bluuebunny/crossref_metadata_2025 huggingface dataset:
Patient specific differences in retinitis pigmentosa in vitro model
Authors: Lukovic Dunja , Garcia‐Bohórquez Belén , Garcia Gema Garcia , Gallardo Maria Esther , Ayuso Carmen , Millán José Maria
Published: January 2025

Aims/Purpose: Mutations in USH2A are the most common cause of autosomal recessive retinitis pigmentosa (RP) and syndromic RP in combined deaf‐blindness, Usher syndrome type 2 (USH2). In both cases, the effective treatment is lacking. The failure of retinal phenotype in available animal models warrants the generation of human tissue mimics in which to explore the underlying molecular mechanism and test available therapeutic modalities. To model this disease in vitro, we generated iPSC‐derived retinal organoids from patients bearing the two most common mutations in USH2A and explored disease specific events. We aimed to depict the mutation specific distinctive in vitro phenotype.

Methods: Patient and isogenic control fibroblasts were reprogrammed into iPSCs using Sendai virus. The iPSCs were subjected toward retinal organoid differentiation according to Zhong et al., 2014 and analysed by fluorescence microscopy throughout the protocol, stage specific retinal cell markers were followed, and ultrastructural changes observed by TEM.

Results: Two retinitis pigmentosa patients affected by USH2A mutation and an isogenic control were induced successfully toward retinal organoids with all mayor retinal cell types. We observe reduced efficiency in neural retina formation and paucity in cellular laminar arrangement of patients’ cells. The isogenic control was able to revert disease related cellular phenotypes and subcellular features. The frequency of cones and rods was examined in organoids of different stages by immunocytochemistry and by gene expression. The notable difference between two USH2A genetic backgrounds is proposed to lie in the abundance of cone photoreceptors. Cell death was more pronounced in the patient with missense mutation.

Conclusions: Our study corroborates the feasibility of generating retinal organoid disease model of USH2A and CRISPR/Cas9 editing of genetic lesion in disease bearing hiPSCs further supporting the applicability of CRISPR/Cas9 machinery in in vivo settings. We have identified mutation specific differences in in vitro disease phenotype.
Assessment of silica as an intravitreal drug delivery vehicle in a preclinical in vivo tolerability study
Authors: Winter Sophie , Dargelas Frederic , Leino Lasse , Pollari Ville , Reay Marcus , Assmuth Tatu , Wirman Linda , Toropainen Elisa , Kaarniranta Kai
Published: January 2025

Aims/Purpose: Many severe ocular diseases leading to blindness are currently treated by frequent intravitreal (IVT) injections that not only cause tolerability issues, but also results in decreased patient treatment‐compliance and ultimately loss of vision. Attempts to reduce IVT administration frequency by sustained release of active ingredients through drug delivery systems have failed due to poor tolerability. Our aim in this study was to evaluate the intraocular tolerability of biodegradable non‐porous silicon dioxide (silica) based test items in a preclinical New Zealand White (NZW) rabbit study.

Methods: Silica microparticles (MPs) were manufactured by sol‐gel chemistry and spray drying and γ‐sterilized. Silica MPs were combined under aseptic conditions with sterile silica hydrogel (HG) or endotoxin free water to form injectable silica MP‐silica HG (depot) or MP suspensions (MPsusp). 24 NZW rabbits received IVT injections of depot ranging between 10‐50μl via 27G UTW needles and 8 rabbits received MPsusp at 50μl. The test items were evaluated up to 3 months via clinical observations, intra ocular pressure (IOP), slit lamp exam with ocular safety and tolerability criteria, fundus imaging, histopathology analysis of ocular tissues and aqueous‐ and vitreous‐humor proteomics.

Results: Clinical observations by veterinarians showed no adverse events. IOP increased immediately after injection but returned to baseline values within 30 minutes. Slit lamp examination revealed no abnormalities in the lid margin, conjunctiva, cornea, lens or retina. Fundus imaging conducted prior to dosing, right after dosing and at days 7 and at 1‐, 2‐, 3‐months showed no deviations. Histopathology confirmed the absence of tissue damage or inflammation. Screening of proteins associated with inflammation revealed no significant changes in the protein profiles of the aqueous and vitreous humor.

Conclusions: The results suggest that both silica depots and silica MP suspensions are well tolerated in rabbit eyes for periods up to 3 months at doses ranging from 10‐50μl in IVT administration.
Lipoic acid's impact on retinitis pigmentosa: Partial protection of photoreceptors and müller cells
Authors: Almansa Inmaculada , López‐Pedrajas Rosa , Valero Javier , Cantó Antolin , Martínez‐González Javier , Hernández‐Rabaza Vicente , Olivar Teresa , Sanz María Miranda
Published: January 2025

Aims/Purpose: Retinitis Pigmentosa (RP) describes a group of hereditary retinopathies. Traditionally, therapeutic approaches have assumed that inner retinal neurons retain function, properties, and connectivity after photoreceptor degeneration. However, it is known that photoreceptor degeneration leads to dramatic changes in second‐ and third‐order neurons, such as amacrine cells and horizontal cells. In the present study, the main objective is to evaluate not only the protective capacity of lipoic acid against photoreceptor death but also its protective effect on these neurons and Müller cells.

Methods: Rd1 mice were treated in accordance with the ARVO statement for the use of animals in ophthalmic and vision research. Mice were sacrificed at different postnatal days (11, 13, 17). Lipoic acid was administered orally (100 mg/kg). It was administered every two days, starting at PN7. The neuroprotective effect of this treatment was analyzed using the TUNEL assay. Müller cells, amacrine cells, and horizontal cells were studied by immunohistochemistry.

