Aflibercept vs. dexamethasone implant for recalcitrant diabetic macular edema in pseudophakic eyes - 1-year outcomes from a quazi-randomized study in India.

PURPOSE: To assess the safety and efficacy of intravitreal Aflibercept (IVA) versus dexamethasone (DEX) implant for treating recalcitrant diabetic macular edema (DME) in pseudophakic eyes at 1-year follow-up. DESIGN: Retrospective comparative case series. PARTICIPANTS: Data of all patients diagnosed with DME between January 2019 and December 2021, who underwent 4-monthly doses of intravitreal ranibizumab but had persistent DME [central macular thickness (CMT) within 10% of baseline value] were extracted from a computerized database. Of these, only pseudophakic eyes that underwent either IVA or DEX implant and had at least 1-year follow-up were included for analysis. METHODS: DEX implant was preferred before December 2020 and IVA after this time point. In the IVA group, patients were followed up every month while DEX were followed at least every 3 months. Reinjections were considered when vision dropped by at least 1 Snellen's line or CMT increased by at least 10% from the previous visit in both groups. MAIN OUTCOME MEASURES: Comparison of change in vision and CMT at 1-year follow-up in DEX versus IVA groups. RESULTS: Eighty-four eyes of 84 patients aged 54.4 + 4.4 years were included, 39 (46%) received DEX and 45 (54%) received IVA. Groups were comparable for baseline vision and CMT. Vision improved equally in both groups from 0.83 + 0.15 logMAR to 0.52 + 0.10 logMAR at 3 months (P < 0.01) and then stabilized till 1 year. However, eyes in the IVA group were 6.5 times more likely (Odds ratio = 6.45, 95% CI = 1.3 - 31.9) to achieve >3-line improvement in vision. The CMT reduction was also comparable between groups (-169 + 51 in DEX vs. -174 + 49 in IVA, P = 0.67). More eyes in the IVA group required >3 injections (91% vs. 69% in DEX, P = 0.01). The IOP was significantly higher at 6 and 9 months in the DEX group and 5 eyes (13%) required IOP lowering medications. CONCLUSION: In pseudophakic eyes with recalcitrant DME not responding to ranibizumab, switching to IVA or DEX implant results in equal visual improvement and CMT reduction. Though >3-line improvement occurs more frequently with IVA, this comes at the expense of a greater number of injections and follow-up visits.

Synthesis of Self Permeable Antisense PMO Using C5-Guanidino-Functionalized Pyrimidines at the 5'-End Enables Sox2 Downregulation in Triple Negative Breast Cancer Cells.

Delivery of macromolecular drugs inside cells has been a huge challenge in the field of oligonucleotide therapeutics for the past few decades. Earliest natural inspirations included the arginine rich stretch of cell permeable HIV-TAT peptide, which led to the design of several molecular transporters with varying numbers of rigid or flexible guanidinium units with different tethering groups. These transporters have been shown to efficiently deliver phosphorodiamidate morpholino oligonucleotides, which have a neutral backbone and cannot form lipoplexes. In this report, PMO based delivery agents having 3 or 4 guanidinium groups at the C5 position of the nucleobases of cytosine and uracil have been explored, which can be assimilated within the desired stretch of the antisense oligonucleotide. Guanidinium units have been connected by varying the flexibility with either a saturated (propyl) or an unsaturated (propargyl) spacer, which showed different serum dependency along with varied cytoplasmic distribution. The effect of cholesterol conjugation in the delivery agent as well as at the 5'-end of full length PMO in cellular delivery has also been studied. Finally, the efficacy of the delivery has been studied by the PMO mediated downregulation of the stemness marker Sox2 in the triple-negative breast cancer cell line MDA-MB 231. These results have validated the use of this class of delivery agents, which permit at a stretch PMO synthesis where the modified bases can also participate in Watson-Crick-Franklin base pairing for enhanced mRNA binding and protein downregulation and could solve the delivery problem of PMO.

Synthesis and Biophysical Properties of Triazole-Incorporated PMOs (TzPMOs): A Convergent, Click Ligation Approach.

