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Purpose: Retinal non‐perfusion (RNP) is fundamental to disease onset and progression in diabetic retinopathy (DR). Whether anti‐vascular endothelial growth factor (anti‐VEGF) therapy can modify RNP progression is unclear. This investigation quantified the impact of anti‐VEGF therapy on RNP progression compared with laser or sham at 12 months. Methods: A systematic review and meta‐analysis of randomised controlled trials (RCTs) were performed; Ovid MEDLINE, EMBASE and CENTRAL were searched from inception to 4th March 2022. The change in any continuous measure of RNP at 12 months and 24 months was the primary and secondary outcomes, respectively. Outcomes were reported utilising standardised mean differences (SMD). The Cochrane Risk of Bias Tool version‐2 and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines informed risk of bias and certainty of evidence assessments. Results: Six RCTs (1296 eyes) and three RCTs (1131 eyes) were included at 12 and 24 months, respectively. Meta‐analysis demonstrated that RNP progression may be slowed with anti‐VEGF therapy compared with laser/sham at 12 months (SMD: −0.17; 95% confidence interval [CI]: −0.29, −0.06; p = 0.003; I2 = 0; GRADE rating: LOW) and 24‐months (SMD: −0.21; 95% CI: −0.37, −0.05; p = 0.009; I2 = 28%; GRADE rating: LOW). The certainty of evidence was downgraded due to indirectness and due to imprecision. Conclusion: Anti‐VEGF treatment may slightly impact the pathophysiologic process of progressive RNP in DR. The dosing regimen and the absence of diabetic macular edema may impact this potential effect. Future trials are needed to increase the precision of the effect and inform the association between RNP progression and clinically important events. PROSPERO Registration: CRD42022314418. [ABSTRACT FROM AUTHOR]

Introduction: Since July 2021, a worldwide shortage of verteporfin (Visudyne®) occurred: an essential medicine required for photodynamic therapy (PDT). PDT with verteporfin has a broad range of indications in ophthalmology, including chronic central serous chorioretinopathy, polypoidal choroidal vasculopathy and choroidal haemangioma. For these disorders, PDT is either the first‐choice treatment or regarded as a major treatment option. Materials and methods: A questionnaire was sent to key opinion leaders in the field of medical retina throughout the world, to assess the role of PDT in their country and the effects of the shortage of verteporfin. In addition, information on the application of alternative treatments during shortage of verteporfin was obtained, to further assess the impact of the shortage. Results: Our questionnaire indicated that the shortage of verteporfin had a major impact on ophthalmic care worldwide and was regarded to be a serious problem by most of our respondents. However, even though there is ample evidence to support the use of PDT in several chorioretinal diseases, we found notable differences in its use in normal patient care throughout the world. Various alternative management strategies were noted during the verteporfin shortage, including lowering the dose of verteporfin per patient, the use of alternative treatment strategies and the use of a centralized system for allocating the remaining ampoules of verteporfin in some countries. Conclusion: The shortage of verteporfin has had a large effect on the care of ophthalmic patients across the world and may have resulted in significant and irreversible vision loss. Mitigation strategies should be developed in consultation with all stakeholders to avoid future medication shortages of verteporfin and other unique ophthalmic medications. These strategies may include mandatory stock keeping, compulsory licensing to an alternative manufacturer or incentivizing the development of competition, for example through novel public‐private partnerships. [ABSTRACT FROM AUTHOR]

Objective: To investigate treat‐and‐extend (T&E) regimens of anti‐vascular endothelial growth factor (anti‐VEGF) therapy for the treatment of macular oedema secondary to retinal vein occlusions (RVOs). Methods: Ovid MEDLINE, Ovid EMBASE and CENTRAL were searched on 25 February 2021. Randomized controlled trials, cohort studies, case–control studies and case series were included. The primary outcome was the change in Early Treatment Diabetic Retinopathy Score (ETDRS) letters from baseline. Conversions from Snellen to ETDRS letters were performed utilizing a published protocol. Secondary outcomes included improvement in retinal thickness from baseline, number of anti‐VEGF injections and frequency of adverse events. Outcomes were examined at 12 and 24 months. Certainty of evidence was assessed utilizing GRADE (Grading of Recommendations Assessments, Development and Evaluations) guidelines. Results: Seven hundred eighty‐six eyes from 16 studies were included. Meta‐analysis demonstrated a mean improvement of 15.7 (95% CI: 13.3–18.0) ETDRS letters at 12 months. Central retinal thickness improved 269.7 μm (95% CI: 233.64–305.90) at 12 months. Injections were performed 8.1 (95% CI: 7.4–8.7) and 13.1 (95% CI: 9.4–16.8) times at 12 and 24 months respectively. Adverse events were infrequent across all studies. Grading of Recommendations Assessments, Development and Evaluations (GRADE) certainty of evidence was very low across all outcomes. Conclusions: The results support the viability of T&E regimens for the treatment of macular oedema secondary to RVOs. [ABSTRACT FROM AUTHOR]

