characterization of a preclinical mouse model of alkali-induced limbal stem cell deficiency","authors":"Lina Sprogyte, Mijeong Park, Lamia Nureen, Nicodemus Tedla, Alexander Richardson, Nick Di Girolamo","doi":"10.1016/j.jtos.2024.08.015","DOIUrl":"10.1016/j.jtos.2024.08.015","url":null,"abstract":"<div><h3>Purpose</h3><p>Limbal stem cell deficiency (LSCD) secondary to ocular surface alkali burn is a blinding condition that features corneal conjunctivalization. Mechanistic insights into its pathophysiology are lacking. Here, we developed a mouse model that recapitulates human disease to comprehensively delineate the clinicopathological features of a conjunctivalized cornea.</p></div><div><h3>Methods</h3><p>LSCD was induced in the right eyes of 6-8-week-old C57BL/6 male and female mice (<em>n = 151</em>) by topical administration of 0.25N sodium hydroxide on the cornea. Uninjured left eyes served as controls. Clinical, histological, phenotypic, molecular, and immunological assessments were performed at multiple time-points over 6-months.</p></div><div><h3>Results</h3><p>Clinically, alkali burn caused persistent corneal opacity (p = 0.0014), increased punctate staining (p = 0.0002), and reduced epithelial thickness (p = 0.0082) compared to controls. Total LSCD was confirmed in corneal whole mounts by loss of K12 protein (p < 0.0001) and mRNA expression (p = 0.0090). Instead, K8<sup>+</sup>, K13<sup>+</sup>, K15<sup>+</sup> and MUC5AC<sup>+</sup> conjunctival epithelia prevailed. 20 % of injured corneas developed islands of K12<sup>+</sup> epithelia, suggesting epithelial transdifferentiation. Squamous metaplasia was detected in 50 % of injured corneas. Goblet cell density peaked early post-injury but decreased over time (p = 0.0047). Intraepithelial corneal basal nerve density remained reduced even at 6-months post-injury (p = 0.0487).</p></div><div><h3>Conclusions</h3><p>We developed and comprehensively characterized a preclinical mouse model of alkali-induced LSCD. Understanding the pathophysiological processes that transpire on the ocular surface in LSCD is key to discovering, testing, and advancing biological and pharmacological interventions that can be dispensed prior to or in conjunction with stem cell therapy to rehabilitate the cornea and restore vision.</p></div>","PeriodicalId":54691,"journal":{"name":"Ocular Surface","volume":"34 ","pages":"Pages 329-340"},"PeriodicalIF":5.9,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1542012424000958/pdfft?md5=592d460a11f75adc137bf2afe15e6ac6&pid=1-s2.0-S1542012424000958-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142116710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ocular SurfacePub Date : 2024-08-28DOI: 10.1016/j.jtos.2024.08.014
Baihui Zeng , Lina Xu , Guoliang Wang , Ruize Shi , Kerui Wang , Shurong Wang , Cheng Li
{"title":"Distinctive small molecules blend: Promotes lacrimal gland epithelial cell proliferation in vitro and accelerates lacrimal gland injury repair in vivo","authors":"Baihui Zeng , Lina Xu , Guoliang Wang , Ruize Shi , Kerui Wang , Shurong Wang , Cheng Li","doi":"10.1016/j.jtos.2024.08.014","DOIUrl":"10.1016/j.jtos.2024.08.014","url":null,"abstract":"<div><h3>Purpose</h3><p>This study aims to develop a novel serum-free culture strategy containing only two small molecules, Y27632 and SB431542 (2C), for <em>in vitro</em> expansion of mouse lacrimal gland epithelial cells (LGECs) and investigate an innovative therapeutic approach for lacrimal gland (LG) injury.</p></div><div><h3>Methods</h3><p>LGECs proliferative capacity was assessed by cell counting, crystal violet staining, qRT-PCR and immunofluorescence. Cell differentiation was achieved by manipulating culture conditions and assessed by qRT-PCR and AQP5 immunofluorescence. LGECs were seeded in Matrigel for three-dimensional culture and assessed by qRT-PCR and immunofluorescence. Secretory function of the cultures was assayed by ELISA. <em>In vivo</em>, 2C injection verified its reparative capacity in a mouse LG injury model. Corneal fluorescein staining, phenol red cotton thread, H&E, immunofluorescence and Western blot were used to assess LG injury repair.