The synthesis of phosphorodiamidate morpholino oligonucleotides (PMOs) incorporating single or double triazole rings in the backbone has been achieved via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The synthetic approach implemented is fundamentally convergent, involving the ligation of a 5'-azide PMO fragment to a 3'-alkyne fragment both in solution and on solid support. To access the 3'-alkyne PMO fragment, we synthesized 3'-N-propargyl chlorophosphoramidate morpholino monomers for all four nucleobases. The resulting triazole-incorporated PMOs (TzPMOs) have exhibited comparable or improved binding affinity toward complementary deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) strands compared to its regular analogues. Finally, a full-length TzPMO was designed to target the Nanog gene, demonstrating almost identical hybridization properties when compared to its regular version. Circular dichroism studies revealed a B-type helical conformation for the duplexes formed by TzPMOs.

Synthesis and Biophysical Studies of High-Affinity Morpholino Oligomers Containing G-Clamp Analogs.

Successful syntheses of chlorophosphoramidate morpholino monomers containing tricyclic cytosine analogs phenoxazine, G-clamp, and G8AE-clamp were accomplished. These modified monomers were incorporated into 12-mer oligonucleotides using trityl-chemistry by an automated synthesizer. The resulting phosphorodiamidate morpholino oligomers, containing a single G-clamp, demonstrated notably higher affinity for complementary RNA and DNA compared to the unmodified oligomers under neutral and acidic conditions. The duplexes of RNA and DNA with G-clamp-modified oligomers adopt a B-type helical conformation, as evidenced by CD-spectra and show excellent base recognition properties. Binding affinities were sequence and position dependent.

The spatio-temporal dynamics of suspended sediment sources based on a novel indexing approach combining Bayesian geochemical fingerprinting with physically-based modelling.

Applications of sediment source fingerprinting continue to increase globally as the need for information to support improved management of the sediment problem persists. In our novel research, a Bayesian fingerprinting approach using MixSIAR was used with geochemical signatures, both without and with informative priors based on particle size and slope. The source estimates were compared with a newly proposed Source Sensitivity Index (SSI) and outputs from the INVEST-SDR model. MixSIAR results with informative priors indicated that agricultural and barren lands are the principal sediment sources (contributing ∼5-85% and ∼5-80% respectively during two sampling periods i.e. 2018-2019 and 2021-2022) with forests being less important. The SSI spatial maps (using % clay and slope as informative priors) showed >78% agreement with the spatial map derived using the INVEST-SDR model in terms of sub-catchment prioritization for spatial sediment source contributions. This study demonstrates the benefits of combining geochemical sediment source fingerprinting with SSI indices in larger catchments where the spatial prioritization of soil and water conservation is both challenging but warranted.

Incidence, clinical features, risk factors, and outcomes of Intraocular inflammation following Brolucizumab in Indian eyes - A multicentric study.

Purpose: To report the incidence, clinical features, potential risk factors, and outcomes of intraocular inflammation (IOI) following brolucizumab in Indian eyes. Methods: All consecutive patients diagnosed with brolucizumab-induced IOI from 10 centers in eastern India between October 2020 and April 2022 were included. Results: Of 758 injections given during the study period across centers, 13 IOI events (1.7%) were recorded attributable to brolucizumab. The IOI occurred after the first dose in two eyes (15%) (median 45 days after brolucizumab), second dose in six eyes (46%) (median = 8.5 days), and third dose (39%) in the remaining five eyes (median 7 days). Reinjections of brolucizumab were administered at a median interval of 6 weeks (interquartile range = 4-10 weeks) in the 11 eyes, where IOI occurred after the second or third dose. Eyes that experienced IOI after the third dose had received a significantly greater number of previous antivascular endothelial growth factor injections (median = 8) compared to those who developed it after the first or second dose (median = 4) (P = 0.001). Anterior chamber cells were seen in almost all eyes (n = 11, 85%), while peripheral retinal hemorrhages were seen in two eyes, and one eye showed branch artery occlusion. Two-thirds of patients (n = 8, 62%) recovered with a combination of topical and oral steroids, while remaining recovered with topical steroids alone. Irreversible visual loss was not seen in any eye, and median vision recovered to pre-IOI levels by 3 months' time point. Conclusion: Brolucizumab-induced IOI was relatively rare, occurring in 1.7% of eyes, was more common after the second or third injection, especially in those who required frequent reinjections every 6 weeks, and occurred earlier with increasing number of previous brolucizumab injections. Continued surveillance is necessary even after repeated doses of brolucizumab.