Aims: This programme investigated topical regorafenib, a multikinase inhibitor, in patients with neovascular age‐related macular degeneration (nAMD). Methods: Topical regorafenib was investigated in an open‐label, phase IIa/b study in which patients with choroidal neovascularization (CNV) secondary to nAMD received regorafenib (25 μl, 30 mg ml–1) three times a day for 12 weeks. The primary endpoint of the phase II/a/b study was mean change in best‐corrected visual acuity (BCVA) from baseline to weeks 4 and 12. Results: In nAMD patients (N = 51), mean changes in BCVA were +1.2 [90% confidence interval (CI) –0.61, 2.97] and −2.4 (90% CI −4.18, −0.54) letters at weeks 4 and 12, respectively. Ocular treatment‐emergent adverse events (TEAEs) (study eye) were reported in 21 patients by week 12. There was one serious ocular TEAE (visual acuity reduced) that was not drug related. Twenty patients required rescue (intravitreal ranibizumab). Conclusions: The programme was terminated after phase IIa ended because efficacy was lower than with current nAMD treatments. According to elaborate post hoc analyses, the most likely reason was insufficient exposure in the target compartment (back of the eye). [ABSTRACT FROM AUTHOR]

This study was performed to systematically assess the prevalence, topography and prognostic impact of disseminated tumor cells (DTCs) in lymph nodes (LN) of patients with primary, regional and distant metastasis-free head and neck squamous cell carcinoma (HNSCC) who underwent resection with elective neck dissection. From the routinely processed resection specimen, we could prospectively analyze a total of 1.137 exactly mapped LNs of 50 pN0-HNSCC patients, classified as tumor free by routine histopathology. Three immunohistochemistry (IHC) assays using antibodies directed against CK5/14, a broad spectrum of CKs (1-8, 10, 14-16 and 19), and CD44v6, respectively, were applied on 4.190 LN sections to detect DTCs. The IHC results were correlated with clinicopathologic parameters and clinical follow-up data. We detected seven micrometastases (MM) in five patients and 31 DTCs in 12 patients. Overall, 15 (30%) patients were positive for DTCs or MMs. Strikingly, the anatomical distribution of LN affected with DTCs was not random, but was dependent on the lateralization of the primary tumor and clustered significantly most proximal to the primary tumor. None of the investigated patients developed loco-regional lymphatic or distant metastasis during the mean follow-up period of 71 months. Our results reveal clinically occult tumor cell dissemination as an early and frequent event in HNSCC. Considering that higher rates of recurrences in therapeutic LN dissection concepts have been reported than in elective neck dissection strategies, our DTC-data support to perform elective neck dissections, since they appear to be effective in preventing loco-regional lymphatic recurrence from LN DTCs or MMs. [ABSTRACT FROM AUTHOR]