</p></div><div><h3>Results</h3><p>LGECs cultured with 2C exhibited high expression of stemness/proliferation markers and maintained morphology and proliferative capacity even after the tenth passage. Removal of 2C was efficacious in achieving LGECs differentiation, characterized by the increased AQP5 expression and LTF secretion. 3D spheroids cultured with 2C demonstrated differentiation potential, forming microglandular structures containing multiple LG cell types with secretory functions after 2C removal. <em>In vivo</em>, 2C improved the structural integrity and function of the injured LG.</p></div><div><h3>Conclusions</h3><p>We present a small molecule combination, 2C, that promotes LGECs expansion and differentiation <em>in vitro</em> and accelerates LG injury repair <em>in vivo</em>. This approach has potential applications for providing a stable source of seed cells for tissue engineering applications, providing new sights for LG-related diseases treatment.</p></div>","PeriodicalId":54691,"journal":{"name":"Ocular Surface","volume":"34 ","pages":"Pages 283-295"},"PeriodicalIF":5.9,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142099513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"β-Catenin gain of function mutant in mouse periocular neural crest-derived mesenchymal cells impairs embryonic eyelid morphogenesis and leads to blepharophimosis syndrome in mice","authors":"Yen-Chiao Wang, Yong Yuan, Jianhua Zhang, Yujin Zhang, Winston W.-Y. Kao, Chia-Yang Liu","doi":"10.1016/j.jtos.2024.08.012","DOIUrl":"10.1016/j.jtos.2024.08.012","url":null,"abstract":"<div><h3>Purpose</h3><p>The aberrant canonical Wnt-β-catenin signaling can cause devastating outcomes of tissue morphogenesis and tumor formation. In this study, we examined the impact of overexpression of constitutive active β-catenin in mouse periocular neural crest-derived mesenchymal cells during embryonic eyelid morphogenesis.</p></div><div><h3>Methods</h3><p>We expressed a stabilized β-catenin in which the exon 3 of the <em>Ctnnb</em>1 gene was deleted in periocular neural crest (PONC)-derived eyelid stromal cells (<em>Ctnnb1</em><sup><em>Δex3-PONC</em></sup>). Histopathological examinations were performed to examine the eyelid morphogenetic alterations in <em>Ctnnb1</em><sup><em>Δex3-PONC</em></sup> mice. Immunohistochemical investigations for cell proliferation, apoptosis, and differentiation were also assessed.</p></div><div><h3>Results</h3><p>We discovered that nuclear accumulation of β-catenin resulted in a reduction of nuclear Ki-67 and phospho-Erk1/2 expression levels and elevation of apoptosis in PONC cells during embryonic eyelid closure morphogenesis. Interestingly, however, the eyelid epithelial migration was not affected, which resulted in only eyelid epidermal closure but lacked underneath dermal formation at embryonic (E) day 16.5. The sequelae of <em>Ctnnb1</em><sup><em>Δex3-PONC</em></sup> revealed the malformation of the eyelid margin and Meibomian gland and deficiency of Muller's smooth muscle fibers formation. Consequently, <em>Ctnnb1</em><sup><em>Δex3-PONC</em></sup> mice manifested blepharophimosis syndrome at P21.</p></div><div><h3>Conclusion</h3><p>Our data suggested that aberrant expression of β-catenin gain of function in PONC interrupts the interplay between epithelium and stroma for the morphogenesis of eyelid closure during embryonic development.</p></div>","PeriodicalId":54691,"journal":{"name":"Ocular Surface","volume":"34 ","pages":"Pages 267-276"},"PeriodicalIF":5.9,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142087227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ocular SurfacePub Date : 2024-08-17DOI: 10.1016/j.jtos.2024.08.009
Namita Saraf , Rajalakshmy Ayilam Ramachandran , Mou Cao , Andrew Lemoff , Hamid Baniasadi , Danielle M. Robertson
