The membrane-bound sodium–calcium exchanger (NCX) proteins shape Ca2+ homeostasis in many cell types, thus participating in a wide range of physiological and pathological processes. Determination of the crystal structure of an archaeal NCX (NCX_Mj) paved the way for a thorough and systematic investigation of ion transport mechanisms in NCX proteins. Here, we review the data gathered from the X-ray crystallography, molecular dynamics simulations, hydrogen–deuterium exchange mass-spectrometry (HDX-MS), and ion-flux analyses of mutants. Strikingly, the apo NCX_Mj protein exhibits characteristic patterns in the local backbone dynamics at particular helix segments, thereby possessing characteristic HDX profiles, suggesting structure-dynamic preorganization (geometric arrangements of catalytic residues before the transition state) of conserved α1 and α2 repeats at ion-coordinating residues involved in transport activities. Moreover, dynamic preorganization of local structural entities in the apo protein predefines the status of ion-occlusion and transition states, even though Na+ or Ca2+ binding modifies the preceding backbone dynamics nearby functionally important residues. Future challenges include resolving the structural-dynamic determinants governing the ion selectivity, functional asymmetry and ion-induced alternating access. Taking into account the structural similarities of NCX_Mj with the other proteins belonging to the Ca2+/cation exchanger superfamily, the recent findings can significantly improve our understanding of ion transport mechanisms in NCX and similar proteins.
Introduction: Evaluating the impact of unplanned treatment gap, secondary to COVID-19 pandemic lockdowns, on visual acuity in previously treated diabetic macular edema (DME) patients. Methods: A multi-center, retrospective, study of DME patients, previously treated with anti-VEGF injections who were followed-up during COVID-19 pandemic (2020) comparing to pre COVID-19 period (2019) Results: A total of 634 DME patients with a mean age of 68.4 years met the inclusion criteria, 385 were assessed in 2019 (pre COVID-19) and 239 patients assessed in 2020 (COVID-19). Baseline BCVA among patients in 2019 and 2020 was 0.52±0.44, 0.45±0.43 (LogMAR, respectively). There was no significant difference between the years 2020 and 2019 in baseline BCVA (p=0.07). Mean number of anti-VEGF injections was significantly lower (5 Vs 6, p<0.01), with a major lower ratio of injections per patient in the COVID-19 first lockdown period (March-June 2020) in the COVID-19 group. Baseline BCVA (p<0.01) was the only significant predictor of final BCVA. Number of injections, age, gender and the year weren’t found as a predictor of final BCVA. Conclusions: In a large cohort of DME patients, an unplanned delay in treatment with anti- VEGF injections for 2-3 months due to COVID-19 pandemic lockdown, had no significance impact on visual acuity. For most patients, returning to routine treatment regimen was sufficient for BCVA maintaining.
Purpose: To explore the dose-response relationship of anti-vascular endothelial growth factor (VEGF) agents, with bevacizumab as 1st line treatment, on visual acuity (VA) outcome during the first year of treatment in neovascular AMD (nAMD) patients in real-life conditions. Methods: A retrospective, observational, single center study at the Ophthalmology Division, Tel Aviv Medical Center. Inclusion criteria was naive AMD patients treated with anti VEGF injections between the years 2017-2020. Electronical medical records (EMRs) were scanned using the MD-Clone software, data from time of diagnosis, containing baseline VA, final VA, number of injections and the injected agent was gathered. Subjects were divided to three groups based on their baseline VA ('good, 'middle' and 'bad'). Results: A total of 672 patients were included. The cohort demonstrated a statistically non-significant correlation with a positive trend between the log transform of the number of annual injections and the change in VA (P=0.145). However, a significant correlation was established within the 'low VA’ group, (P = 0.015). The 'good' and 'middle' VA groups did not reach statistical significance. Baseline VA was the single significant predictor for VA gain within patients with baseline VA of 6/12 or less. Conclusions: A dose-response relationship between anti-VEGF injections and VA outcome was found only for patients with low baseline VA. Individual patient characteristics might need to be included to precise individualized treatment regimen and improve visual outcome.