Background and Purpose: Evidence of remote optic neuritis is often used to support a diagnosis of multiple sclerosis (MS). Optical coherence tomography (OCT) can provide qualitative and quantitative data on the retina, where the effects of optic neuritis can be seen. Our aim was to determine whether there is a quantitative difference in retinal structures in eyes with optic neuritis compared with those without, and which measures were best able to discriminate eyes with a history of optic neuritis from nonoptic neuritis eyes in MS patients.Methods: We performed a prospective cohort study of 30 MS-optic neuritis patients, 22 MS-nonoptic neuritis patients, and 24 healthy participants. Patients underwent visual acuity testing and OCT imaging. Retinal measurements were compared across groups. OCT measurements and visual acuities were analyzed for their ability to discriminate between optic neuritis and nonoptic neuritis eyes.Results: Optic neuritis eyes exhibited a thinner peripapillary retinal nerve fiber layer, papillomacular bundle, and ganglion cell + inner plexiform layer thicknesses compared to MS eyes without optic neuritis and healthy controls. Papillomacular bundle thickness was the best model to discriminate between eyes with optic neuritis and nonoptic neuritis eyes in MS patients. Visual acuity alone yielded rather poor models.Conclusions: Optic neuritis is associated with thinning in multiple regions of the retina. Optic neuritis eyes can be differentiated most accurately from nonoptic neuritis eyes using OCT. Our work suggests a potential role for OCT in documenting a remote history of optic neuritis to corroborate a diagnosis of MS. [ABSTRACT FROM AUTHOR]

The evaluation of several case histories of tunnels in swelling rock with sulfate bearing minerals shows that brittle fracture plays an important role in the development of swelling processes. Brittle failure by spalling has been directly observed in several tunnels, as early as the 19th century and more recently. Numerical analyses applied to different case histories with observed heave and development of strong swelling pressure, considering different construction processes; agree with the observed swelling zones. The effect of construction procedures on swelling in particular the development of pressures and swelling zones becomes evident from these analyses. For a better understanding of swelling processes brittle failure processes have to be considered in the analyses. Die Auswertungen von Beobachtungen aus ausgeführten Tunneln im Sulfat führenden Gebirge zeigen, dass Sprödbruchvorgänge eine entscheidende Rolle spielen im Aufbau von Quelldrücken und Quellhebungen. Einerseits wurden in verschiedenen Tunneln, teilweise im 19. Jahrhundert, Sprödbruchvorgänge direkt beobachtet, wenn Abschalungen auftraten. Andererseits konnte mit numerischen Analysen gezeigt werden, dass je nach Bauvorgang unterschiedlich große, zerbrochene Zonen auftreten, die mit beobachteten Quellzonen und Hebungen an ausgeführten Bauwerken gut übereinstimmen. Die Auswirkung unterschiedlicher Bauvorgänge auf Größe der Quelldrücke und der quellenden Bereiche kann zumindest qualitativ nachgewiesen werden. Bei Tunnelbauten in quellendem Gebirge ist die Ausbildung von Sprödbrüchen zu berücksichtigen. [ABSTRACT FROM AUTHOR]

Purpose: Single-centre consecutive interventional case series by retrospective chart review to evaluate the efficacy of verteporfin (Visudyne™) photodynamic therapy (PDT) of retinal capillary haemangioma (RCH). Methods: Following an initial period of observation, six eyes of five patients with RCH (juxtapapillary 3 and extrapapillary (EP) 3) received 1-3 sessions of standard verteporfin PDT upon the development of progressive visionthreatening complications. Four of the five patients had von Hippel-Lindau (VHL) disease. Follow-up included documentation of best-corrected Snellen visual acuity (BCVA), tumour regression, and presence or absence of subretinal fluid (SRF) and / or lipid exudation as assessed by dilated fundus examination (DFE), fundus photos, and optical coherence tomography (OCT). These parameters were documented at 1 week, 1 month, and 3 months following each PDT session and up to 32 months following the first PDT. Results: All eyes showed favourable response to PDT as defined by tumour regression or stabilization as well as improvement of SRF and lipid exudation. BCVA improved or stabilized in three eyes. Three eyes required PDT retreatment for recurrent SRF. Epiretinal membrane (ERM) worsened in three eyes, requiring vitreoretinal surgery at a median of 6 months following PDT. Conclusions: PDT is a moderately effective treatment for juxtapapillary and EP RCH. In this series, PDT resulted in tumour regression or stabilization as well as in the improvement of SRF and lipid exudation in all cases. However, stabilization or improvement of visual acuity was observed in only 50 per cent of the cases. The treatment benefits may be limited by pre-existing macular changes and worsening of ERM. A larger prospective study is necessary to validate these findings. [ABSTRACT FROM AUTHOR]

