The Role of Immune Cells and Signaling Pathways in Diabetic Eye Disease: A Comprehensive Review.

Diabetic eye disease (DED) encompasses a range of ocular complications arising from diabetes mellitus, including diabetic retinopathy, diabetic macular edema, diabetic keratopathy, diabetic cataract, and glaucoma. These conditions are leading causes of visual impairments and blindness, especially among working-age adults. Despite advancements in our understanding of DED, its underlying pathophysiological mechanisms remain incompletely understood. Chronic hyperglycemia, oxidative stress, inflammation, and neurodegeneration play central roles in the development and progression of DED, with immune-mediated processes increasingly recognized as key contributors. This review provides a comprehensive examination of the complex interactions between immune cells, inflammatory mediators, and signaling pathways implicated in the pathogenesis of DED. By delving in current research, this review aims to identify potential therapeutic targets, suggesting directions of research for future studies to address the immunopathological aspects of DED.

An Instrumented Glove for Restoring Sensorimotor Function of the Hand Through Augmented Sensory Feedback.

The loss of sensitivity of the upper limb due to neurological injuries severely limits the ability to manipulate objects, hindering personal independence. Non-invasive augmented sensory feedback techniques are used to promote neural plasticity hence to restore the grasping function. This work presents a wearable device for restoring sensorimotor hand functions based on Discrete Event-driven Sensory Control policy. It consists of an instrumented glove that, relying on piezoelectric sensors, delivers short-lasting vibrotactile stimuli synchronously with the relevant mechanical events (i.e., contact and release) of the manipulation. We first performed a feasibility study on healthy participants (20) that showed overall good performances of the device, with touch-event detection accuracy of 96.2% and a response delay of 22 ms. Later, we pilot tested it on two participants with limited sensorimotor functions. When using the device, they improved their hand motor coordination while performing tests for hand motor coordination assessment (i.e., pick and place test, pick and lift test). In particular, they exhibited more coordinated temporal correlations between grip force and load force profiles and enhanced performances when transferring objects, quantitatively proving the effectiveness of the device.

Virtual reconstruction and geometric morphometric analysis of the Kocabas hominin fossil from Turkey: Implications for taxonomy and evolutionary significance.

The Kocabas specimen comes from a travertine quarry near the homonymous village in the Denizli basin (Turkey). The specimen comprises three main fragments: portions of the right and left parietal and left and right parts of the frontal bone. The fossil was assumed to belong to the Homo erectus s.l. hypodigm by some authors, whereas others see similarities with Middle Pleistocene fossils (Broken Hill 1/Kabwe, Bodo, or Ceprano). Here, we present the first attempt to make a complete reconstruction of the missing medial portion of the frontal bone and a comprehensive geometric morphometric analysis of this bone. We restored the calotte by aligning and mirroring the three preserved fragments. Afterward, we restored the missing portion by applying the thin-plate spline interpolation algorithm of target fossils onto the reconstructed Kocabas specimen. For the geometric morphometric analyses, we collected 80 landmarks on the frontal bone (11 osteometric points, 14 bilateral curve semilandmarks, and 41 surface semilandmarks). The comparative sample includes 21 fossils from different chronological periods and geographical areas and 30 adult modern humans from different populations. Shape analyses highlighted the presence in Kocabas of features usually related to Middle Pleistocene Homo, such as a developed supraorbital torus associated with a relatively short frontal squama and reduced post-toral sulcus. Cluster analysis and linear discriminant analysis classification procedure suggest Kocabas being part of the same taxonomic unit of Eurasian and African Middle Pleistocene Homo. In light of our results, we consider that attributing the Kocabas hominin to H. erectus s.l. may be unwarranted. Results of our analyses are compatible with different evolutionary scenarios, but a more precise chronological framework is needed for a thorough discussion of the evolutionary significance of this specimen. Future work should clarify its geological age, given uncertainties regarding its stratigraphic provenance.

Artificial Intelligence (AI) for Early Diagnosis of Retinal Diseases.