{"title":"Serum-derived extracellular vesicles for the treatment of severe ocular surface disease","authors":"Namita Saraf , Rajalakshmy Ayilam Ramachandran , Mou Cao , Andrew Lemoff , Hamid Baniasadi , Danielle M. Robertson","doi":"10.1016/j.jtos.2024.08.009","DOIUrl":"10.1016/j.jtos.2024.08.009","url":null,"abstract":"<div><h3>Purpose</h3><p>Autologous serum is widely used for the treatment of severe ocular surface disease with mixed efficacy. Extracellular vesicles (EVs) are small membrane bound structures present in all body fluids, including serum. This study compared the proteomic, metabolomic, and inflammatory cytokine composition of serum-derived EVs (SDEVs) to that of the soluble free protein fraction and the subsequent capacity of SDEVs to induce corneal epithelial cell migration and inflammation.</p></div><div><h3>Methods</h3><p>SDEVs were isolated from human serum using size exclusion chromatography. SDEVs were analyzed using nanoparticle tracking analysis, transmission electron microscopy, and western blotting. The effects of SDEVs on corneal epithelial cell migration were tested using a standard scratch assay. Inflammatory cytokines in SDEVs and the free protein fraction were quantified using a microarray. A mutli-omics approach was further used to define SDEV cargo. The ability of SDEVs to modulate inflammation in corneal epithelial cells was quantified using ELISAs.</p></div><div><h3>Results</h3><p>Western blot and TEM confirmed the presence of SDEVs. Proinflammatory cytokines, along with complement proteins and TGF-β, were decreased in SDEVs compared to serum. Metabolites present in SDEVs were mostly involved in amino acid biosynthesis, the TCA cycle and oxidative phosphorylation. SDEVs exhibited pro-migratory effects similar to serum however, SDEVs did not induce secretion of IL-6 or IL-8.</p></div><div><h3>Conclusions</h3><p>SDEVs exhibit reduced levels of pro-inflammatory cytokines while retaining the beneficial wound healing properties of serum. Unlike serum, SDEVs do not induce inflammation. SDEVs may represent an alternative option for patients with severe ocular surface disease where traditional autologous serum has failed.</p></div>","PeriodicalId":54691,"journal":{"name":"Ocular Surface","volume":"34 ","pages":"Pages 317-325"},"PeriodicalIF":5.9,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142006254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ocular SurfacePub Date : 2024-08-15DOI: 10.1016/j.jtos.2024.08.011
Alexis Ceecee Britten-Jones , Mengliang Wu , Leslie J. Roberts , Richard J. MacIsaac , Haihan Jiao , Jennifer P. Craig , Holly R. Chinnery , Laura E. Downie
{"title":"Tear neuropeptide Y as a non-invasive marker of peripheral microvascular complications in type 1 diabetes","authors":"Alexis Ceecee Britten-Jones , Mengliang Wu , Leslie J. Roberts , Richard J. MacIsaac , Haihan Jiao , Jennifer P. Craig , Holly R. Chinnery , Laura E. Downie","doi":"10.1016/j.jtos.2024.08.011","DOIUrl":"10.1016/j.jtos.2024.08.011","url":null,"abstract":"<div><h3>Aims</h3><p>To investigate tear neuropeptide Y (NPY) and substance P concentrations in individuals with type 1 diabetes, comparing those with and without both diabetic retinopathy (DR) and peripheral neuropathy.</p></div><div><h3>Methods</h3><p>This cross-sectional study involved 41 participants with type 1 diabetes and none to moderate DR, and 22 healthy controls. Assessments included clinical ocular surface parameters, quantification of corneal nerve attributes (based on <em>in vivo</em> confocal microscopy imaging), DR grading, and evaluation for small and large fibre neuropathy. Concentrations of NPY and substance P in tear samples were measured using enzyme-linked immunosorbent assay.</p></div><div><h3>Results</h3><p>Mean (± standard deviation) tear NPY concentrations in participants with type 1 diabetes and length-dependent small fibre neuropathy (SFN) was lower than in controls (10.84 ± 4.10 ng/mL vs 14.72 ± 3.12 ng/mL; <em>p=</em>0.004), but not significantly different from type 1 diabetes participants without SFN (13.39 ± 4.66 ng/mL; <em>p=</em>0.11). Tear NPY levels were lower in individuals with type 1 diabetes and mild/moderate non-proliferative DR (10.44 ± 3.46 ng/mL) compared to none/minimal DR (13.79 ± 4.76 ng/mL; <em>p=</em>0.0005) and controls. In separate linear regression models, both the presence of SFN (β = −0.75, <em>p=</em>0.02) and the presence of mild/moderate DR (β = −0.84, <em>p=</em>0.009) were significantly associated with tear NPY levels relative to controls, after adjusting for participant age, sex, and dry eye disease. There were no inter-group differences for tear substance P concentrations.