bluuebunny/crossref_metadata_2025 huggingface dataset:
Testosterone therapy in diabetes and pre‐diabetes
Authors: Corona Giovanni , Vena Walter , Pizzocaro Alessandro , Vignozzi Linda , Sforza Alessandra , Maggi Mario
Published: December 2022

Background

Type 2 diabetes mellitus and pre‐diabetes are associated with reduced circulating testosterone levels. However, the role of testosterone replacement therapy in these patients is still conflicting.

Objectives

To summarize and critically analyze available data on the possible effect of testosterone administration in men with glucose abnormalities.

Materials and methods

A comprehensive systematic review was performed. When available, meta‐analytic data were preferred. To better analyze the relationship between testosterone and the pre‐diabetes condition, a systematic analysis was performed and the data obtained with the latter search were used for a meta‐analytic approach. Finally, clinical data derived from a consecutive series of 4682 patients seeking medical care for sexual dysfunction at the University of Florence were also considered.

Results

Patients with impaired fasting glucose were characterized by a 3 nmol/L lower level of total testosterone when compared to controls. Similarly, impaired fasting glucose was associated with a 1.8‐fold increased risk of hypogonadism, when compared to subjects with normal glucose levels. Waist circumference and body mass index resulted as being the best predictors of reduced total testosterone levels. Secondary hypogonadism was two times higher in subjects with impaired fasting glucose when compared to rates observed in the general population. Testosterone replacement therapy was able to improve body composition, insulin resistance, and glucose profile both in impaired fasting glucose and type 2 diabetes mellitus whereas its role on body weight, lipid profile, and sexual function was less evident.

Discussion and conclusion

Weight loss and physical activities are able to improve both metabolic profile and testosterone levels. The combined approach of testosterone replacement therapy and lifestyle modifications could be suggested in symptomatic hypogonadal men to better motivate patients to perform physical activity which can eventually result in weight loss as well as metabolic profile and sexual function improvement. Whether or not these approaches can prevent the development of type 2 diabetes mellitus from pre‐clinical conditions requires more studies.
Quantitative end‐tidal carbon dioxide at initiation of resuscitation may help guide the ventilation of infants born at less than 30 weeks gestation
Authors: Shah Dharmesh , Tracy Mark , Hinder Murray , Badawi Nadia
Published: December 2022

Aim

Estimation of end‐tidal carbon dioxide (EtCO2) with capnography can guide mask ventilation in infants born at less than 30 weeks of gestation. Chemical‐sensitive colorimetric devices to detect CO2 are widely used at resuscitation. We aimed to quantify EtCO2 in the first breaths following initiation of mask ventilation at birth and correlated need for endotracheal intubation.

Methods

Infants <30 weeks gestation receiving mask ventilation were randomised into two groups of mask‐hold technique (one‐person vs. two‐person). Data on EtCO2 in the first 30 breaths, time to achieve 5 mmHg, 10 mmHg and 15 mmHg CO2 using a respiratory function monitor was determined.

Results

Twenty‐five infants with a mean gestation of 27.3 (±3 weeks) and mean birth weight 920.4 (±188.3 g) were analysed. The median EtCO2 was 5.6 mmHg in the first 10 breaths, whereas it was 12.6 mmHg for 11–20 breaths and 18 mmHg for 21–30 breaths. There was no significant difference in maximum median EtCO2 for the first 20 breaths, although EtCO2 was significantly lower in infants who were intubated (32.0 vs. 15.0, p = 0.018).

Conclusion

EtCO2 monitoring in infants <30 weeks gestation at birth is feasible and reflective of alveolar ventilation. EtCO2 may help guide ventilation of preterm infants at birth.
Effects of social norms and message framing on reducing the stigma of gynecological diseases: A cognitive‐affective‐behavioral model
Authors: Dong Yujie , Chen Meng , Wu Yuheng
Published: December 2022

This paper presents an experiment exploring message strategies to reduce the stigma of gynecological diseases and promote women's sexual and reproductive health. Drawing on the cognitive‐affective‐behavioral model of stigma, we propose that social norms and message framing as two message strategies, respectively, address the cognitive and affective components of the stigma of gynecological diseases, which lead to desired changes in the help‐seeking intention as the behavioral component. We conducted a 3 (no norm vs. descriptive norm vs. descriptive plus injunctive norms) by 2 (gain‐framed vs. loss‐framed) between‐subject experiment (N = 202). The results reveal that messages with the combination of descriptive and injunctive norms reduce the greatest cognitive components of stigma. Gain‐framed messages induced fewer affective components than loss‐framed ones. The results suggest that changes in the cognitive and affective components of stigma may sequentially lead to favorable changes in the behavioral component. This study contributes to public understanding of the stigma of gynecological diseases by disentangling the various components and identifying the specific message strategies for stigma reduction.
Exploratory pharmacovigilance with machine learning in big patient data: A focused scoping review
Authors: Kaas‐Hansen Benjamin Skov , Gentile Simona , Caioli Alessandro , Andersen Stig Ejdrup
Published: December 2022

Background

Machine learning can operationalize the rich and complex data in electronic patient records for exploratory pharmacovigilance endeavours.

Objective

The objective of this review is to identify applications of machine learning and big patient data in exploratory pharmacovigilance.

Methods

We searched PubMed and Embase and included original articles with an exploratory pharmacovigilance purpose, focusing on medicinal interventions and reporting the use of machine learning in electronic patient records with ≥1000 patients collected after market entry.