Artificial intelligence (AI) has emerged as a transformative tool in the field of ophthalmology, revolutionizing disease diagnosis and management. This paper provides a comprehensive overview of AI applications in various retinal diseases, highlighting its potential to enhance screening efficiency, facilitate early diagnosis, and improve patient outcomes. Herein, we elucidate the fundamental concepts of AI, including machine learning (ML) and deep learning (DL), and their application in ophthalmology, underscoring the significance of AI-driven solutions in addressing the complexity and variability of retinal diseases. Furthermore, we delve into the specific applications of AI in retinal diseases such as diabetic retinopathy (DR), age-related macular degeneration (AMD), Macular Neovascularization, retinopathy of prematurity (ROP), retinal vein occlusion (RVO), hypertensive retinopathy (HR), Retinitis Pigmentosa, Stargardt disease, best vitelliform macular dystrophy, and sickle cell retinopathy. We focus on the current landscape of AI technologies, including various AI models, their performance metrics, and clinical implications. Furthermore, we aim to address challenges and pitfalls associated with the integration of AI in clinical practice, including the "black box phenomenon", biases in data representation, and limitations in comprehensive patient assessment. In conclusion, this review emphasizes the collaborative role of AI alongside healthcare professionals, advocating for a synergistic approach to healthcare delivery. It highlights the importance of leveraging AI to augment, rather than replace, human expertise, thereby maximizing its potential to revolutionize healthcare delivery, mitigate healthcare disparities, and improve patient outcomes in the evolving landscape of medicine.

The Middle Pleistocene human metatarsal from Sedia del Diavolo (Rome, Italy).

The peopling of Europe during the Middle Pleistocene is a debated topic among paleoanthropologists. Some authors suggest the coexistence of multiple human lineages in this period, while others propose a single evolving lineage from Homo heidelbergensis to Homo neanderthalensis. The recent reassessment of the stratigraphy at the Sedia del Diavolo (SdD) site (Latium, Italy), now dated to the beginning of marine isotope stage (MIS) 8, calls for a revision of the human fossils from the site. In this paper, we present the morphometric, biomechanical and palaeopathological study of the second right metatarsal SdD2, to both re-evaluate its taxonomical affinities and possibly determine the levels of physical activity experienced by the individual during lifetime. Results demonstrate the persistence of archaic features in SdD2 suggesting new insights into the technology and hunting strategies adopted by Homo between MIS 9 and MIS 8.

HYPERACUTE PSEUDOPHAKIC MACULAR EDEMA VANISHING WITHIN 72 HOURS: A CASE SERIES.

PURPOSE: To report three cases of massive pseudophakic macular edema occurring the day after uneventful cataract surgery and resolving in 24 to 72 hours. METHODS: Observational case series. RESULTS: A 68-year-old woman affected by systemic lupus erythematosus and antiphospholipid syndrome displayed massive macular edema on optical coherence tomography scan one day after uneventful cataract surgery. Routine postoperative topical eye drops (chloramphenicol/betamethasone 4 times a day and bromfenac 2 times a day) were continued without additional medications. Three days later, optical coherence tomography showed a completely recovered, normal fovea. Two similar cases were documented. A 73-year-old man and a 53-year-old man underwent cataract surgery and started the mentioned topical postoperative therapy. Severe macular edema was diagnosed the day after surgery and resolved in 24 and 48 hours, respectively. CONCLUSION: Massive macular edema may occur immediately after uncomplicated cataract and then disappear within 1 to 3 days, without invasive therapies. This is a very significant event that may follow cataract surgery, and that was previously unreported.

Tissue remodeling in adult vernal keratoconjunctivitis.

Our aim is to describe local tissue remodeling in a cohort of adult VKC patients. Male patients diagnosed with active VKC were enrolled in an open pilot study into two groups according disease onset: childhood classic VKC and adult VKC. Visual acuity and ocular surface clinical examination focusing on chronic inflammatory sequelae and impression cytology were performed in all enrolled subjects. Conjunctival imprints were processed for molecular, biochemical and immunofluorescent analysis for tissue remodeling (TGFß1,2,3 and αSMA) and epigenetic (DNMT3a, Keap1; Nrf2) markers as well as androgen receptors were investigated and compared between groups. Clinical assessment showed increased conjunctival scarring in adult VKC compared to classic VKC. Immunoreactivity for αSMA and expression of TGFß were higher in adult VKC group. Significantly higher levels of TGFß3 (3.44 ± 1.66; p < 0.05) were detected in adult VKC compared to childhood VKC, associated with an increasing trend of TGFß1 (1.58 ± 0.25) and TGFß2 (1.65 ± 0.20) isoforms levels. Molecular analysis showed a relative increase in tissue remodeling/fibrogenic transcripts (TGFß isoforms and αSMA) associated to a significant increase of selective epigenetic targets (DNMT3, Nrf2 and keap1) in adult VKC phenotype. Increased local conjunctival androgen receptors was detected in patients with adult variants compared to classic childhood VKC and healthy subjects. Finally, a direct correlation between TGFß and androgen receptor expression was also detected. A pro-fibrotic clinical and biomolecular trait was unveiled in adult variant of VKC, which causes ocular surface disease and visual impairment.