</p></div><div><h3>Conclusions</h3><p>Tear NPY has potential utility as an indicator of peripheral microvascular complications associated with type 1 diabetes.</p></div>","PeriodicalId":54691,"journal":{"name":"Ocular Surface","volume":"34 ","pages":"Pages 309-316"},"PeriodicalIF":5.9,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141997162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The clinical outcomes of minor salivary gland transplantation for severe dry eye disease secondary to chronic Stevens-Johnson syndrome","authors":"Namrata Sharma, Vishal Kumar, Aafreen Bari, Renu Venugopal, Shivam Sharma, Tushar Agarwal, Tanuj Dada, Neelam Pushker","doi":"10.1016/j.jtos.2024.08.010","DOIUrl":"10.1016/j.jtos.2024.08.010","url":null,"abstract":"<div><h3>Purpose</h3><p>To study the outcomes of minor salivary gland transplantation for severe dry eye disease secondary to chronic Steven Johnson Syndrome.</p></div><div><h3>Methods</h3><p>It was an ambispective, interventional case series conducted at Rajendra Prasad Centre for Ophthalmic Sciences, Delhi, India from 2022 to 2023 evaluating the outcomes of minor salivary gland transplantation with anchorage of the minor salivary glands to superior rectus muscle in twenty cases of severe dry eye disease secondary to chronic Steven-Johnson Syndrome. The pre-operative clinical parameters were compared to those at post-operative 1 year follow-up.</p></div><div><h3>Results</h3><p>At 1 year follow-up, there was an improvement in mean Schirmer-1 value (p = 0.0004), hyperemia score (p = 0.0004), keratinization score (p = 0.04), corneal epithelial defect score (p = 0.0004), corneal opacification score (p = 0.001), corneal neovascularization score (p = 0.001), palisades of Vogt score (p = 0.007), corneal keratinization score (p = 0.04) and corneal conjunctivalization score (p = 0.08).</p></div><div><h3>Conclusion</h3><p>The minor salivary gland transplantation is a viable management option for cases with severe dry eye disease secondary to chronic Steven Johnson Syndrome with clinical improvement in corneal and conjunctival parameters of the ocular surface.</p></div>","PeriodicalId":54691,"journal":{"name":"Ocular Surface","volume":"34 ","pages":"Pages 277-282"},"PeriodicalIF":5.9,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141918473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ocular SurfacePub Date : 2024-08-09DOI: 10.1016/j.jtos.2024.08.006
Ashish Ranjan , Sayan Basu , Swati Singh
{"title":"Punctal cautery in dry eye disease: A systematic review","authors":"Ashish Ranjan , Sayan Basu , Swati Singh","doi":"10.1016/j.jtos.2024.08.006","DOIUrl":"10.1016/j.jtos.2024.08.006","url":null,"abstract":"<div><h3>Purpose</h3><p>To critically appraise the evidence on the efficacy and recanalization rates of permanent punctal occlusion via thermal or surgical means in managing dry eye disease (DED).</p></div><div><h3>Methods</h3><p>In PubMed, Scopus, and Cochrane databases, two authors systematically reviewed the literature for prospective studies on punctal cautery or surgical occlusion (excluding punctal plugs) for DED. The studied outcomes were changes in tear volume, tear film stability, punctal recanalization rates, and patient symptomatology.</p></div><div><h3>Results</h3><p>Nine studies (all single-arm) had 150 subjects (96 females). Five studies were on thermal punctal cauterization, and four used surgical occlusion techniques. One hundred eighty puncta were operated for eyes not responding to maximal lubricants or recurrent plug extrusion. DED etiologies were Sjogren's syndrome (78), cicatricial ADDE (27), graft-versus-host disease (12), and non-SS DED (50). Follow-up ranged from 3 to 24 months. At the final follow-up, improvements in Schirmer I and TBUT were 2.5 mm and 0.8s with thermal and 2.1 mm and 0.6s with surgical methods, respectively (P = 0.17 for Schirmer, P = 0.18 for TBUT). Punctal recanalization rates varied between thermal (0–38.7 %) and surgical (5–9%) techniques (p = 0.22). Different cautery devices show different recanalization rates; disposable thermal cautery tips directly inserted into the punctum had lesser recanalization than radiofrequency monopolar cautery. Most patients reported subjective improvement following the procedure, but no quantification measure was given in the studies. None of the published studies had a comparison group for performing a meta-analysis.