Findings

Of 2557 studies screened, seven were included. Those covered six countries and were published between 2015 and 2021. The most prominent machine learning methods were random forests, logistic regressions, and support vector machines. Two studies used artificial neural networks or naive Bayes classifiers. One study used formal concept analysis for association mining, and another used temporal difference learning. Five studies compared several methods against each other. The numbers of patients in most data sets were in the order of thousands; two studies used what can more reasonably be considered big data with >1 000 000 patients records.

Conclusion

Despite years of great aspirations for combining machine learning and clinical data for exploratory pharmacovigilance, only few studies still seem to deliver somewhat on these expectations.
Acquired Haemophilia A in four north European countries: survey of 181 patients
Authors: Lindahl Rickard , Nummi Vuokko , Lehtinen Anna‐Elina , Szanto Timea , Hiltunen Leena , Olsson Anna , Glenthoej Andreas , Chaireti Roza , Vaide Ines , Funding Eva , Zetterberg Eva
Published: December 2022

Acquired haemophilia A (AHA) is a rare bleeding disorder caused by acquired antibodies against coagulation factor VIII. In the Nordic countries, treatment and outcomes have not been studied in recent times. To collect retrospective data on patients diagnosed with AHA in the Nordic countries between 2006 and 2018 and compare demographic data and clinical outcomes with previously published reports, data were collected by six haemophilia centres: three Swedish, one Finnish, one Danish and one Estonian. The study included 181 patients. Median age at diagnosis was 76 (range 5–99) years, with even gender distribution. Type and severity of bleeding was comparable to that in the large European Acquired Haemophilia Registry study (EACH2). Bleedings were primarily treated with activated prothrombin complex concentrate (aPCC) with a high success rate (91%). For immunosuppressive therapy, corticosteroid monotherapy was used most frequently and this may be the cause of the overall lower clinical remission rate compared to the EACH2 study (57% vs. 72%). Survey data on 181 patients collected from four north European countries showed similar demographic and clinical features as in previous studies on AHA. aPCC was used more frequently than in the EACH2 study and the overall remission rate was lower.
Survival rate prediction of nasopharyngeal carcinoma patients based on MRI and gene expression using a deep neural network
Authors: Zhang Qihao , Wu Gang , Yang Qianyu , Dai Ganmian , Li Tiansheng , Chen Pianpian , Li Jiao , Huang Weiyuan
Published: December 2022

To achieve a better treatment regimen and follow‐up assessment design for intensity‐modulated radiotherapy (IMRT)‐treated nasopharyngeal carcinoma (NPC) patients, an accurate progression‐free survival (PFS) time prediction algorithm is needed. We propose developing a PFS prediction model of NPC patients after IMRT treatment using a deep learning method and comparing that with the traditional texture analysis method. One hundred and fifty‐one NPC patients were included in this retrospective study. T1‐weighted, proton density and dynamic contrast‐enhanced magnetic resonance (MR) images were acquired. The expression level of five genes (HIF‐1α, EGFR, PTEN, Ki‐67, and VEGF) and infection of Epstein–Barr (EB) virus were tested. A residual network was trained to predict PFS from MR images. The output as well as patient characteristics were combined using a linear regression model to provide a final PFS prediction. The prediction accuracy was compared with that of the traditional texture analysis method. A regression model combining the deep learning output with HIF‐1α expression and Epstein–Barr infection provides the best PFS prediction accuracy (Spearman correlation R2 = 0.53; Harrell's C‐index = 0.82; receiver operative curve [ROC] analysis area under the curve [AUC] = 0.88; log‐rank test hazard ratio [HR] = 8.45), higher than a regression model combining texture analysis with HIF‐1α expression (Spearman correlation R2 = 0.14; Harrell's C‐index =0.68; ROC analysis AUC = 0.76; log‐rank test HR = 2.85). The deep learning method does not require a manually drawn tumor region of interest. MR image processing using deep learning combined with patient characteristics can provide accurate PFS prediction for nasopharyngeal carcinoma patients and does not rely on specific kernels or tumor regions of interest, which is needed for the texture analysis method.
Genetic diversity in global populations of the critically endangered addax (Addax nasomaculatus) and its implications for conservation
Authors: Dicks Kara L. , Ball Alex D. , Banfield Lisa , Barrios Violeta , Boufaroua Mohamed , Chetoui Abdelkader , Chuven Justin , Craig Mark , Faqeer Mohammed Yousef Al , Garba Hamissou Halilou Mallam , Guedara Hela , Harouna Abdoulaye , Ivy Jamie , Najjar Chawki , Petretto Marie , Pusey Ricardo , Rabeil Thomas , Riordan Philip , Senn Helen V. , Taghouti Ezzedine , Wacher Tim , Woodfine Tim , Gilbert Tania
Published: December 2022

Threatened species are frequently patchily distributed across small wild populations, ex situ populations managed with varying levels of intensity and reintroduced populations. Best practice advocates for integrated management across in situ and ex situ populations. Wild addax (Addax nasomaculatus) now number fewer than 100 individuals, yet 1000 of addax remain in ex situ populations, which can provide addax for reintroductions, as has been the case in Tunisia since the mid‐1980s. However, integrated management requires genetic data to ascertain the relationships between wild and ex situ populations that have incomplete knowledge of founder origins, management histories, and pedigrees. We undertook a global assessment of genetic diversity across wild, ex situ and reintroduced populations in Tunisia to assist conservation planning for this Critically Endangered species. We show that the remnant wild populations retain more mitochondrial haplotypes that are more diverse than the entirety of the ex situ populations across Europe, North America and the United Arab Emirates, and the reintroduced Tunisian population. Additionally, 1704 SNPs revealed that whilst population structure within the ex situ population is minimal, each population carries unique diversity. Finally, we show that careful selection of founders and subsequent genetic management is vital to ensure genetic diversity is provided to, and minimize drift and inbreeding within reintroductions. Our results highlight a vital need to conserve the last remaining wild addax population, and we provide a genetic foundation for determining integrated conservation strategies to prevent extinction and optimize future reintroductions.
DCUN1D1, a new molecule involved in depigmentation via upregulating CXCL10
Authors: Zhao Yan , Hu Yebei , Shen Qingmei , Xiong Renxue , Song Xiuzu , Guan Cuiping
Published: December 2022