Ocular surface toll like receptors in ageing.

BACKGROUND: To evaluate changes in Toll Like Receptors (TLRs) expression at the ocular surface of healthy volunteers within different age groups. METHODS: Fifty-one healthy volunteers were enrolled in a pilot observational study. Clinical function tests (OSDI questionnaire, Schirmer test type I and Break Up time) were assessed in all subjects. Temporal Conjunctival imprints were performed for molecular and immunohistochemical analysis to measure TLRs expression (TLR2, 4, 3, 5, 7, 8, 9 and MyD88). RESULTS: Immunofluorescence data showed an increased TLR2 and decreased TLR7 and TLR8 immunoreactivity in old conjunctival imprints. Up-regulation of TLR2 and down-regulation of TLR7, TLR8 and MyD88 transcripts expression corroborated the data. A direct correlation was showed between increasing ICAM-1 and increasing TLR2 changes with age. Within the age OSDI score increases, T-BUT values decrease, and goblet cells showed a decreasing trend. CONCLUSION: Changes in TLRs expression are associated with ageing, suggesting physiological role of TLRs in modulating ocular surface immunity. TLRs age related changes may participate to the changes of ocular surface homeostatic mechanisms which lead to inflammAging.

Effect of minimonovision in bilateral implantation of a novel non-diffractive extended depth-of-focus intraocular lens: Defocus curves, visual outcomes, and quality of life.

PURPOSE: To evaluate overall patient satisfaction, spectacle independence, visual acuity, and prevalence of optical phenomena following bilateral implantation of a new non-diffractive extended depth-of-focus intraocular lens targeted for minimonovision. METHODS: Multicenter prospective case series. Postoperative far and near visual acuity at 3 months and patient quality of life by NEI-VFQ-25 questionnaire were assessed. Postoperative evaluation included defocus curves analysis, spectacle independence assessment, and recording of photic phenomena. RESULTS: The study enrolled 97 eyes of 59 patients that underwent femtosecond-assisted cataract surgery with AcrySof IQ Vivity intraocular lens implantation. Thirty subjects (60 eyes) were eligible for analysis. After 3 months, postoperative achieved binocular uncorrected visual acuity was -0.03 ± 0.06 logarithm of the minimum angle of resolution for distance, 0.06 ± 0.06 logarithm of the minimum angle of resolution for intermediate, and 0.19 ± 0.03 logarithm of the minimum angle of resolution for near. Defocus curve showed a smooth profile with no abrupt decrease of visual acuity. Minimonovision significantly improved visual acuity compared to when minimonovision was neutralized, for values of defocus curves from -1 to -3 D (p < 0.05). Twenty-six (87%) patients reported complete spectacle independence. High levels of satisfaction for distance and near vision resulted at VFQ-25 questionnaire. Only two patients complained of halos (6.7%) and one of them also of glare (3.3%). CONCLUSIONS: Implantation of this new non-diffractive extended depth-of-focus intraocular lens with minimonovision resulted in satisfying far, intermediate, and near visual acuity with a consistent reduction of spectacle dependence and improvement in patient's quality of life.

Long-term restoration of corneal sensitivity in neurotrophic keratopathy after rhNGF treatment.