Underground construction in rock prone to swelling behaviour may result in long-term problems, especially in the invert, if the structure cannot resist swelling pressures. Swelling phenomena are not only a consequence of ground conditions but are strongly influenced by excavation and construction procedures. Evidence of brittle failure observed in the field will be presented and analyzed to prove that brittle failure is the trigger effect of swelling phenomena in shale and clay-anhydrite rocks. Brittle fractures have also been observed in laboratory swelling tests. Brittle failure can create cracks that form pathways for water, leading to changes in the stress-state, and as a consequence trigger swelling phenomena. In clay-anhydrite rock, the swelling pressure is caused by the crystallization pressure of gypsum. The excavation and construction procedures used for the tunnel are a decisive factor for controlling swelling behaviour. Quellvorgänge in Tongesteinen und Ton-Anhydritgesteinen führen oft zu langfristigen Problemen in Untertagebauten, insbesondere wenn der Ausbauwiderstand der Tragkonstruktion langfristig zu gering ist. Die Quellvorgänge, die besonders im Sohlbereich auftreten, sind nicht bloß eine Folge der Gesteinseigenschaften, sondern werden auch von den gewählten Bauvorgängen und der Tragkonstruktion beeinflusst. Sprödbruchvorgänge wurden in vielen Untertagbauten in Felsgesteinen mit geringer Festigkeit beobachtet. Deren Ursachen werden mit numerischen Modellen analysiert. Sprödbrüche wurden aber auch in Laborquellversuchen in Ton-Anhydritgesteinen, wo sich Gips bildete, beobachtet. Die unterschiedlichen Beobachtungen werden in einen gemeinsamen Rahmen zusammengefügt. Sprödbrüche führen zur Bildung von Rissen und damit von Wasserwegen. Weiter ergeben sich wesentlichen Änderungen des Spannungszustands um die unterirdische Öffnung, und als Folge dieser Vorgänge werden Quellerscheinungen ausgelöst. In Ton-Anhydritgesteinen wird der höhere Quelldruck durch den Kristallisationsdruck von Gips verursacht. Der gewählte Bauvorgang muss Sprödbruchvorgänge möglichst vermeiden und ist ein wesentlicher Faktor des aufzunehmenden Quelldrucks und der Quellerscheinungen. [ABSTRACT FROM AUTHOR]

Purpose: Validation of the targeting and dose delivery of the IRay™ low voltage age-related macular degeneration treatment system. Methods: Ten human cadaver eyes were obtained for this study and mounted in the IRay™ system. Using gel and vacuum, an I-Guide™ immobilization device was coupled to the eyes and radiochromic film was affixed to the posterior aspect of the globes. Three narrow x-ray beams were delivered through the pars plana to overlap on the predicted nominal fovea. A needle was placed through the center of the film’s beam spot and into the eye to register the film and the inner retina. The process was performed three times for each of the ten eyes (30 simulated treatments; 90 individual beams). The globes were dissected to assess the targeting accuracy by measuring the distances from the needles to the fovea. The dose to the fovea was calculated from the radiochromic film. Results: X-ray targeting on the retina averaged 0.6±0.4 mm from the fovea. Repeated treatments on the same eye showed a reproducibility of 0.4±0.4 mm. The optic nerve was safely avoided, with the 90% isodose edge of the beam spot between 0.4 and 2.6 mm from the edge of the optic disk. Measured dose matched that prescribed. Conclusions: This study provides confidence that the IRay™, with an average accuracy of 0.6 mm and a precision of 0.4 mm, can reliably treat most AMD lesions centered on the fovea. With the exception of motion, all sources of error are included. [ABSTRACT FROM AUTHOR]