</p></div><div><h3>Conclusion</h3><p>Based on non-comparative studies, thermal or surgical punctal occlusion improves tear volume in DED with similar recanalization rates; however, randomized controlled trials are needed to ascertain the real effects of punctal cautery on DED.</p></div>","PeriodicalId":54691,"journal":{"name":"Ocular Surface","volume":"34 ","pages":"Pages 235-240"},"PeriodicalIF":5.9,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1542012424000879/pdfft?md5=b5fce60ef7482cd63e0f7b8b891c36aa&pid=1-s2.0-S1542012424000879-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141914996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ocular SurfacePub Date : 2024-08-08DOI: 10.1016/j.jtos.2024.08.008
Petros Moustardas , Mojdeh Abbasi , Dina Javidjam , Cindy Saah Asamoah , Arnaud Schweitzer-Chaput , Salvatore Cisternino , Dominique Bremond-Gignac , Daniel Aberdam , Neil Lagali
{"title":"Duloxetine enhances PAX6 expression and suppresses innate immune responses in murine LPS-induced corneal inflammation","authors":"Petros Moustardas , Mojdeh Abbasi , Dina Javidjam , Cindy Saah Asamoah , Arnaud Schweitzer-Chaput , Salvatore Cisternino , Dominique Bremond-Gignac , Daniel Aberdam , Neil Lagali","doi":"10.1016/j.jtos.2024.08.008","DOIUrl":"10.1016/j.jtos.2024.08.008","url":null,"abstract":"<div><h3>Background-aim</h3><p><em>PAX6</em> is a key regulator of eye development and epithelial homeostasis in the cornea. When deficient, chronic corneal inflammation, neovascularization and limbal stem cell deficiency can occur. Here we investigated the potential of duloxetine, a generic serotonin reuptake inhibitor that can upregulate PAX6 <em>in vitro</em>, for its <em>in vivo</em> activity in the context of corneal inflammation.</p></div><div><h3>Methods</h3><p>Duloxetine tolerance was tested in a human limbal stem cell line and isogenic CRISPR-knockout <em>PAX6</em><sup>+/−</sup> cells. C57BL/6-Wildtype mice were administered duloxetine eye drops at concentrations of 1 μM - 2 mM and tested for toxicity and corneal PAX6 expression. In LPS-induced corneal inflammation in mice, duloxetine's effect on PAX6 expression, corneal opacification and inflammatory responses were evaluated by <em>in vivo</em> corneal imaging, immunostaining, and whole-transcriptome microarray analysis.</p></div><div><h3>Results</h3><p>No toxicity was observed <em>in vitro</em> for duloxetine concentrations up to 10μΜ. <em>In vivo</em>, duloxetine drops were well-tolerated up to 50 μM. Duloxetine drops at 10μΜ significantly upregulated PAX6 protein levels in the cornea by 30 % within 2 days. In the LPS model, duloxetine resulted in a sustained 33 % PAX6 protein upregulation in the cornea at 7 days, and in reduced opacity within 2 days, accompanied by a significant dampening of IL-17A signaling, neutrophil degranulation, microglial activation, macrophage markers, and <em>MMP</em> expression, despite non-significant changes in total inflammatory cell infiltration.</p></div><div><h3>Conclusion</h3><p>Short-term administration of a repurposed generic drug, duloxetine, upregulates PAX6 protein levels in the cornea of mice and exerts an anti-inflammatory activity by dampening innate immune responses.</p></div>","PeriodicalId":54691,"journal":{"name":"Ocular Surface","volume":"34 ","pages":"Pages 225-234"},"PeriodicalIF":5.9,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1542012424000867/pdfft?md5=6678d99b0a1e71244ed995c1d9482a7c&pid=1-s2.0-S1542012424000867-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141914994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}