CD8+ T cells in the lesioned site play a crucial role in the pathogenesis of vitiligo. The chemokine CXCL10 secreted by keratinocytes regulates the migration of CD8+ T cells into the skin. In our previous study, we found that DCUN1D1 expression in vitiligo lesions positively correlates with Cxcl10 expression. In this study, the regulatory effect of DCUN1D1 on CXCL10 and cell function was investigated. DCUN1D1 protein expression was significantly higher in the skin tissue from vitiligo lesions compared with samples from healthy controls. High expression of DCUN1D1 in keratinocytes caused local hair depigmentation in mice, reduced melanin content, high infiltration of CD8+ T cells and increased CXCL10 expression. This suggested that DCUN1D1 may regulate CD8+ T‐cell infiltration and depigmentation through CXCL10. Inhibition of DCUN1D1 expression in HaCaT cells abolished the IFN‐γ‐induced upregulation of p‐JAK1, p‐STAT1 and CXCL10, suppressed the H2O2‐induced ROS generation and apoptosis, and upregulated tyrosinase expression in melanocytes. Collectively, these results show that DCUN1D1 is an important regulator of CXCL10 and may be a new target for the treatment of vitiligo.
The emerging role of PKM in keratinocyte homeostasis and pathophysiology
Authors: Demeter Jenna B. , Elshaarrawi Ahmed , Dowker‐Key Presley D. , Bettaieb Ahmed
Published: December 2022

Increased aerobic glycolysis in keratinocytes has been reported as a hallmark of skin diseases while its pharmacological inhibition restores keratinocyte homeostasis. Pyruvate kinase muscle (PKM) isoforms are key enzymes in the glycolytic pathway and, therefore, an attractive therapeutic target. Simon Nold and colleagues used CRISPR/Cas9‐mediated gene editing to investigate the outcomes of PKM splicing perturbations and specific PKM1 or PKM2 deficiency in human HaCaT keratinocytes. Collectively, the study demonstrated different effects of PKM1 or PKM2 depletion on the reciprocal PKM isoform and on keratinocyte gene expression, metabolism and proliferation. Findings from this study provide novel insights into the role of PKM in keratinocyte homeostasis, warranting additional investigations into the underlying molecular mechanisms and potential therapeutic applications.
The end of ESG
Authors: Edmans Alex
Published: December 2022

ESG is both extremely important and nothing special. It's extremely important because it's critical to long‐term value, and so any academic or practitioner should take it seriously, not just those with “ESG” in their research interests or job title. Thus, ESG doesn't need a specialized term, as that implies it's niche—considering long‐term factors isn't ESG investing; it's investing. It's nothing special since it's no better or worse than other intangible assets that create long‐term financial and social returns, such as management quality, corporate culture, and innovative capability. Companies shouldn't be praised more for improving their ESG performance than these other intangibles; investor engagement on ESG factors shouldn't be put on a pedestal compared to engagement on other value drivers. We want great companies, not just companies that are great at ESG.
Earlier leaf senescence dates are constrained by soil moisture
Authors: Wang Xiaoyue , Wu Chaoyang , Liu Ying , Peñuelas Josep , Peng Jie
Published: December 2022

The unprecedented warming that has occurred in recent decades has led to later autumn leaf senescence dates (LSD) throughout the Northern Hemisphere. Yet, great uncertainties still exist regarding the strength of these delaying trends, especially in terms of how soil moisture affects them. Here we show that changes in soil moisture in 1982–2015 had a substantial impact on autumn LSD in one‐fifth of the vegetated areas in the Northern Hemisphere (>30° N), and how it contributed more to LSD variability than either temperature, precipitation or radiation. We developed a new model based on soil‐moisture‐constrained cooling degree days (CDDSM) to characterize the effects of soil moisture on LSD and compared its performance with the CDD, Delpierre and spring‐influenced autumn models. We show that the CDDSM model with inputs of temperature and soil moisture outperformed the three other models for LSD modelling and had an overall higher correlation coefficient (R), a lower root mean square error and lower Akaike information criterion (AIC) between observations and model predictions. These improvements were particularly evident in arid and semi‐arid regions. We studied future LSD using the CDDSM model under two scenarios (SSP126 and SSP585) and found that predicted LSD was 4.1 ± 1.4 days and 5.8 ± 2.8 days earlier under SSP126 and SSP585, respectively, than other models for the end of this century. Our study therefore reveals the importance of soil moisture in regulating autumn LSD and, in particular, highlights how coupling this effect with LSD models can improve simulations of the response of vegetation phenology to future climate change.
THE WELFARE EFFECTS OF MANDATORY REEMPLOYMENT PROGRAMS: COMBINING A STRUCTURAL MODEL AND EXPERIMENTAL DATA
Authors: Maibom Jonas
Published: December 2022

This article estimates a model of job search with utility costs and benefits triggered by mandatory reemployment programs. I use data from an experiment that generates exogenous variation in the threat of program participation and an increase in the job finding rate. I calculate the impact of the experiment on worker welfare, and find that participants would be willing to give up 1.5–1.7 weeks of unemployment benefits to avoid participation. These welfare costs vary across workers and are larger for workers with weaker employment prospects. Overall, welfare costs are substantial and therefore important to take into account.
Serum Bile Acids in Cattle: Diurnal Variations and Variations Due to Stage of Lactation
Authors: Olsson T.
Published: December 2022

Serum bile acid (SBA) concentrations in dairy cows were determined by an enzymatic method (Enzabile®, Nyegaard, Norway). The method showed a good reproducibility and an acceptable accuracy for routine determination of SBA in dairy cows. Storage of serum at —20 C for up to 210 days did not intluence the SBA concentration.