BACKGROUND: To report the long-term effects of the new rhNGF treatment on corneal sensitivity in patients with. CASES PRESENTATION: We present three cases of corneal ulcers due to NK that were treated with rhNGF. In each patient wound healing evolution was documented by clinical pictures and corneal sensitivity measured by Cochet-Bonnet aesthesiometry. Best corrected visual acuity and Type I Schirmer test were also assessed neurotrophic keratopathy.All patients healed within 8 weeks and NK showed no recurrences in the mean follow-up period of 35 weeks. Each subject showed a significant increase of corneal sensitivity and tear secretion, with concomitant improvement in visual acuity. CONCLUSION: Corneal sensitivity, measured by Cochet-Bonnet aesthesiometer, markedly increased in all eyes. Further studies are warranted to demonstrate a possible mechanism of nerve restoration with rhNGF treatment.

Surgical management of post-uveitic epiretinal membranes.

PURPOSE: Previous reports described unfavorable visual outcomes after surgery for uveitic macular pucker. Our goal was to demonstrate that patients with history of uveitis may benefit from vitrectomy for epiretinal membrane if executed under appropriate circumstances. METHODS: We performed pars plana vitrectomy with ERM and ILM peeling in patients with post-uveitic macular pucker who did not show signs of ocular inflammation for at least 3 months after the suspension of immunosuppressive therapy. Visual acuity, central macular thickness at OCT, ocular inflammation, and complications were recorded. RESULTS: Twenty-six eyes were operated. Mean duration of follow-up was 67 months. Visual acuity significantly improved from 20/80 to 20/40 after surgery. Vision increased in 20 (77%), remained stable in 4 (15%), and decreased in 2 (8%) eyes. Best-corrected visual acuity ameliorated by at least 2 ETDRS lines in 14 eyes (54%). Contingency analysis did not show any statistical difference among the different types of uveitis (p = 0.46). Mean central foveal thickness improved postoperatively (428 ± 104 vs 328 ± 130 microns; p = 0.017). CONCLUSION: Patients with uveitic epiretinal membrane benefit from vitrectomy with membranectomy if operated when intraocular inflammation had subsided.

Exploring directional and fluctuating asymmetry in the human palate during growth.

OBJECTIVES: Palate morphology is constantly changing throughout an individual's lifespan, yet its asymmetry during growth is still little understood. In this research, we focus on the study of palate morphology by using 3D geometric morphometric approaches to observe changes at different stages of life, and to quantify the impact of directional and fluctuating asymmetry on different areas at different growth stages. MATERIALS AND METHODS: The sample consists of 183 individuals (1-72 years) from two identified human skeletal collections of 19th and early 20th Century Italian contexts. A 3D-template of 41 (semi)landmarks was applied on digital palate models to observe morphological variation during growth. RESULTS: Asymmetrical components of the morphological structure appears multidirectional on the entire palate surface in individuals <2 years old and become oriented (opposite bilateral direction) between 2 and 6 years of age. Specifically, directional asymmetry differentially impacts palate morphology at different stages of growth. Both the anterior and posterior palate are affected by mild alterations in the first year of life, while between 2 and 6 years asymmetry is segregated in the anterior area, and moderate asymmetry affects the entire palatal surface up to 12 years of age. Our results show that stability of the masticatory system seems to be reached around 13-35 years first by females and then males. From 36 years on both sexes show similar asymmetry on the anterior area. Regarding fluctuating asymmetry, inter-individual variability is mostly visible up to 12 years of age, after which only directional trends can be clearly observed at a group level. DISCUSSION: Morphological structure appears instable during the first year of life and acquires an opposite asymmetric bilateral direction between 2 and 6 years of age. This condition has been also documented in adults; when paired with vertical alteration, anterior/posterior asymmetry seems to characterize palate morphology, which is probably due to mechanical factors during the lifespan. Fluctuating asymmetry is predominant in the first period of life due to a plausible relationship with the strength of morphological instability of the masticatory system. Directional asymmetry, on the other hand, shows that the patterning of group-level morphological change might be explained as a functional response to differential inputs (physiological forces, nutritive and non-nutritive habits, para-masticatory activity as well as the development of speech) in different growth stages. This research has implications with respect to medical and evolutionary fields. In medicine, palate morphology should be considered when planning orthodontic and surgical procedures as it could affect the outcome. As far as an evolutionary perspective is concerned the dominance of directional asymmetries in the masticatory system could provide information on dietary and cultural habits as well as pathological conditions in our ancestors.

Challenges in Acanthamoeba Keratitis: A Review.