Results: Lipoic acid treatment reduced photoreceptor death at PN11 and PN13, with no differences observed at PN17 in rd1 mice, demonstrating a partial treatment effect. The expression of GFAP was increased in the retinas at PN11, 13, and 17 rd1 mice, and lipoic acid treatment significantly reversed this effect.

Regarding second‐ and third‐order neurons, there was an increase in amacrine cells at PN13 and PN17 in rd1 mice, but lipoic acid had no effect on this increase. As for horizontal cells, no changes were observed at PN13, but at PN17, there was a decrease in these cells that lipoic acid could not reverse.

Conclusions: Lipoic acid partially protects photoreceptor death. However, no effect was seen on the studied amacrine and horizontal cells. Further research is necessary to deepen our understanding of RP, specifically examining the remaining neuronal populations.
Fundus autofluorescence patterns in retinitis pigmentosa
Authors: Sahli Esra , Atilla Huban
Published: January 2025

Aims/Purpose: To evaluate the fundus autofluorescence (AF) patterns in retinitis pigmentosa (RP) patients at different clinical stages.

Methods: Patients with a diagnosis of RP confirmed by fundus examination, visual field (VF) and ERG with visual acuity of 20/200 and above were included in the study. Fundus AF imaging was used to evaluate the AF patterns in the macula.

Results: Seventy eyes of 36 RP patients were included in the study. Twelve eyes of 6 patients had no hyperautofluorescent ring on fundus AF imaging (type 1). A hyperautofluorescent ring was observed in 22 eyes of 11 patients (type 2). Double hyperautofluorescent rings were present in 4 eyes of 2 patients (type 3). The fovea was hyperautofluorescent in 8 eyes (type 4). In 24 eyes, the macula was completely hypoautofluorescent (type 5). Excluding type 3 with double hyperautofluorescent rings, there was a weak negative correlation between AF typing and visual acuity and a very weak positive correlation between AF typing and VF MD index (correlation coefficients 0.31 and 0.13, respectively).

Conclusions: The genetic test results of the patients with double hyperautofluorescent rings were compatible with USH2A gene mutation in accordance with the literature. We believe that patterns other than the double hyperfluorescent ring appearance, which was attributed to a specific genotype in previous studies, are related to the severity or stage of the disease. Type 1 AF suggests early stage disease where the hyperautofluorescent ring does not fall within the area tested in the visual field test, while type 2 AF suggests more advanced disease with a hyperautofluorescent ring. In type 4 AF, only enough retinal pigment epithelium is preserved to give AF in the foveal region. In type 5 AF, there is extensive degeneration involving the fovea. Since the different AF patterns are related to the macular involvement of the disease and the involvement of the cone cells, some correlation with visual acuity has been found.
Macular and optic nerve microvascular changes in patients with type 1 diabetes mellitus
Authors: Chatziralli Irini , Risi‐Koziona Alexia , Agapitou Chrysa , Lampsas Stamatios , Kyratzidis Fotis , Pappelis Konstantinos , Theodossiadis Panagiotis
Published: January 2025

Aims/Purpose: The purpose of this study was to evaluate the changes of foveal avascular zone (FAZ) area and vessel density (VD) in superficial (SCP) and deep capillary plexus (DCP), as well as changes in optic nerve VD, in association with functional changes in patients with type 1 diabetes mellitus (DM) with and without retinopathy.

Methods: The study included 23 patients (23 eyes) with type 1 DM, and 20 control subjects without DM (20 eyes). All participants underwent best‐corrected visual acuity (BCVA) measurement, optical coherence tomography (OCT) and OCT angiography (OCTA) of the macular and optic nerve. Comparison of OCTA parameters between eyes of DM patients and controls was performed.

Results: There was a statistically significant decrease in vessel density (VD) in the foveal and parafoveal area in the SCP and DCP in eyes with DM compared to control eyes (p = 0.019 for SCP and p < 0.001 for DCP). The two groups did not differ in FAZ area, FAZ perimeter and FAZ circularity. The change in VD was associated with the severity of diabetic retinopathy (DR) in these patients. There was also a decrease in VD in the optic nerve in patients with DM compared to controls (p = 0.018)

Conclusions: The OCTA reveals that the macular and optic nerve was early‐altered in type 1 DM and the alterations were associated with DR severity.
Clinical spectrum of retinal dystrophy caused by pathogenic variants in the cerkl gene
Authors: Paavo Maarjaliis , Sankila Eeva‐Marja , Seitsonen Sanna , Majander Anna , Krootila Julia , Turunen Joni
Published: January 2025

Aims/Purpose: Two disease‐causing variants of the CERKL gene, (c.375C > G, c.193G > T), are enriched in the Finnish population due to the specific population history. Here we present a large patient cohort with biallelic pathogenic variants in CERKL with long follow‐up time and a reduced spectrum of pathogenic variants.

Methods: In this retrospective cohort study medical record data were collected from 50 patients with CERKL‐associated retinopathy followed in the Department of Ophthalmology, Helsinki University Hospital. The age, sex, symptoms, onset of symptoms, best corrected visual acuity (BCVA), colour fundus photography, spectral‐domain optical coherence tomography (SD‐OCT), fundus autofluorescence (AF) and genetic data were collected.

Results: The median age at the first visit was 24 years (range 5‐51), and the follow‐up time was 12 years (median, range 0,8‐19). The most common symptoms were nyctalopia (33 patients), reduced BCVA (25 patients) and glare (24 patients). In 11 patients, the disease manifested in the macular area ranging from mild bull's eye maculopathy to geographic atrophy. In 28 patients, both macular and peripheral retina were affected. Eleven patients had severe panretinal degeneration. The median age at onset of visual impairment according to the WHO classification was 38 years (range 23‐60), which corresponds to a 14‐year period (median; range 7‐27) after receiving the diagnosis. Forty‐three (88 %) patients carried at least one allele of the most common pathogenic variant c.375C > G, and 34 (69 %) were homozygous for this variant. Twelve patients (24 %) carried at least one allele of the second most common variant, c.193G > T.