Tlie SBA concentrations varied considerably between individual cows (mean 37.4μmol/l, S. D. 25.5 μmol/l, range 5—180 μmol/1) but did not show any significant diurnal variation. Thus, in contrast to what is reported from monogastric species, no postprandial increase was observed in cattle. There was no effect of parity or season, whereas a successive and significant decrease of the SBA levels was imticed through lactation.
Selective laser trabeculoplasty (SLT) in eyes with angle recession glaucoma
Authors: Abdi Rhizlane
Published: December 2022

Purpose: To describe the results of selective laser trabeculoplasty (SLT) in eyes with angle recession glaucoma.

Methods: a retrospective case series of 8 eyes of 8 patients with history of non‐penetrating injury to the eye resulted in angle recession glaucoma. All eyes underwent SLT. Post‐treatment, the best‐corrected visual acuity (BCVA), intraocular pressure (IOP), number of glaucoma medications, additional need for intervention, and complications were recorded. Success of treatment was defined as an IOP reduction of 20% or reduction in medications and maintaining target IOP without further intervention during follow up period of more than 3 months.

Results: Mean patient age was 44 years, 6 males and 2 females. Mean pre‐ and post‐SLT IOP were 20.31 ± 3.59 and 15.04 ± 3.13 mmHg, respectively. IOP decreased significantly in all follow‐up visits. SLT treatment resulted in decreased IOP by 21% in 2 patients and by 25% with reduced medication burden in 4 patients and reduced medication burden in 2 patients who stopped glaucoma medication with no significant change in IOP (from 10 to 14 mmHg) at last follow up visit at 45 months.

Conclusions: SLT is a safe procedure that cloud be a reasonable alternative management in angle recession glaucoma when patients are unwilling to try medical or surgical intervention.
Exposure to subthreshold dose of UVR‐B does not induce apoptosis in the rat lens in vivo during the first 24 hours
Authors: Galichanin Konstantin , Falkman Lovisa , Yu Zhaohua
Published: December 2022

Purpose: The aim of this study is to investigate the time evolution of active caspase 3 in the rat lens after in vivo exposure to subthreshold dose of UVR‐B.

Methods: Twenty six‐week‐old female albino Sprague–Dawley rats were exposed to subthreshold dose (1 kJ/m2) of UVR‐B unilaterally and sacrificed at 1, 8, 16 and 24 h after exposure. Lenses were enucleated and active caspase 3 protein was detected by Western Blot. The time evolution was then plotted as a function of relative mean difference in active caspase 3 between exposed and nonexposed lenses.

Results: There is expression of active caspase 3 in both exposed and nonexposed lenses but there is no difference in relative mean difference in active caspase 3 between exposed and nonexposed lenses in all four postexposure groups.

Conclusions: Exposure to subthreshold dose of UVR‐B does not induce apoptosis in the rat lens in vivo within first 24 hours. Apoptosis occurs in the rat lens independently from the exposure to subthreshold dose of UVR‐B.
Dyschromatopsia in multiple sclerosis reflects diffuse chronic neurodegeneration beyond anatomical landmarks
Authors: González Antonio Barreiro , Sanz Maria T. , Carratalà‐Boscà Sara , Pérez‐Miralles Francisco , Alcalá Carmen , España‐Gregori Enrique , Casanova Bonaventura
Published: December 2022

Purpose: To formulate and validate a dyschromatopsia linear regression model in patients with multiple sclerosis (MS).

Methods: 64 MS patients (50 to formulate the model and 14 for its validation) underwent neurological (Expanded Disability Status Scale, EDSS), colour vision (Farnsworth D15 test), and peripapillary retinal nerve fibre layer (pRNFL) and retinal evaluation with spectral‐domain optical coherence tomography (SD‐OCT). Neuroradiological examination permitted to obtain brain parenchymal fraction (BPF) and cervical spinal cord volume (SC). Ophthalmic parameters were calculated as the average of both non‐optic neuritis (ON) eyes, and in case the patient had previous ON, the value of the fellow non‐ON eye was taken. The influence of sex, age, disease duration and history of disease‐modifying treatment (first‐ or second‐line DMT) was tested as covariables that could influence colour perception.

Results: Colour confusion index (log CCI) correlated with pRNFL (r = −0.322, p = 0.009), ganglion cell layer (GCL, r = −0.321, p = 0.01), BPF (r = −0.287, p = 0.021), SC volume (r = −0.33, p = 0.008), patients' age (r = 0.417, p = 0.001), disease duration (r = 0.371, p = 0.003) and EDSS (r = 0.44, p = 0.001). The following CCI equation was obtained: log (CCI) = 0.316–0.224 BPF –0.187 SC volume (mm3) +0.226 age (years) +0.012 disease duration (years) −0.372 GCL (μm).