Purpose: Evaluating the impact of delayed care, secondary to coronavirus disease 2019 (COVID-19) pandemic lockdowns, on visual acuity in previously treated neovascular agerelated macular degeneration (nAMD) patients.Methods: This was a multicenter, retrospective, study of patients with nAMD previously treated with anti-VEGF injections who were followed up during 2019 (pre-COVID-19) and compared with patients with nAMD during 2020 (COVID-19).Results: A total of 1,192 patients with nAMD with a mean age of 81.5 years met the inclusion criteria. Of these, 850 patients were assessed in 2019 (pre-COVID-19) and 630 patients were assessed in 2020 (COVID-19). Three hundred eight patients were assessed through both 2019 and 2020 and thus were included in both cohorts. There was no significant difference between 2020 and 2019 in baseline and change in best-corrected visual acuity (BCVA; P = 0.342 and P = 0.911, respectively). The mean number of anti-VEGF injections was significantly lower (5.55 vs. 6.13, P , 0.01), with constant lower ratio of injections per patient in the COVID-19 period. Baseline BCVA (0.859, P , 0.01), number of injections (20.006, P = 0.01), and age (0.003, P , 0.01) were predictors of final BCVA. Conclusion:In patients with nAMD, delayed care secondary to COVID-19 pandemic lockdowns has no statistically significant impact on BCVA. Best-corrected visual acuity, older age, and lower number of yearly anti-VEGF injections are predictors for decrease BCVA.
Purpose To evaluate the impact of postponed care attributed to coronavirus disease (COVID-19) pandemic lockdowns on visual acuity and the number of anti-VEGF injections in patients with retinal vein occlusion (RVO). Methods A multicenter, retrospective study of consecutive RVO patients previously treated with anti-VEGF injections, which compared data from pre- (2019) and during (2020) COVID-19 lockdown period. Results A total of 814 RVO patients with a mean age of 72.8 years met the inclusion criteria. Of them, 439 patients were assessed in 2019 and 375 in 2020. There was no significant difference between the COVID-19 and pre-COVID-19 period in terms of baseline and final BCVA ( p = 0.7 and 0.9 respectively), but there was a significantly reduced mean number of anti-VEGF injections during the COVID-19 period (5.0 and. 5.9 respectively, p < 0.01), with a constant lower ratio of injections per patient. A noticeable decline was found during March–May ( p < 0.01) in 2020. Baseline BCVA (0.69, p < 0.01) and the number of injections (− 0.01, p = 0.01) were predictors of final BCVA. Conclusions In a large cohort of RVO patients, during 2020 lockdowns imposed due to the COVID-19 pandemic, a significant reduction in the annual number of anti-VEGF injections was noted. The postponed care did not result in a significant impact on the final BCVA. Baseline BCVA and the number of annual injections serve as predictors for final BCVA in RVO patients.
Objectives To evaluate visual outcomes after switching from Bevacizumab to Ranibizumab or Aflibercept in patients with macular edema (ME) secondary to branch retinal vein occlusion (BRVO). Methods A retrospective, multi-center, observational study of BRVO patients treated with at least three Bevacizumab injections, prior to anti VEGF switch. Follow up period was 36 months and the primary study outcomes assessed changes in best corrected visual acuity (BCVA) after anti VEGF switch. Results A total of 263 eyes of 263 patients with a mean age of 71.5 ± 11.2 years of which 50% were of male gender met the inclusion criteria. Of these 175 eyes did not underwent switch while 88 eyes underwent anti-VEGF switch. There was not significant difference in mean age (p = 0.634) and gender (p = 0.269) between groups. Baseline BCVA of the no-switch group was 0.47 ± 0.43 logMAR (20/59 Snellen) Vs. 0.6 ± 0.49 logMAR (20/79 Snellen) (p = 0.031) in the switch group and at 36-months it was 0.41 ± 0.39 (20/51 Snellen) logMAR Vs. 0.54 ± 0.49 logMAR (20/69 Snellen) (p = 0.035) respectively. Difference between the rate of change in BCVA per year was insignificant between groups (p = 0.414). in multivariate analysis baseline BCVA was the single significant predictor for switch (Beta 0.137, p = 0.035). Patients with more than one anti VEGF switch suffer from decrease in BCVA. Conclusions Worse BCVA is a significant predictor for anti-VEGF switch execution, though the switch has no significant impact on the change in BCVA over time. Multiple anti VEGF switch is not recommended.
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