Conclusions: The disease spectrum is broad in this large CERKL‐associated retinopathy cohort ranging from macular disease to severe panretinal degeneration. The over a decade period from diagnosis to visual impairment provides an optimal time window for future therapeutic interventions.
Aged‐related changes in connexins‐based mediated intercellular channels in retina
Authors: Domenech‐Bendaña Alicia , Ponce‐Mora Alejandro , Locascio Antonella , Salazar Nicolle , Mallench Lucía Gimeno , Bejarano Eloy
Published: January 2025

Aims/Purpose: Connexins (Cxs) are a family of structurally‐related transmembrane proteins that form gap junction channels. These channels are essential for direct intercellular communication in many tissues. Cxs play a crucial role in retina homeostasis and visual information processing. Cxs connect photoreceptors, horizontal cells, bipolar cells, amacrine cells and ganglion cells in the mammalian retina. They are proposed as therapeutic targets for several retinal diseases. Although retinal aging is considered a risk factor for different retinal disorders, it remains unclear if the retinal connectome changes with age. This study systematically analyzes the relationship between retinal Cxs isoforms and age.

Methods: Retinas from C57BL/6J mice were harvested at 1‐, 4‐, 12‐ and 24 months. Immunohistochemical and qPCR analysis for various retinal Cxs isoforms were performed, including Cx50, Cx43, Cx36 and Cx57. Colocalization analysis was carried out using antibodies against different retinal layers or retinal cell types. Images were captured using the EVOS M7000 microscope, and 3D modelling was performed using the Celleste 3D Deconvolution Module.

Results: Differences in expression and location were found in different aged‐groups in an isoform‐dependent manner. For example, Cx50 is expressed in ganglion cell layer in young retina and, as mice aged, Cx50 is highly expressed in Müller cells. Cx36 is highly expressed in both OPL and IPL; higher levels and accumulation of Cx36 are found in aged retina.

Conclusions: This study provides new pieces of evidence about the impact of aging in the retinal connexins‐based connectome. A comprehensive understanding of the impact of aging on the retinal connectome is imperative for the design of connexins‐mimetic peptides as therapeutic tools in the treatment of connexin‐related retinal diseases.

Funding: RYC 2018‐024434‐I, MINECO PID 2020‐119466RB‐I00, and FUSP‐PPC‐19‐B53C4C64.
Pseudoxanthoma elasticum: A case study of three family members
Authors: Laguna Candela Congost , Gil Romana García , Sánchez Anselmo Feliciano , Peláez Blanca Casado , Moreno Sergio Inat
Published: January 2025

Aims/Purpose: To evaluate the evolution and various clinical presentations of pseudoxanthoma elasticum in three family members.

Methods: Continuous follow‐up was conducted in the outpatient ophthalmology clinics at our hospital. Clinical characteristics, including the presence of exudation, neovascular membranes, angioid streaks, and posterior pole atrophy, were documented and analyzed through detailed ophthalmological examinations and imaging tests. Visual acuity was assessed, and autofluorescence imaging was performed. Additionally, optical coherence tomography (OCT) and OCT angiography (OCT‐A) were utilized to obtain high‐resolution images of the retina and its blood flow.

Results: One daughter presented with exudation accompanied by a neovascular membrane, which was treated with intravitreal anti‐VEGF injections. The other daughter maintains good vision and shows angioid streaks in the fundus without macular involvement. The mother is in an advanced stage of the disease, with significant retinoschisis and posterior pole atrophy.

Conclusions: This case study highlights the variability in the presentation and progression of pseudoxanthoma elasticum within the same family. Continuous and personalized follow‐ up is crucial for the appropriate management and early detection of complications in PXE patients.
Macular thicknesses of the outer retinal and choroid layers measured by automatic segmentation with artificial inteligence in non‐pathological high myopia
Authors: Darriba David Blanco , Cedrun‐Sanchez Juan , Peña Monica Narvaez , Santos Maria Jimenez , López Juan Donate , Puell María
Published: January 2025

Aims/Purpose: To compare structural changes in photoreceptor sublayers, retinal pigment epithelium and choroid using optical coherence tomography (OCT) with artificial intelligence‐based automatic segmentation between subjects with simple myopia and non‐pathological high myopia.

Methods: This observational case‐control study included a total of 45 eyes of 45 subjects comprised of n = 22 eyes with simple myopia (axial length between 24.00mm and 25.50mm; spherical equivalent between ‐0.50D and ‐4.50D) and n = 23 eyes with non‐pathological high myopia (axial length greater than or equal to 26.00mm; spherical equivalent less than or equal to ‐6.00D). Images were obtained from OCT Spectralis® HRA/OCT2 (Heidelberg Engineering Inc. Heidelberg, Germany) and sublayers were analysed: outer nuclear layer + Henle's fiber layer (ONL+HFL), myoid zone (MZ), ellipsoid zone (EZ)+outer photoreceptor layer (OPR)+interdigitation zone (IZ), retinal pigment epithelium (RPE), choriocapillaris (CC) + stromal choroid (CS) sectorially from the Early Treatment Diabetic Retinopathy Study (ETDRS) 1, 3, 6 mm grid using automatic segmentation by artificial intelligence based software (Discovery® 4.1, RetinAI, Switzerland).