Conclusions: CCI correlates with MS clinical and paraclinical established biomarkers suggesting chronic diffuse neurodegeneration in MS operates at brain, SC and retina linking all three compartments. Colour vision outcome can be calculated through the aforementioned variables for clinical and research purposes.
Signal shadowing during intraoperative optical coherence tomography assisted vitreoretinal surgery: A systemic analysis
Authors: Reyna Erick Carlos , Öztek Melisa , Binder Susanne , Stieger Knut , Lytvynchuk Lyubomyr
Published: December 2022

Purpose: To analyse the clinical significance of signal shadowing during intraoperative optical coherence tomography (iOCT) assisted vitreoretinal surgery (PPV) caused by vitreoretinal instruments (VRI), dyes, and vitreous substitutes and to quantify its impact on iOCT imaging.

Methods: In this retrospective observational study, imaging data from thirty‐five (35) patients undergoing an iOCT‐assisted PPV with Rescan® 700 (Zeiss, Oberkochen, Germany) were analysed. The iOCT image data were divided into three groups: VRI (17 cases), tissue dyes (8 cases), and vitreous substitutes (10 cases). The images were then post‐processed using a graphic software (histogram, grey level (GL)) and compared with paired image controls without clinically perceptive interference to measure the grade of picture quality distortion. Data were statistically analysed.

Results: The intraocular portion of all VRI caused a high average GL interference compared to controls (26.9 ± 2.3 vs. 35.9 ± 0.83; p < 0.05), obscuring the area of interest. The instruments' tips produced a low‐grade shadowing, allowing the underlying tissue to be distinguished. The stains analysed demonstrated a wide interference range, indocyanine green (9.2 ± 1.4) and triamcinolon acetonide (13.9 ± 10.0) showed a high shadowing, while lutein‐based dye (38.4 ± 6.4) and Brilliant Blue (39.9 ± 3.3) exhibited no significant distortion. All vitreous substitutes analysed showed an insignificant shadowing effect on iOCT (Air 42.9 ± 5.1, PFCL 46.0 ± 5.1 vs. 44.5 ± 0.32; p < 0.05).

Conclusions: All intraocular instruments showed a significant image interference during iOCT assisted surgery. All dyes except Brilliant Blue produced additional shadowing effect compared to controls. Implementation of new imaging techniques or/and materials with low‐grade interference for surgical instruments could overcome a clinically relevant shadow effect on iOCT and maximize the technology's visual accuracy.
Association of transforming growth factor beta induced mutations with congenital and juvenile onset open angle glaucoma
Authors: Gupta Viney , Panigrahi Arnav , Somarajan Bindu , Gupta Shikha , Tripathy Koushik , Singh Abhishek , Sharma Anshul , Kishore Krishna , Pradhan Dibyabhaba , Sharma Arundhati
Published: December 2022

Purpose: To investigate the molecular basis of congenital glaucoma in a family with GAPO (growth retardation, alopecia, pseudoanodontia, and progressive optic atrophy) syndrome.

Methods: We report ocular features of three girls with GAPO syndrome born of consanguineous marriage in a multi‐ generation consanguineous family. The proband (4 year old girl) and her younger sibling (1 year old girl) were operated for bilateral congenital glaucoma in both eyes. The elder sibling (10 year old female) had features of GAPO syndrome but did not manifest features of glaucoma.

Results: A genetic evaluation using whole exome sequencing revealed a homozygous ANTXR1 mutation in all 3 affected siblings with GAPO. No other mutations were detected in the genes associated with glaucoma. A rare missense mutation in Transforming Growth Factor Beta Induced (TGFBI) gene was shared in the two siblings with congenital glaucoma and GAPO syndrome. We then looked for the presence of TGFBI gene mutations in another cohort of 54 unrelated patients with early onset glaucoma (before 25 years of age) in whom Whole exome sequencing was previously done and no known glaucoma mutations were detected. We found three TGFBI mutations present in three unrelated juvenile onset open angle glaucoma (JOAG) patients, one of whom also had an associated corneal granular dystrophy. None of these patients had any other mutations associated with known genes for glaucoma.

Conclusions: Mutations in TGFBI gene could have a role in the pathogenesis of congenital and juvenile onset open angle glaucoma.

References

1. Pang CP, Fan BJ, Canlas O, Wang DY, Dubois S, Tam PO, Lam DS, Raymond V, Ritch R. A genome‐wide scan maps a novel juvenile‐onset primary open angle glaucoma locus to chromosome 5q. Mol Vis. 2006;12:85–92.

2. Kim JE, Han MS, Bae YC, Kim HK, Kim TI, Kim EK, Kim IS. Anterior segment dysgenesis after overexpression of transforming growth factor‐beta‐induced gene, beta igh3, in the mouse eye. Mol Vis. 2007;13:1942–52. doi: v13/a219.
Assessment of visual function and the neuroretina in subjects diagnosed with colour blindness
Authors: Tello Alvaro , Castro‐Roger Luisa , Mallen Victor , Palomar Elisa Viladés , Ciordia Beatriz Cordón , Altabás María José Vicente , Rodrigo Maria Jesus , Perié Manuel Subías , Campo Lorena Arias , Munuera Inés , Fuertes María Isabel , Garcia‐Martin Elena
Published: December 2022

Purpose: To assess whether the existence of colour vision deficiency or colour blindness involves impairment of visual acuity, contrast sensitivity and colour vision and results in variations in retinal nerve fibre layer (RNFL) thickness, macular area, retinal ganglion cell complex and retinal layers that contain photoreceptors (bastons and cones) versus subjects with normal colour vision within the same age and gender distribution.