Real-world outcomes and complications of different surgical approaches for significant submacular haemorrhages.

Purpose: To evaluate the outcomes and complications after different surgical management of cases with significant sumacular hemorrhage (SMH) of size more than 4 disc diameter (DD). Methods: It was a retrospective interventional study. All consecutive 103 cases of significant SMHs were treated by vitrectomy and divided into three groups. In Group A (<4 weeks, confined to the macula or extending inferiorly, n = 62), vitrectomy, subretinal cocktail of tissue plasminogen activator (tPA), antivascular endothelial growth factor, and air with SF6 gas; in Group B (4-8 weeks, extending beyond macula, n = 31), subretinal tPA followed by SMH drainage either by retinotomy (Group B-1, n = 17) or by temporal 180-degree retinectomy (Group B-2, n = 14) with silicone oil (SO) tamponade; and in Group C (>8 weeks, extending beyond macula, n = 10), SMH removal with autologous retinal pigment epithelium (RPE)-Choroid patch graft transplantations with SO tamponade were performed. Parameters evaluated were best corrected visual acuity (BCVA), Optos, optical computerized tomography, and ultrasonography as required. Results: Significant visual improvement was seen from mean preoperative to mean postoperative BCVA in Group A (P < 0.001), Group B (P < 0.001), and Group C (P < 0.001). Postoperative complications were recurrent SMH (4.84% vs 12.90% vs 10%), vitreous hemorrhage (6.45%, GroupA), hyphema (4.84% vs 12.90% vs 10%), hypotony (nil vs 3.23% vs 20%), macular hole formation (6.45%, Group A), epiretinal membrane (16.13%, Group B), and retinal detachment (3.23%, Group A and 10%, Group C). Conclusion: Surgical approaches for significant submacular hemorrhage are visually awarding, though certain specific complications may arise.

Biosimilar versus InnovAtor MoLecule of RAnibizumab in Neovascular Age-Related MaCular DEgeneration (The BALANCE Trial): Real-World Evidence.

Purpose: To analyse outcomes of innovator ranibizumab (IRM) (Lucentis) and biosimilar ranibizumab (BRM) (Razumab) in Indian eyes with neovascular age-related macular degeneration (nAMD). Methods: Retrospective observational study in nAMD patients, who were treated with IRM or BRM (3 loading doses followed by pro re nata (PRN). Primary outcome measures were change in best corrected visual acuity (BCVA) and central macular thickness (CMT) along with safety analysis. Secondary outcomes measures were changes in the subretinal fluid (SRF) and intraretinal fluid (IRF). Results: Inclusion criteria were satisfied in 164 eyes (60.74%). A total of 87 eyes were treated with IRM, and 77 eyes received BRM. Baseline BCVA was 0.57±0.27 logMAR in IRM group and 0.61±0.25 in the BRM group. At 3, 6, 9, and 12 months BCVA was 0.27±0.22 (p<0.0001), 0.34±0.23 (p<0.0001), 0.39±0.25 (p<0.0001), and 12 months 0.41±0.23 (p<0.0001) in the IRM group and 0.24±0.16 (p<0.0001), 0.27±0.16 (p<0.0001), 0.34±0.17 (p<0.0001), 0.38±0.18 (p<0.0001) in the BRM group. Baseline CMT was 420.39±54.45 µm in IRM group and 407.82±53.07 µm in BRM group. At 3, 6, 9, and 12 months, CMT decreased to 258.28±20.4 µm (p<0.0001), 268.38±19.5 µm (p<0.0001), 269.51±32.41 µm (p<0.0001), and 278.28±16.56 µm (p<0.0001) in the IRM group and 258.84±17.47 µm (p<0.0001), 265.69±17.29 µm (p<0.0001), 273.64±23.13 µm (p<0.0001), and 283.09±19.66 µm (p<0.0001) in the BRM group. Similar improvements in IRF and SRF levels in the patients were noted in both groups. Required number of doses of IRM and BRM was similar over the 12 month period in both groups. A similar profile of adverse events was noted in both the groups. Conclusion: Intravitreal injection of IRM and BRM show similar efficacy and safety in Indian eyes with nAMD.