Results: Subjects with non‐pathological high myopia showed greater mean thinning in the ONL+HFL (p = 0.001), MZ (p = 0.003), EZ+OPR+IZ (p = 0.001), EPR (p = 0.003) and CC+CS (p < 0.001) sublayers. Specifically, the external regions at the nasal level were the segmentation values with the greatest thinning. Axial length showed a negative correlation in all sublayers analysed (rONL+HFL = ‐0.469, p = 0.001; rMZ = ‐0.535, p ≤ 0.001; rEZ+OPR+IZ = ‐0.549, p ≤ 0.001; rRPE = ‐0.333, p = 0.025; rCC+CS = ‐0.667, p ≤ 0.001).

Conclusions: There is greater thinning of the different outer layers of the retina and choroid in non‐pathological high myopia than in simple myopia. The increase in axial length in non‐pathological high myopia may be the determining factor in the presence of these changes. Automatic segmentation using artificial intelligence may be a useful tool in the characterisation and analysis of these layers.
Is intravitreal faricimab an effective treatment for diabetic macular oedema not‐responsive to aflibercept? An audit of treated patients at the princess alexandra eye pavilion
Authors: Lowe Cameron , Das Meghomala
Published: January 2025

Aims/Purpose: We aim to evaluate both functional and anatomical outcomes of patients switched from aflibercept to faricimab for management of treatment‐resistant diabetic macular oedema (DMO) in a real‐world environment, and the proportion of patients who achieved improvement, stability or deterioration.

Methods: Casenotes of 20 eyes not responding to aflibercept, then switched to faricimab were reviewed. Patient demographics, best‐corrected visual acuity (BCVA) and presence of macular oedema on OCT pre‐switch and at post‐treatment clinic review, and injection intervals were recorded. We then categorised whether there was an improvement, stability or deterioration in both BCVA and presence of macular oedema on OCT.

Results: Of 16 eyes where analysis was complete for BCVA, there was improvement in 31% (n = 5), stability in 19% (n = 3) and deterioration in 50% (n = 8). Of the eyes where there was deterioration, 4 had other co‐morbidity which affected BCVA. Of 17 eyes with pre‐ and post‐switch macular OCT, there was improvement in macular oedema in 71% (n = 12), stability in 24% (n = 4) and deterioration in 6% (n = 1). The mean injection interval where prescribed 4x 1 monthly (n = 13) was 61 days, with a range from 35 – 138 days.

Conclusions: In this real‐world setting with challenges providing patients with regular monthly treatment, faricimab demonstrates the ability to improve DMO in chronic disease with sub‐optimal dosing regimens. A majority of patients demonstrated anatomical improvements, and functional stability or improvement was seen in half of treated eyes. Though the anatomical outcomes were more positive than the functional outcomes on BCVA, this likely reflects the chronicity of DMO in affected eyes, and notably in half of the eyes treated where BCVA deteriorated, there was an alternative cause for this. Given the poorer prognosis of treatment non‐responsive DMO, faricimab is promising as a further option for these harder to treat patients. Overall, there would appear to be a role for faricimab to be a treatment option in chronic‐DMO, and its increased durability is beneficial in busy centres where it is challenging to provide patients with 1‐monthly dosing. This could be further supported by investigating outcomes in patients with treatment‐naive disease.
Comparative retinal study by OCT in Alzheimer's disease: Insights from the APP NL‐F/NL‐F model
Authors: Sanchez‐Puebla Lidia , López‐Cuenca Inés , Vázquez Alberto Arias , Salobrar‐Garcia Elena , Matamoros José A. , Lozano María Pilar Rojas , Fernández‐Albarral José A. , Elvira‐Hurtado Lorena , Ramirez Ana Isabel , Salazar Juan Jose , Saido Takaomi , Saito Takashi , Nieto‐Vaquero Carmen , Cuartero María Isabel , Moro María Ángeles , de Hoz Rosa , Ramirez Jose Manuel
Published: January 2025

Aims/Purpose: Transgenic mouse models of Alzheimer's disease (AD) have shown a correlation between retinal abnormalities and brain pathology. The APPNL‐F/NL‐F murine humanized AD model accurately replicates many pathological features seen in AD patients. This study aims to analyze, using manual retinal segmentation by optical coherence tomography (OCT), the changes occurring in several retinal layers in the APPNL‐F/NL‐F AD model at 6, 9, 12, 15, 17, and 20 months of age, in comparison to C57BL/6J mice (WT).

Methods: A diachronic study was conducted using OCT for manual retinal segmentation to evaluate changes in retinal layers. The analysis focused on retinal thickness in the retinal nerve fiber layer (RNFL)‐ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), and outer nuclear layer (ONL) based on Early Treatment Diabetic Retinopathy Study (ETDRS) sectors. The study included both the APPNL‐F/NL‐F AD model and age‐matched WT controls, with measurements taken at 6, 9, 12, 15, 17, and 20 months.

Results: Both the APPNL‐F/NL‐F model and WT animals exhibited changes in retinal thickness at various study time points. WT mice showed significant changes in the INL, OPL, and ONL. In contrast, the AD model exhibited significant changes in all analyzed retinal layers except for the IPL. The APPNL‐F/NL‐F model displayed significant thickness variations in the retinal layers analyzed, which closely resemble those found in humans during pre‐clinical, as well as mild and moderate stages of AD.

Conclusions: The study identifies early retinal vascular and structural changes in the APPNL‐F/NL‐F model that precede cognitive changes observed at later stages. These findings suggest that the retinal changes in this model more closely resemble those in human AD compared to other transgenic models, highlighting the potential of retinal assessments in early AD diagnosis.
Comparing membrane peeling techniques in lamellar macular hole surgery: A systematic review and meta‐analysis
Authors: Abu‐Dieh Anas , Er‐Reguyeg Yosra , Rhalem Elyazid , You Eunice , Hébert Mélanie , Dirani Ali
Published: January 2025

Aims: To compare outcomes of standard and alternative membrane peeling techniques in LMH surgery.