Methods: Cross‐sectional and observational study including 50 eyes of subjects with colour blindness and 50 eyes of control subjects. Visual function (visual acuity, contrast sensitivity and colour vision) and neuroretinal structure were assessed in all subjects using optical coherence tomography (OCT).

Results: Significant thinning of the retinal nerve fibre layer, ganglion cell layer and retina were observed in the colour blindness group. Significant thinning was also recorded in layers that involve photoreceptor nuclei (between the outer limiting layer and the Bruch membrane and between the outer plexiform layer and the outer limiting membrane).

Conclusions: Significantly reduced thicknesses in the RNFL and several retinal layers (ganglion cell and photoreceptor layers) were found, demonstrating that colour blindness is associated with thinning in retinal and RNFL thickness, and in the retinal layers that involve photoreceptor nuclei. OCT study with retinal segmentation therefore seems to be a marker of colour blindness of utility in clinical practice in the case of doubt regarding diagnosis. This analysis could be useful in evaluating the effectiveness of potential therapies such as gene treatment.
Autophagy and inflammation related RNA levels are elevated in Finnish age‐related macular degeneration patient blood serum
Authors: Liukkonen Mikko , Ghimire Bishwa , Kivinen Niko , Siintamo Leea , Koskela Ali , Kaarniranta Kai
Published: December 2022

Purpose: Patients with wet age‐related macular degeneration (wAMD) exhibit altered levels of genetic and epigenetic material in their systemic circulation. Cellular level processes related to autophagy and inflammation have previously been shown to associate with wAMD and its progression. Thus, measuring RNA levels in peripheral blood may help understand the causes of wAMD, explain why there exist differences in patient response to treatments, and find genetic commonalities between other diseases and wAMD.

Methods: Blood samples as well as patient characteristics were collected from 63 wAMD patients and 65 controls. Serum was separated and Illumina Stranded Total RNA library preparation kits were used for RNA‐sequencing. Data was processed and analysed for differentially expressed (DE) genes in R using the edgeR package.

Results: Preliminary results show that, among others, microtubule associated protein 1 light chain 3 beta 2 (MAP1LC3B2) levels are significantly elevated (p = 0.028, logFC = 1.631) in Finnish wAMD patients compared to the control group. Higher levels of ankyrin 3 (ANK3) and cluster of differentiation 96 (CD96) were found in the control group (p = 0.001, logFC = −1.805; p = 0.002, logFC = −1.725). In addition, MAP1LC3B2 levels were elevated in patients with blood pressure medication (p = 0.025, logFC = 1.943).

Conclusions: LC3B2, produced by MAP1LC3B2, is a member of LC3 protein family involved in autophagosomal vacuole formation and mitophagy. Significant changes in the expression of LC3 family members can be a sign of issues in the autophagic process. Ankyrin‐3 is part of the cytoskeleton structure and takes part in vesicle‐mediated transport. Ankyrins have been found to have notable interactions with the LC3 family. CD96 promotes immune cell adhesion during late‐stage immune response, helping movement in inflamed areas. Though we have found several DE genes, further analysis is needed to better understand these differences and their interplay with the various patient characteristics.
chronic glaucoma in rats induced by single injection of fibronectin‐loaded PLGA microspheres
Authors: Munuera Ines , Perié Manuel Subías , Campo Lorena Arias , Altabás María José Vicente , Tello Alvaro , Castro‐Roger Luisa , Mallen Victor , Palomar Elisa Viladés , Ciordia Beatriz Cordón , Pablo Luis , Rodrigo Maria Jesus
Published: December 2022

Purpose: To generate a model of chronic glaucoma in rats, by means of a single injection that simulates the pathology that occurs in humans.

Methods: A total of 47 Long‐Evans rats of both sexes were used; 30 rats received an intracameral injection of a suspension of fibronectin‐loaded poly‐lactic‐glycolic acid microspheres into the right eye, and the other 17 served as controls. They were followed up for 24 weeks, evaluating intraocular pressure (IOP) with a rebound tonometer, neuro‐retinal structure by optical coherence tomography (OCT) with segmentation protocols for the analysis of the entire retina, the ganglion cell layer (GCL) and the peripapillary retinal nerve fibre layer (pRNFL); as well as retinal functionality by electroretinography (ERG).

Results: The IOP of the induced eyes increased progressively and chronically (11.64 ± 1.43 to 21.89 ± 3.94 mmHg) compared to the controls (p = 0.025) and with higher levels than the contralateral eyes (p < 0.05) until week 20, when this trend reversed. The induced eyes showed fluctuations in OCT retinal thickness over time. A trend of less thickness in the retina and GCL was measured in the induced eye and its contralateral eye; but at the end of the study, greater thicknesses were quantified than in the control eyes (p = 0.036). In addition, a lower ERG signal was recorded in the induced eyes. Ganglion cell functionality progressively decreased and was lower than contralateral eyes and control eyes at 12 and 24 weeks (p < 0.05). Males showed higher IOP (p < 0.05), greater thicknesses in the retina and lesser in the GCL and pRNFL (p < 0.05), with decreased functionality at 12 and 24 weeks compared to females.

Conclusions: A minimally invasive chronic glaucoma model was obtained using single‐injection by pharmaceutical technology, which produced a progressive increase in intraocular pressure and structural and functional neuro‐retinal damage.
Long‐term efficacy and safety of idebenone in patients with Leber's hereditary optic neuropathy (LHON) in the chronic phase: Results from the prospective, natural history‐controlled LEROS study
Authors: Yu‐Wai‐Man Patrick , Carelli Valerio , Tomasso Livia , Klopstock Thomas ,   the LEROS study group
Published: December 2022

Purpose: LHON is a rare mitochondrial disorder which results in bilateral vision loss. Idebenone is approved in Europe for the treatment of LHON, but relatively little controlled data exists to support use in chronic patients. Here, we report primary results from LEROS, a Phase 4, externally controlled interventional study in patients with chronic LHON (1 to ≤5 years since onset) treated with idebenone for up to 24 months.