Here we describe a study of the feasibility of lipid and phospholipid (PL) profiling using matrix assisted laser desorption/ionization (MALDI) Fourier transform mass spectrometry (FTMS) for two different applications. In this work PL profiles of different mammalian tissues as well as those of whole cell organisms were examined. In particular, comparative analysis of lipid and PL profiles of tissues from mice fed different diets was done and, in another application, MALDI FTMS was used to analyze PL profiles of genetically modified Saccharomyces cerevisiae. Computational sorting of the observed ions was done in order to group the lipid and PL ions from complex MALDI spectra. The PL profiles of liver tissues from mice fed different diets showed a cross correlation coefficient of 0.2580, indicating significant dissimilarity, and revealed more than 30 significantly different peaks at the 99.9% confidence level. Histogram plots derived from the spectra of wild type and genetically modified yeast resulted in a cross correlation coefficient 0.8941 showing greater similarity, but still revealing a number of significantly different peaks. Based on these results, it appears possible to use MALDI FTMS to identify PLs as potential biomarkers for metabolic processes in whole cells and tissues. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the effect of intravitreal injections of triamcinolone acetonide (IVTA) combined with panretinal photocoagulation (PRP) on visual acuity (VA) and foveal thickness in patients with concomitant high-risk proliferative diabetic retinopathy (PDR) and clinically significant macular oedema (CSMO). Methods: This retrospective interventional case series included seven eyes diagnosed with both high-risk PDR and CSMO that underwent PRP and a single injection of 4 mg of IVTA. The main outcome measures were VA and foveal thickness, measured by optical coherence tomography (OCT) before treatment and throughout the follow-up period. Results: Median follow-up was 301 days (range 180–715 days). Foveal thickness data were available for four of seven eyes. Before the combined treatment, median LogMAR (logarithm of the minimum angle of resolution) VA and median foveal thickness were 1 (Snellen 20/200, range 20/40–20/800) and 559 µm (range 333–689 µm), respectively. After treatment, median vision improved to LogMAR 0.544 (Snellen 20/70, range 20/40–20/1000) ( P = 0.13). Vision improved or remained stable in six of seven eyes. Median foveal thickness at final follow-up was 436 µm (range 259–623 µm) ( P = 0.15). Foveal thickness decreased or remained stable in all eyes. Conclusion: The addition of IVTA to PRP in the treatment of eyes with high-risk PDR and CSMO may prevent PRP-induced foveal thickening and loss of vision. [ABSTRACT FROM AUTHOR]

We have recently developed the HB tag as a useful tool for tandem-affinity purification under native as well as fully denaturing conditions. The HB tag and its derivatives consist of a hexahistidine tag and a bacterially-derived in vivo biotinylation signal peptide, which support sequential purification by Ni2+-chelate chromatography and binding to immobilized streptavidin. To facilitate tagging of budding yeast proteins with HB tags, we have created a series of plasmids with various selectable markers. These plasmids allow single-step PCR-based tagging and expression under control of the endogenous promoters or the inducible GAL1 promoter. HB tagging of several budding yeast ORFs demonstrated efficient biotinylation of the HB tag in vivo by endogenous yeast biotin ligases. No adverse effects of the HB tag on protein function were observed. The HB tagging plasmids presented here are related to previously reported epitope-tagging plasmids, allowing PCR-based tagging with the same locus-specific primer sets that are used for other widely used epitope-tagging strategies. The Sequences for the described plasmids were submitted to GenBank under Accession Numbers [ABSTRACT FROM AUTHOR]

Focuses on a study that screened probands to determine the frequency of uniparental disomy (UPD) among carriers of balanced Robertsonian translocation (RT) involving chromosome 14. Use of molecular markers; Identificaton of RT human carriers; Examples of polymerase chain reaction polymorphisms used on chromosome 14; Cases of UPD14.

Heterogeneous blood and lymphatic vascular trees often develop from homogeneous vascular networks, and within an organ or tissue homogeneous capillary networks often associate closely with their supporting vascular trees. We are analyzing normal and abnormal vasculature within several developmental and pathological contexts that include human retinal disease and experimental perturbations of the mouse retina and avian coronary, yolksac and chorioallantoic (CAM) vessels. To automate and improve quantification of vascular remodeling, we are completing development of the computer program VESGEN as a NASA software plug-in for NIH ImageJ. VESGEN measures critical parameters within vascular trees, networks, and tree-network composites that include vessel length, diameter, branching point and generational branching, as well as the density of these parameters and the fractal dimension. Inhibition or stimulation of blood and lymphatic vascular trees or networks typically result in maximum changes in vessel density or other critical parameters that range from approximately 1.5X to 4.0X. Each cytokine or therapeutic tested such as VEGF-165 or bFGF has induced a unique 'fingerprint' or 'signature' change in vascular patterning within specific sites of the tree or network. [ABSTRACT FROM AUTHOR]