Methods: A systematic review and meta‐analysis was performed per the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines. Pairwise meta‐analysis of mean change in best corrected visual acuity (BCVA as logMAR) and LMH closure rate between flap embedding (FE) and standard peeling (ST) were conducted. A proportional meta‐analysis evaluated FTMH prevalence for each technique.

Results: 36 studies of 1200 eyes were included. Three techniques were identified: ST (29 studies), FE (7 studies) and fovea‐sparing peeling (4 studies). FE was superior to ST in BCVA change (MD ‐0.21; CI ‐0.33 to ‐0.10), LMH closure (RR 1.53; CI 1.23–1.90) and postoperative FTMH (RR 0.08; CI 0.01 to 0.58). LMH closure rate was higher (0.97; CI 0.88 to 0.99 vs. 0.81; CI 0.70 to 0.88) in alternative vs. ST, with postoperative FTMH occurring only in ST peelings (0.026; CI 0.013‐0.054).

Conclusions: Alternative peeling techniques have superior outcomes. Further randomized controlled studies are needed to confirm their efficacy and innocuity.
Progression of diabetic retinopathy during pregnancy: Retrospective study from birmingham and solihull
Authors: Khalifa Ahmad , Sobha Joseph
Published: January 2025

Aims/Purpose: To assess the progression of diabetic retinopathy (DR) in pregnant women with pre‐existing diabetes in the Birmingham and Solihull area and to evaluate adherence to recommended screening guidelines.

Methods: A retrospective review was conducted over 12 months (01/09/2022‐31/08/2023) using data from the Diabetic Eye Screening Program (DESP) and hospital records (Medisoft, OCT, and retina images). The study included pregnant women with pre‐existing diabetes who received maternity services at University Hospitals Birmingham (UHB) and were referred to DESP. Patients with gestational diabetes were excluded. Data collected included demographics, DR screening attendance, progression rates, and clinical outcomes.

Results: Out of 149 pregnant women with pre‐existing diabetes, 54 (36.2%) were not referred for initial screening by 12 weeks due to late presentation and delayed diabetes status confirmation. Of the total, 88 (59%) missed the 12‐week screening, 57 (40%) missed the 16‐20 week screening, and 67 (48%) missed the 28‐week screening. At 12 weeks, 27% were R0M0, 9% R1M0, 3% R1M1, and 1% R2M0/R2M1, with 8 referred to HES. At 16‐20 weeks, 43% were R0M0, 16% R1M0, 1% R3SM0, and 1% were unable to assess, with 2 referred to HES. By 28 weeks, 37% were R0M0, 12% R1M0, 1% R3SM1, and 2% were still being graded, with 1 referred to HES. The study highlighted significant cases, including one patient who progressed to severe NPDR and required bilateral PRP and Ozurdex treatment, and another who developed DMO treated with Ozurdex.

Conclusions: Diabetic retinopathy progression during pregnancy remains a significant concern, with many patients missing critical screening appointments, leading to advanced DR stages and severe visual impairment. Despite adherence to screening guidelines, patient non‐compliance and late referrals hinder effective management. Improved patient education and follow‐up strategies are essential to enhance screening attendance and outcomes, thereby preventing severe DR progression during pregnancy. Further research is necessary to develop targeted interventions for better compliance and timely treatment.
Anti‐Youth Ageism: What It Is and Why It Matters
Authors: Wray‐Lake Laura , Rottenberg Julia , Kennedy Heather
Published: January 2025

Ageism against older adults has been well studied, yet adolescents also experience ageism in pervasive and harmful ways. In this article, we describe anti‐youth ageism as a system of oppression that encompasses negative stereotypes, prejudices, and discrimination against adolescents that uphold power hierarchies and marginalize young people based on their age. Drawing from interdisciplinary theory and research, we examine adolescents' experiences of anti‐youth ageism at interpersonal, cultural, and institutional levels, and consider the ways anti‐youth ageism is internalized. Across many levels, anti‐youth ageism is understood in concert with other systems of oppression such as racism and cis‐heterosexism. The field needs a new wave of anti‐oppressive developmental science to understand the multilayered, intersectional manifestations of anti‐youth ageism and the impacts of anti‐youth ageism on various domains of development. Research can help foster the creation of intervention strategies to reduce harm to adolescents and their development.
Correction of Peri‐Implant Buccal Bone Dehiscence Following Sub‐Periosteal Peri‐Implant Augmented Layer Technique With Either Block or Particulate Xenograft: A Retrospective Study
Authors: Severi Mattia , Chiara Franzini , Simonelli Anna , Scapoli Chiara , Trombelli Leonardo
Published: January 2025

Objective

To evaluate the effectiveness of Sub‐periosteal Peri‐implant Augmented Layer (SPAL) technique performed with deproteinized bovine bone mineral (DBBM), delivered either as particulate (pDBBM) or block (bDBBM), in correcting a peri implant bone dehiscence (PIBD). Implants showing a thick (≥ 2 mm) peri‐implant buccal bone plate (PBBP) at placement were also examined.

Material and Methods

Patients with a PIBD ≥ 1 mm, treated with SPAL with either pDBBM (SPALparticulate) or bDBBM (SPALblock), and patients with an implant showing a PBBP ≥ 2 mm at insertion (CONTROL) were included. Re‐entry was performed either at 6 months (SPAL groups) or 3 months (CONTROL). The rate of patients presenting no PIBD at re‐entry was the primary outcome. Bone dehiscence height (BDH) and width (BDW), thickness of buccal tissues (BTT) and marginal bone level (MBL) were secondary outcomes.