Synthesis of Chlorophosphoramidate Monomer Morpholinos and PMOs.

Phosphorodiamidate morpholino oligonucleotides (PMOs) are a successful class of antisense reagents that efficiently modulate gene expression. Because PMOs do not follow standard phosphoramidite chemistry, optimized synthetic protocols for these compounds are relatively scarce in the literature. This paper presents detailed protocols for synthesizing full-length PMOs using chlorophosphoramidate chemistry by manual solid-phase synthesis. We first describe the synthesis of Fmoc-protected morpholino hydroxyl monomers, and the corresponding chlorophosphoramidate monomers, from commercially available protected ribonucleosides. The new Fmoc chemistry necessitates the use of a milder base, such as N-ethylmorpholine (NEM), and coupling reagent, such as 5-(ethylthio)-1H-tetrazole (ETT), which are also tolerated for acid-sensitive trityl chemistry. These chlorophosphoramidate monomers are then employed for PMO synthesis in a manual solid-phase procedure using four sequential steps. The synthetic cycle for each nucleotide incorporation consists of (a) deblocking of the 3'-N protecting group using an acidic deblocking cocktail for trityl and base deblocking for Fmoc, (b) neutralization, (c) coupling in the presence of ETT and NEM, and (d) capping of the unreacted morpholine ring-amine. The method uses safe, stable, and inexpensive reagents, and the process is expected to be scalable. After full-length PMO synthesis and ammonia-mediated cleavage from the solid support and deprotection, a range of PMOs with different lengths can be obtained conveniently and efficiently with reproducible good yields. © 2023 Wiley Periodicals LLC. Basic Protocol 1: Synthesis of the novel Fmoc-protected morpholino monomers Basic Protocol 2: Synthesis of the phosphorylating reagent (N,N-dimethylphosphoramic dichloride) required for chlorophosphoramidate monomer synthesis Basic Protocol 3: Synthesis of chlorophosphoramidate monomers of Fmoc-protected morpholino monomers Basic Protocol 4: Solution-phase standardization of dimer and trimer PMO synthesis using Fmoc chemistry Basic Protocol 5: Solid-phase synthesis, purification, and characterization of full-length (25-mer) no-tail PMO using both trityl and Fmoc chemistry.

C5-pyrimidine-functionalized morpholino oligonucleotides exhibit differential binding affinity, target specificity and lipophilicity.

C5-substituted uridine and cytidine morpholino chlorophosphoramidate monomers were synthesized and incorporated into a 12-mer Phosphorodiamidate Morpholino Oligonucleotide (PMO) using semi-automated solid phase synthesis. PMOs with most of the tested pyrimidine C5-substitutions have significantly increased thermal stability when bound to the complementary RNA strand relative to the PMO. They exhibit higher binding with RNA than DNA. CD-spectra show B-type helical conformation of duplexes. HPLC analysis indicates their greater lipophilicity compared to regular PMOs. These chemical modifications have significant potential towards the development of better antisense technologies.

Complete manuscript title: role of sub-silicone oil application of triamcinolone acetonide (TA) drops on outcomes after 360° relaxing retinectomy: a pilot study.