To review challenges in the diagnosis and management of Acanthamoeba keratitis (AK), along with prognostic factors, in order to help ophthalmologists avoid misdiagnosis, protracted treatment periods, and long-term negative sequelae, with an overarching goal of improving patient outcomes and quality of life, we examined AK studies published between January 1998 and December 2019. All manuscripts describing clinical manifestations, diagnosis, treatment, prognosis, and challenges in short- and long-term management were included. The diagnosis of AK is often challenging. An increased time between symptom onset and the initiation of appropriate therapy is associated with poorer visual outcomes. The timely initiation of standardized antiamoebic therapies improves visual outcomes, decreases the duration of treatment, and reduces the chances of needing surgical intervention. In clinical practice, AK diagnosis is often missed or delayed, leading to poorer final visual outcomes and a negative impact on patient morbidity and quality of life.

Ocular surface diabetic disease: A neurogenic condition?

PURPOSE: To investigate clinical and inflammatory changes in the ocular surface of insulin-dependent type I diabetic patients. METHODS: Two hundred and nine eyes of 106 patients with diagnosis of type I diabetes were recruited in a prospective observational study. Ocular surface clinical assessment, corneal sensitivity and tear film stability tests were performed to evaluate ocular surface system function. Ocular Surface Disease Index (OSDI) questionnaire was administered to all enrolled subjects. Conjunctival impression cytology specimens were also collected to detect neuromediators and inflammatory molecules. Duration of disease, HbA1c levels and diabetic retinopathy stage were recorded. RESULTS: Corneal sensitivity assessed by Cochet-Bonnet esthesiometer was reduced in patients with more chronic disease, higher HbA1c levels and proliferative diabetic retinopathy. Tear break-up time (TBUT) was reduced in subjects with long-standing diabetes or with more severe retinopathy. OSDI questionnaire scores showed direct correlation with increased HbA1c values. Significant increase of NPY, STAT-5 and ICAM-1 was found in diabetic patients compared to healthy controls. A direct correlation between NPY concentration and ICAM-1 values in patients with type I diabetes was demonstrated. CONCLUSIONS: Patients with long-standing type I diabetes showed chronic inflammation of the ocular surface, due to neurogenic dysregulation of para-inflammatory homeostatic mechanisms. These patients with ocular surface system failure complained of ocular discomfort but had modest reduction of corneal sensitivity and no signs of neurotrophic keratopathy. Disease duration, increased HbA1c levels and severe diabetic retinopathy appear the most critical factors.

Single-piece S-plasty for small-incision IOL removal.

A foldable acrylic intraocular lens (IOL) with a 6.0 mm optic was removed through a 2.2 mm corneal incision as a single piece with minimal wound trauma. By viscodissection, the IOL was freed from its position in the capsular bag and moved into the anterior chamber. Vannas scissors were introduced through a 2.2 mm corneal incision. A 4.5 mm straight slit was cut at each optic-haptic junction on opposite sides, perpendicular to each haptic shaft. This pair of parallel cuts generated 3 IOL segments in an S configuration that remained connected. The IOL was grasped by 1 haptic and removed as a single piece.

Frontal bone virtual reconstruction and geometric morphometric analysis of the mid-Pleistocene hominin KNM-OG 45500 (Olorgesailie, Kenya).

KNM-OG 45500 is a hominin fossil composed of parts of a frontal bone, left temporal bone, and cranial vault pieces. Since its discovery along the Olorgesailie Formation (Kenya) in 2003, it has been associated with the Homo erectus hypodigm. The specimen, derived from a geological context dated to ca. 900 Ka BP, has been described as a very small individual of probable female sex. However, despite its status as an important hominin specimen, it has not been used in a quantitative comparative framework because of its fragmentary condition. Here, we undertake a virtual reconstruction of the better-preserved fragment, the frontal bone. We additionally apply geometric morphometric analyses, using a geographically diverse fossil and modern human sample, in order to investigate the morphological affinities of KNM-OG 45500. Our results show that the frontal shape of KNM-OG 45500 exhibits similarities with Early Pleistocene fossils from Eurasia and Africa that are assigned to H. erectus sensu lato (s.l.). Its size, on the other hand, is notably smaller than most other Homo erectus fossils and modern humans and similar to the specimens from Dmanisi (Georgia) and to Homo naledi. Taken together, our analyses of the frontal bone suggest a taxonomic attribution of KNM-OG 45500 to H. erectus s.l. and extend even further the range of size variability associated with this taxon around 900 Ka BP.