Results

Thirty‐nine implants in 39 patients (14 in SPALparticulate,14 in SPALblock and 11 in CONTROL) were analyzed. No PIBD were found in SPALparticulate whereas in SPALblock one PIBD was present. Two patients in CONTROL presented a PIBD. A reduction in both BDH and BDW was observed in both SPALparticulate (2.7 ± 1.6 mm for BDH and 3.9 ± 0.2 mm for BDW) and SPALblock (2.5 ± 1.8 mm for BDH and 3.8 ± 1.1 mm for BDW). SPALblock showed a higher BTT than SPALparticulate at re‐entry (3.6 ± 1.3 mm for SPALblock and 2.6 ± 0.6 mm for SPALparticulate, p = 0.0160). All groups showed similar MBL.

Conclusion

SPAL performed with either a pDBBM or bDBBM is similarly effective in correcting a PIBD as well as in increasing BTT.
Automatic Vertical Root Fracture Detection on Intraoral Periapical Radiographs With Artificial Intelligence‐Based Image Enhancement
Authors: Ozsari Sifa , Kamburoğlu Kıvanç , Tamse Aviad , Yener Suna Elçin , Tsesis Igor , Yılmaz Funda , Rosen Eyal
Published: January 2025

Background/Aim

To explore transfer learning (TL) techniques for enhancing vertical root fracture (VRF) diagnosis accuracy and to assess the impact of artificial intelligence (AI) on image enhancement for VRF detection on both extracted teeth images and intraoral images taken from patients.

Materials and Methods

A dataset of 378 intraoral periapical radiographs comprising 195 teeth with fractures and 183 teeth without fractures serving as controls was included. DenseNet, ConvNext, Inception121, and MobileNetV2 were employed with model fusion. Prior to evaluation, Particle Swarm Optimization (PSO) and Deep Learning (DL) image enhancement were applied. Performance assessment included accuracy rate, precision, recall, F1‐score, AUC, and kappa values. Intra‐ and inter‐observer agreement, according to the Gold Standard (GS), were assessed using ICC and t‐tests. Statistical significance was set at p < 0.05.

Results

The DenseNet + Inception fusion model achieved the highest accuracy rate of 0.80, with commendable recall, F1‐score, and AUC values, supported by precision (0.81) and kappa (0.60) values. Molar tooth examination yielded an accuracy rate, precision, recall, and F1‐score of 0.80, with an AUC of 0.84 and kappa of 0.60. For premolar teeth, the fusion network showed an accuracy rate of 0.78, an AUC of 0.78, and notable metrics, including F1‐score (0.80), recall (0.85), precision (0.71), and kappa (0.55). ICC results demonstrated acceptable agreement (≥ 0.57 for molars, ≥ 0.52 for premolars).

Conclusion

TL methods have demonstrated significant potential in enhancing diagnostic accuracy for VRFs in radiographic imaging. TL is emerging as a valuable tool in the development of robust, automated diagnostic systems for VRF identification, ultimately supporting clinicians in delivering more accurate diagnoses.
Impacts of Weather Anomalies and Climate on Plant Disease
Authors: Kirk Devin , Cohen Jeremy M. , Nguyen Vianda , Childs Marissa L. , Farner Johannah E. , Davies T. Jonathan , Flory S. Luke , Rohr Jason R. , O'Connor Mary I. , Mordecai Erin A.
Published: January 2025

Predicting the effects of climate change on plant disease is critical for protecting ecosystems and food production. Here, we show how disease pressure responds to short‐term weather, historical climate and weather anomalies by compiling a global database (4339 plant–disease populations) of disease prevalence in both agricultural and wild plant systems. We hypothesised that weather and climate would play a larger role in disease in wild versus agricultural plant populations, which the results supported. In wild systems, disease prevalence peaked when the temperature was 2.7°C warmer than the historical average for the same time of year. We also found evidence of a negative interactive effect between weather anomalies and climate in wild systems, consistent with the idea that climate maladaptation can be an important driver of disease outbreaks. Temperature and precipitation had relatively little explanatory power in agricultural systems, though we observed a significant positive effect of current temperature. These results indicate that disease pressure in wild plants is sensitive to nonlinear effects of weather, weather anomalies and their interaction with historical climate. In contrast, warmer temperatures drove risks for agricultural plant disease outbreaks within the temperature range examined regardless of historical climate, suggesting vulnerability to ongoing climate change.
Between Merit and Patronage: Hybrid Appointments of Top Civil Service
Authors: Mamshae Ari
Published: January 2025

This article examines the complex balancing of political loyalty and meritocratic competence in the appointment of top civil servants—a pivotal aspect of public administration that is particularly relevant in developing contexts. Focusing on the Kurdistan Regional Government (KRG) of Iraq, this study aims to unravel how merit and patronage converge in the appointment processes of director generals (DGs). To this end, the article develops an analytical framework that conceptualizes “hybrid appointments” as a process in which merit‐based and patronage considerations are intricately interwoven. The article uses a mixed‐method research design, combining elite interviews with senior politicians and a quantitative analysis of original biographical data on top civil servants. It shows how politicians weigh merit‐based qualifications alongside political considerations in the appointment process, rather than substituting loyalty for competence. This finding challenges the traditional dichotomous understanding of merit versus patronage appointments, advancing our understanding of how top civil service appointments function in developing contexts.
Best Practices Guidelines for the Engagement of People With Lived Experience and Family Members in Mental Health and Substance Use Health Research: A Modified Delphi Consensus Study
Authors: Hawke Lisa D. , Dada‐Phillips Wuraola , Seiyad Hajar , Orson Josh , Goldsmith Lianne , Conway Susan , Jordan Adam , Sheikhan Natasha Y. , Hiebert Melissa , Kidd Sean , Kuluski Kerry
Published: January 2025

Introduction

People with lived experience of mental health and/or substance use conditions and their families (PWLE) are increasingly engaged in research, yet rigorous guidelines for engagement are lacking. This study aims to co‐design best practice guidelines to support the authentic, meaningful engagement of PWLE in mental health and/or substance use health research.