Methods: Patients with LHON onset ≤5 years prior were enrolled and stratified by time since onset: subacute/dynamic (≤1 year) and chronic (>1 but ≤5 years). Visual acuity (VA) outcomes from 181 patients, treated for up to 24 months were compared to retrospective data from an external natural history (NH) cohort (N = 372) matched by time since onset. Outcome measures, from baseline, were clinically relevant recovery (CRR): improvement from ‘off‐chart’ VA to at least 1.6 logMAR, or a ≥0.2 logMAR improvement if already ‘on‐chart’; clinically relevant stabilization (CRS): maintenance of VA <1.0 logMAR; and clinically relevant benefit (CRB): reaching a CRR, a CRS, or both.

Results: As was observed in the subacute/dynamic phase, the frequency of a CRB from baseline at 12 months was significantly higher in treated, chronic eyes than in matched NH eyes (50.3% [72/143] vs. 38.6% [59/153] [p = 0.0087]). This difference was largely driven by a higher proportion of eyes with a CRR of visual acuity (VA) (32.9% [47/143] vs. 19.6% [30/153] [p = 0.0034]). The distribution of patients between VA categories changed over the study duration. At baseline, 34.5% of patient's best VA was off‐chart, with 35.6% between 1.0–1.68 logMAR, and 29.9% < 1.0 logMAR. By 24 months, these proportions had changed to 16.4, 41.8 and 41.8%, respectively.

Conclusions: LEROS provides evidence of a significant therapeutic benefit of idebenone treatment in patients with LHON in the chronic stage up to 5 years from onset.
Relationship between ganglion cell complex thickness and brief presentation stimuli ‐ visual acuity across foveal and parafoveal locations in healthy eyes
Authors: Pérez‐Carrasco M°. Jesús , Silva Erika Sarco , Marcos Claudia Sacristán , Puell María
Published: December 2022

Purpose: Knowledge of the retinal structure ‐ visual function relationship of healthy eyes would be important to the early detection of neuropathies of the retina. This study investigated the association between brief presentation stimuli ‐ visual acuity (BPS‐VA) and the thicknesses of the retina in healthy young eyes.

Methods: Photopic and high‐mesopic BPS‐VA was measured in 35 healthy eyes of 35 young subjects (24.3 ± 3.1 years) with the Acuity‐Plus test in the fovea and the parafovea (5° eccentricity) using an optotype presentation of duration 160 ms. The macular thicknesses of the central fovea, parafovea, and macular ganglion cell complex (mGCC), and the thickness of the peripapillary retinal nerve fibre layer (pRNFL) were measured by spectral‐domain optical coherence tomography (SD‐OCT). Relationships between foveal and parafoveal BPS‐VA and the retinal thickness in the corresponding region were examined after adjusting for confounding variables.

Results: In photopic luminance conditions, the inferior mGCC thickness was the only structural significant predictor to the foveal BPS‐VA (p = 0.007). Under high‐mesopic level, retinal illuminance and inferior mGCC thickness were contributing factors to the foveal BPS‐VA (p = 0.001). Retinal thicknesses were not predictors of parafoveal BPS‐VA at any of the light levels.

Conclusions: The inferior mGCC thickness predicts foveal BPS‐VA measured at both photopic and high‐mesopic light levels in healthy eyes of young subjects.
Structural and functional analysis of binocularity after surgery for long‐standing strabismus
Authors: Mallen Victor , Palomar Elisa Viladés , Ciordia Beatriz Cordón , Altabás María José Vicente , Tello Alvaro , Perié Manuel Subías , Campo Lorena Arias , Munuera Ines , Castro‐Roger Luisa , Garcia‐Martin Elena , Rodrigo Maria Jesus
Published: December 2022

Purpose: Assess structurally and functionally binocularity and deviation before and after strabismus surgery on patients with long‐standing strabismus.

Methods: Four patients with strabismus of more than 1 year of evolution were evaluated in three visits: 1 week before surgery (preoperative), in the first week (immediate postoperative) and 1 month after (delayed postoperative). For functional assessment, visual acuity test with Snellen optotype, near vision test, TNO and Titmus test to assess stereopsis, quantification of deviation with prisms and binocular computerized campimetry were performed. For structural analysis, optical coherence tomography (OCT) was performed with Spectralis and Triton devices.

Results: All patients presented significant changes with respect to the preoperative period both in the number of prismatic diopters and in the results of the OCT test in the immediate and delayed postoperative period. The binocular campimetric results also showed significant differences in the delayed postoperative period with respect to the patient's preoperative situation. In none of the cases were significant variations observed in the thickness of retinal ganglion cells, inner plexiform layer or retinal nerve fibres.