Basicranial ontogeny comparison in Pan troglodytes and Homo sapiens and its use for developmental stage definition of KNM-ER 42700.

OBJECTIVE: This study aims to develop a comparative basis for assessing the developmental stage of KNM-ER 42700 based on the ontogenetic pattern of the ectocranial surface of the basicranium in modern humans and chimpanzees. MATERIALS AND METHODS: A total of 33 landmarks were collected from an ontogenetic sample of modern humans (80), chimpanzees (51), and 12 individuals classified as Homo erectus s.l. Ontogenetic trajectories were analyzed, and common aspects were extracted for the purpose of discriminating age groups. A regression of size on the extracted shape variables was used to investigate common ontogenetic allometry. RESULTS: The basicranial development of chimpanzees and humans follows different trajectories; however, similarities are also present. The common shape component of development extracted can be used to define age groups in both chimpanzees and modern humans. The extracted shape component presents a similar ontogenetic and static-allometric pattern in these two species. The developmental stages of H. erectus s.l. specimens were attributed following these common traits. Our analysis correctly assigned developmental stages to those specimens of H. erectus for which developmental ages are known. DISCUSSION: The component used for assessing the developmental stage has an ontogenetic allometric component. However, this shape component can discriminate age group irrespective of size and is no longer related to size when static allometry is considered. Adult H. erectus s.l. specimens were attributed to the adult category. KNM-WT 15000 fell with the late juvenile age group, whereas D2700 plotted in the region of overlap between the juvenile and adult age groups and Mojokerto with the younger age groups, as predicted by their known developmental ages. KNM-ER 42700 fell within the adult variability despite its incompletely fused spheno-occipital synchondrosis.

Lamellar macular holes: monitoring and management strategies.

Lamellar macular holes are a vitreoretinal condition characterized by abnormalities in foveal contour with splitting of the neuroepithelium and often an intact photoreceptor layer. Recent developments in high-resolution imaging have increased our ability to study the details of the vitreoretinal interface and to distinguish between different forms of lamellar holes. A new classification is needed to help clinicians in the management of lamellar macular holes. Some clinicians prefer to observe these clinical entities, especially when visual acuity is maintained or alterations of the photoreceptor layer are present. Nevertheless, lamellar holes may sometimes progress, and visual acuity can deteriorate. On the other hand, surgical treatment may lead to positive anatomical and functional outcomes, but not without risks. This review provides a critical overview of the available data on lamellar macular holes, focusing on diagnosis and managing options.

Ages-at-death distribution of the early Pleistocene hominin fossil assemblage from Drimolen (South Africa).

OBJECTIVES: A prevailing hypothesis in paleoanthropology is that early Pleistocene hominin bones were accumulated in South African caves by carnivores, which used those shelters, and the trees surrounding them, as refuge and feeding sites. We tested this hypothesis at the site of Drimolen, by comparing its hominin age-at-death distribution to that of the nearby and roughly contemporaneous site of Swartkrans. MATERIALS AND METHODS: We employed standard dental aging systems in order to categorize the Drimolen hominin teeth into age classes of 5 years each. We then compared the age-at-death distribution for Drimolen with the published data available for the Swartkrans hominins. RESULTS: Age-at-death distributions indicate that the age category "young adults" is the best represented age category at Swartkrans and the most poorly represented one at Drimolen. Moreover, Drimolen has a preponderance of infant specimens. Both sites have a low frequency of old adult specimens. CONCLUSIONS: Differences observed in frequencies of the age-at-death categories suggest different mechanisms of hominin skeletal accumulation at Drimolen and Swartkrans. Swartkrans' frequency curve reflects mortality in a population subjected to predation and is thus consistent with the carnivore-accumulating hypothesis. In contrast, the Drimolen curve is similar to that of wild populations of living apes. Living primates have been observed exploiting caves as sleeping shelters, for nutritional, security, drinking, and thermoregulatory purposes. We suggest that similar cave use by Pleistocene hominins can explain, in large part, the accumulation of hominin bones at Drimolen. Such a conclusion is another illustration of the growing awareness that a "one-size-fits-all" taphonomic model for South African early Pleistocene hominin sites is probably insufficient.