Methods

A multi‐panel modified Delphi study was conducted with 61 expert panelists (35 PWLE and family members, 26 researchers/research support staff from across Canada). Participants rated 56 recommendations for importance and clarity. Consensus was defined as ≥ 70% of participants rating items at 6 or 7 on a 7‐point Likert scale (‘very important’ or ‘essential’). Qualitative feedback was analysed using content analysis to identify new items and reviewed for improvements in item clarity. After each round, items not meeting the established threshold of importance were removed. Items with low clarity scores were reworded. A PWLE advisory panel was actively involved throughout the study's design, implementation, interpretation, and reporting, ensuring that the perspectives of people with lived experience were integrated throughout the research process.

Results

Three Delphi Rounds were conducted. In Round 1, importance ratings ranged from 51.7% to 96.7% of participants ranking the items above the established threshold (average 80.1%), with clarity ratings ranging from 39.3% to 86.9% (average 70.7%) and an average importance coefficient of variation (CV) of 0.16. Four items were deleted, two new items were added and fifty‐five items were revised. In Round 2, 60 (98.4%) participants responded. Importance ratings ranged from 57.6% to 96.7% (average 80.2%; average CV = 0.20). Clarity ratings ranged from 50.9% to 93.2% (average 77.9%). Five items were deleted and eleven revised. In Round 3, 60 (98.4%) participants provided importance ratings ranging from 66.7% to 98.3% (average 80.8%; average CV = 0.20), and clarity ratings ranging from 63.3% to 94.9% (average 81.1%). Three items were deleted and nine were revised. Forty‐four final best practices are proposed.

Conclusion

These co‐developed best practice guidelines offer recommendations for meaningful PWLE engagement in mental health and/or substance use health research. By following these guidelines, research teams can ensure that PWLE contributions are genuinely valued and effectively integrated, ultimately enhancing the quality and impact of the research and fostering authentic collaboration.

Patient and public involvement

People with lived experience were engaged throughout the project as key team members, from a patient‐oriented research perspective. They are also co‐authors on this manuscript.
Vascular flow alteration is a dominant pattern of liver pathology in patients with orthotopic lung transplants: a retrospective observational study
Authors: McCollum Kasey J. , LeClair Bethany Freeland , Chen Wei , Shi Chanjuan , Wegermann Kara , Pendse Avani A.
Published: January 2025

Aims

The number of orthotopic lung transplants (OLT) has skyrocketed since the 1960s, generating an ever‐increasing cohort of post‐OLT patients. Many challenges exist in the post‐OLT timeframe, including donor graft dysfunction, infection, malignancy, and immunosuppression‐related conditions. A rather elusive topic in the posttransplant setting remains the impact of the underlying disease process and donor lungs on other organ systems and the complications arising from the complex physiologic interactions. The liver represents a vital organ often impacted in many ways by the lung transplant procedure. Also, there is a higher likelihood of adverse outcomes in OLT recipients who have significant liver pathology. Yet little is known about the morphologic changes in liver after patients have received an OLT. In this study we retrospectively reviewed liver pathology cases obtained after the patient received an OLT.

Methods and results

Histology was reviewed by three pathologists and evaluated with a standardized checklist format. In our cohort, we found morphologic features of hepatic injury in the form of vascular outflow obstruction, nodular regenerative hyperplasia, portal vessel changes, and steatosis/steatohepatitis, but there was a striking absence of advanced fibrosis in our cohort.

Conclusion

Here we present the first comprehensive account of morphologic changes in livers of post‐OLT patients. We believe that this information will aid clinical decision‐making during monitoring of hepatic function and fibrosis in patients with OLT and other complex pulmonary diagnoses.
Ecological drivers of variation in the extent of the post‐fledging dependence period in the largest group of diurnal raptors
Authors: Gallego‐García Diego , Sarasola José Hernán
Published: January 2025

The post‐fledging dependence period (PFDP) is a fundamental stage in the life cycle of altricial birds that influences their long‐term survival and fitness. However, research on the duration of this period in raptors, and on the factors affecting it, is scarce. We performed the first literature review on the length of the PFDP in Accipitridae, the largest family among diurnal raptors, and a meta‐analysis examining the effects of breeding latitude and hemisphere, body weight and migratory status, controlling for species phylogeny. Hypotheses were tested at the levels of both species and populations. The length of the PFDP is known for less than half of Accipitridae species, with no data for two‐thirds of the threatened and near‐threatened species. Larger species and individuals breeding at lower latitudes showed a longer PFDP, as did non‐migrants and southern‐hemisphere breeders. The effect of latitude was more marked in larger species, in resident populations and in southern‐hemisphere breeders. This extended PFDP in larger and tropical raptors may promote juvenile survival. Migration timing and the effects of continentality in the northern hemisphere constrain the PFDP. These findings highlight the importance of encouraging the study of this key, but poorly known, life‐cycle stage of raptors.
Mechanism Study of E2F8 Activation of SPC25‐Mediated Glutamine Metabolism Promoting Immune Escape in Lung Adenocarcinoma
Authors: Luo Machang , Xie Lingyan , Lin Baoyan , Su Xia , Liang Rongzhang , Ma Zhiyi , Li Youtang
Published: January 2025