Conclusions: Strabismus surgery provides improvements, not only in the correction of the alignment of both eyes, but also in the patient's stereopsis and binocular visual field. The traction movements of the eyeball or the changes caused during surgery do not seem to be a risk factor for axonal damage or damage to the inner retinal layers.
Nanofibrous scaffolds with ex vivo cultured human iPSC‐derived RPE cells for transplantation into porcine eyes
Authors: Ardan Taras , Erceg Slaven , Artero‐Castro Ana , Studenovská Hana , Mueller Brigitte , Stieger Knut , Popelka Štěpan , Lytvynchuk Lyubomyr , Straňák Zbyněk , Tichotová Lucie , Ellederová Zdeňka , Čížková Jana , Juhásová Jana , Motlík Jan , Petrovski Goran
Published: December 2022

Purpose: There are several retinal degenerative diseases including age‐related macular degeneration (AMD) where the retinal pigment epithelium (RPE) is affected primarily and photoreceptors secondarily. The RPE replacement based on changing of diseased RPE by ex vivo cultured iPSC‐derived RPE cells on nanofibrous membranes can prolong the survival of adjacent photoreceptors.

Methods: The feeder‐free system of culturing and differentiation of human iPSCs was used. The phenotypic maturation was examined using immunolabelling for the differentiation and polarization markers. Scaffolds with confluent human iPSC‐derived RPE were implanted into the right eye of 7 minipigs using 3‐port pars plana vitrectomy. Because the human cells were transplanted into the porcine eye (xenogeneic transplantation), immunosuppression therapy with Tacrolimus was applied. At 1–4 weeks upon transplantation, noninvasive examinations of the implanted retina were performed by OCT and fundus camera.

Results: The iPSC‐derived RPE cells showed typical cellular morphology and express the RPE markers such as ZO1, BEST, RPE65, and others, with no traces of pluripotent stem cells. Scaffolds with seeded RPE were successfully implanted into subretinal space of porcine eyes. OCT and fundus camera examinations were able to localize the implant in the retina and demonstrated a normal neuroretina in the place of the implant with healed retinotomy, without inflammatory reaction on the implant.

Conclusions: In conclusion, we can state that the functional and morphological properties of human iPSC‐derived RPE cells cultured on nanomembranes confirmed the good quality of this epithelium including proper differentiation, confluency of the polarized monolayer, and ability to long‐term survival. The correct placing of implants in the subretinal space testified to the rightness of employed surgical techniques and functionality of the delivery instrumentarium.
VEGF levels in the aqueous humour of patients with primary open angle glaucoma: A systematic review and a meta‐analysis
Authors: Dimtsas Georgios , Tsiogka Anastasia , Moschos Marilita
Published: December 2022

Purpose: To compare the VEGF levels in the aqueous humour of patients with Primary Open Angle Glaucoma (POAG) and non‐glaucomatous eyes and reveal any potential statistically significant correlations.

Methods: We searched PubMed, from inception to December 31, 2021. Key search terms included VEGF and Glaucoma. All relevant studies that evaluated the VEGF levels in patients with POAG and in the control group were included in this systematic review. The Preferred Reporting Items for Systematic Reviews and Meta‐Analysis of Diagnostic Test Accuracy Studies (PRISMA‐DTA) guidelines were followed. Data were extracted independently by 2 authors. Heterogeneity was statistically quantified by Q, H, and I2 statistics, and a meta‐analysis was performed using the random‐effects model.

Results: Seven cross‐sectional studies were included in the meta‐analysis. 144 eyes were enrolled in the POAG group and 162 eyes in the control group. The random effect model showed no statistically significant difference between the two groups (SMD = 0.284, 95% CI = −0.173 to 0.741; p = 0.223), but we noticed a trend towards elevated VEGF levels in the aqueous humour of POAG patients. Significant heterogeneity was detected (I2 = 74.1%, p = 0.001).

Conclusions: This systematic review and meta‐analysis indicates a trend towards elevated VEGF‐A levels in the aqueous humour of patients with POAG and suggests a potential neuroprotective role of VEGF in patients with POAG. Future studies are required to evaluate the exact role of VEGF in POAG.
The impact of visual impairment and other risk factors on health‐related quality of life among people living in retirement homes in Armenia
Authors: Giloyan Aida , Babayan Ani , Harutyunyan Tsovinar , Petrosyan Varduhi
Published: December 2022

Purpose: The study aimed to examine the effect of visual impairment, eye diseases and other risk factors on health‐related quality of life (HRQoL) in retirement home residents in Armenia.

Methods: The survey was conducted among 313 beneficiaries from retirement homes. Interviewer‐administered structured questionnaire explored socio‐demographic characteristics of participants, presence of chronic non‐communicable diseases, depressive symptoms, HRQoL, smoking, physical activity, receiving and giving instrumental and emotional social support, sleeping disorder, and adverse life events. Ophthalmic examinations were conducted to assess participants' visual acuity and presence of eye diseases.

Results: The mean age was 72.5 years. Women constituted 50% of the sample. About 28% of participants reported depressive symptoms. The prevalence of normal vision was 49%, mild/moderate and severe visual impairment was 46%, and blindness was 5%. Uncorrected refractive errors were found in 20% of participants. In the adjusted linear regression model, presence of chronic non‐communicable diseases (β = −11.3; CI: −15.3; −7.39), physical activity (β = 15.3; CI: 9.04; 21.5), sleeping disorders (β = −5.58; CI: −10.2; −0.96), receiving emotional support (β = 0.09; CI: 0.01; 0.17) and giving instrumental support (β = 0.17; CI: 0.08; 0.25), presence of depressive symptoms (β = −11.7; CI: −16.0; −7.46) and uncorrected refractive errors (β = −9.15; CI: −17.3; −1.04) were associated with HRQoL.

Conclusions: This study found high prevalence of uncorrected refractive errors, visual impairment and blindness among people in retirement homes. Regular eye screening programs and distribution of spectacles could improve eye health in the target population. Promote healthy behaviours including regular physical activity to enhance HRQoL. A focus on people with chronic non‐communicable diseases and depressive symptoms is warranted.