Tumour cell immune infiltration is linked to spindle pole component 25 (SPC25). The purpose of this work was to examine the function and molecular mechanism of SPC25 in immune escape in lung adenocarcinoma (LUAD). SPC25 expression in LUAD was examined using The Cancer Genome Atlas (TCGA) database, and RT‐qPCR was used to confirm the results. The study involved the use of CD8+ T lymphocytes for immunoinfiltration analysis of SPC25, Gene Set Enrichment Analysis (GSEA) analysis of signalling pathways enriched by SPC25, identification of putative regulatory molecules of SPC25, and confirmation through the use of dual‐luciferase and ChIP tests. To evaluate LUAD cell capacity for immune escape, a co‐culture technique was employed. Measurements of glutamine uptake, glutamate and α‐ketoglutarate levels, NADPH/NADP and GSH/GSSG ratios, and SLC1A5 expression were used to assess the levels of glutamine metabolism. LUAD had increased SPC25 expression. In LUAD cells, immune escape was facilitated by SPC25 knockdown, whereas overexpression had the reverse effect. SPC25 enrichment in the glutamine metabolism pathway was shown by GSEA analysis. Through increased glutamine metabolism brought on by SPC25 overexpression, immune escape was improved in LUAD and could be mitigated by GPNA therapy. E2F8 was also shown to be the transcription factor associated with SPC25, and they showed a binding interaction. By inhibiting glutamine metabolism through SPC25, knocking down E2F8 prevented immune escape in LUAD cells. On the other hand, the suppression of immune escape in LUAD cells caused by E2F8 knockdown was overcome by overexpression of SPC25. In LUAD, E2F8 stimulates SPC25 expression to facilitate glutamine metabolism and encourage immune escape. Our research validates a novel immune escape pathway driven by SPC25 in LUAD cells, providing LUAD patients with potentially effective immunotherapeutic approaches.
Imeglimin, unlike metformin, does not perturb differentiation of human induced pluripotent stem cells towards pancreatic β‐like cells and rather enhances gain in β cell identity gene sets
Authors: Imada Tasuku , Sasaki Shugo , Yamaguchi Hiroki , Ueda Ayaka , Kawamori Dan , Katakami Naoto , Shimomura Iichiro
Published: January 2025

Aims/Introduction

Metformin treatment for hyperglycemia in pregnancy (HIP) beneficially improves maternal glucose metabolism and reduces perinatal complications. However, metformin could impede pancreatic β cell development via impaired mitochondrial function. A new anti‐diabetes drug imeglimin, developed based on metformin, improves mitochondrial function. Here we examine the effect of imeglimin on β cell differentiation using human induced pluripotent stem cell (iPSC)‐derived pancreatic islet‐like spheroid (SC‐islet) models.

Materials and Methods

Human iPSCs are differentiated into SC‐islets by three‐dimensional culture with and without imeglimin or metformin. Differentiation efficiencies of SC‐islets were analyzed by flow cytometry, immunostaining, quantitative PCR, and insulin secretion assay. RNA sequencing and oxygen consumption rate were obtained for further characterization of SC‐islets. SC‐islets were cultured with proinflammatory cytokines, in part mimicking the uterus environment in HIP.

Results

Metformin perturbed SC‐islet differentiation while imeglimin did not alter it. Furthermore, imeglimin enhanced the gene expressions of β cell lineage markers. Maintenance of mitochondrial function and optimization of TGF‐β and Wnt signaling were considered potential mechanisms for augmented β cell maturation by imeglimin. In the presence of proinflammatory cytokines, imeglimin ameliorated β cell differentiation impaired by cytokines and metformin.

Conclusions

Imeglimin does not perturb differentiation of SC‐islet cells and rather enhances gain in β cell identity gene sets in contrast to metformin. This may lead to the improvement of in vitro β cell differentiation protocols.
Boosting Dietary Compliance After Bariatric Surgery: Winning Tactics for Patients
Authors: Deng Ling , Tao Yuli , Li Nianxing
Published: January 2025

Background

Bariatric metabolic surgery has emerged as a pivotal intervention for managing obesity, with strict adherence to postoperative nutritional guidelines being paramount for patient outcomes. This study seeks to evaluate dietary compliance levels and the factors that influence them among patients who have undergone bariatric surgery, offering insights to enhance clinical strategies.

Method

Our research encompassed patients who underwent bariatric metabolic surgery at our institution from February 2022 to December 2023. We utilised a validated dietary compliance scale to assess how well patients followed postoperative nutritional advice. To determine factors linked to dietary compliance, we conducted Pearson correlation and logistic regression analyses.

Results

The study comprised 176 individuals who underwent bariatric metabolic surgery, with a concerning 60.23% exhibiting inadequate dietary compliance. The Pearson correlation analysis revealed significant correlations between poor dietary compliance and several demographic factors: age (r = −0.516), gender (r = 0.467), educational attainment (r = −0.605) and monthly household income (r = −0.558). Logistic regression analysis confirmed age (OR = −2.157, 95% CI: −3.120 to −1.403), gender (OR = 2.006, 95% CI: 1.821–2.665), education level (OR = −3.081, 95% CI: −4.147 to −1.679), and average monthly family income (OR = −2.847, 95% CI: −3.516 to −1.225) as independent predictors of poor dietary compliance in post‐bariatric metabolic surgery patients.

Conclusion

The high incidence of poor dietary compliance among patients following bariatric metabolic surgery is a significant concern and is notably influenced by demographic variables such as age, gender, education and economic status. It is imperative for healthcare professionals to consider these variables when developing personalised interventions aimed at improving dietary compliance within this patient group.