PURPOSE: To perform a pilot study to evaluate the role of sub-silicone oil Triamcinolone Acetonide (TA) crystal drops in complex Retinal Detachment (RD) with extreme proliferative vitreoretinopathy (PVR) requiring 360-degree relaxing retinectomy (RR). DESIGN: It was a retrospective pilot study. MATERIALS AND METHODS: It was a retrospective case-control pilot study. TA-assisted 23G or 25G vitrectomy was done in 24 complex RDs with extreme PVR where 360 degree RR had to be performed. Group A (n = 13) included cases where additional TA crystal drops were applied, after settling the detached retina, over the site of RR under silicone oil (SO 5000 CSt) tamponade. In the control arm, group B (n = 11), additional TA crystals were not applied. MAIN OUTCOMES MEASURED: Mean pre- and post-operative BCVA, ultra-widefield fundus photograph by Optos 200Tx, macular OCT and the propensity to remove silicone oil were measured. RESULTS: Mean pre-operative and post-operative BCVA at final follow-up were Log MAR 2.69 ± 0.41 and Log MAR 1.51 ± 0.90 (Mann-Whitney U test, p < 0.05), respectively, in Group A and Log MAR 2.9 and Log MAR 2.37 ± 0.86 (Mann-Whitney U test, p < 0.05), respectively, in group B. Visual improvement in group A was significantly better than group B (Wilcoxon W test, p < 0.025) with significantly less recurrence of RD (Fisher's Exact Test, p = 0.002). Silicone oil removal was done significantly more in group A (Fisher's Exact Test, p = 0.0017). CONCLUSION: Sub-silicone oil crystals application over sites of RR after 360-degree relaxing retinectomy leads to improved postoperative visual recovery as well as improved anatomical outcomes with fewer complications.

Physical Characteristics, Movement Pattern, and Heart Rate Response of Indian Cricketers During Batting in Twenty20 (T20) Matches.

The study aims to provide a morphological profile of Indian cricketers and find physiological demands and positional differences of the batsmen in T20 matches according to their batting order. Eighty-three male cricketers (age: 17.93 ± 2.23 years) participated in this study and categorized into upper-order (n = 36), middle-order (n = 35) and lower-order (n = 12) batsmen. Height, weight, body fat%, and somatotype were measured. Movement analysis and heart rate (HR) responses were recorded during batting in T20 matches using PolarV800 smart-watch and H7 HR sensor. Descriptive statistics, one-way ANOVA followed by post-hoc analysis examined group differences. Results indicated that upper-order batsmen were balanced mesomorph, middle-order batsmen were mesomorphic-endomorph, and lower-order batsmen were mesomorphic-ectomorph. Cricket-specific movement patterns showed that standing made-up the majority of time spent (54.1 - 60.9%), while maximum distance was covered by walking (68.5 - 73.3%) during batting. Lower-order batsmen spent significantly lesser time (p < 0.01; d = 1.02) in the crease and covered lesser total distance (p < 0.05; d = 0.85) compared to upper and middle-order batsmen, respectively. Upper-order batsmen maintained a significantly lower average HR throughout batting compared to middle (p < 0.01; d = 1.07) and lower-order (p < 0.01; d = 2.04) batsmen. Moreover, upper-order batsmen spent significantly more time in the low-intensity target HR (THR) zone (~9.9%) compared to the middle (~3.2%; p < 0.01; d = 0.72) and lower-order (~2.3%; p < 0.05; d = 0.69). Additionally, upper-order batsmen spent significantly less time (20.8%; p < 0.01) in the high-intensity THR compared to the middle (55.3%) and lower-order (52.2%) batsmen. Therefore, the findings highlight distinct movement and physiological demands associated with batting at different orders during T20 matches, which conditioning coaches and cricketers can utilize to optimize training programs and enhance individual performance.

Intravitreal Injection of Brolucizumab for Recalcitrant Macular Edema due to Central Retinal Vein Occlusion: A Small Case Series.

This was a single center, prospective uncontrolled nonrandomized case series. Two eyes with recalcitrant ME secondary to CRVO, who have received a minimum of ten intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections, underwent IVI brolucizumab (BRZ). Patients underwent best corrected visual acuity (BCVA) testing, ophthalmic examination, and optical coherence tomography at baseline and follow-up visits (weeks 4, 8, 12, and 16). Both patients demonstrated notable improvement in BCVA and reduction of fluid on SD-OCT lasting up to week 12. At week 16, though both the eyes maintained the visual acuity gains, early increase in fluid was noted in both cases, for which second dose of IVI BRZ was given. No ocular or systemic adverse events were noted in these 2 cases.

Brolucizumab in Neovascular Age-Related Macular Degeneration - Indian Real-World Experience: The BRAILLE Study - Fifty-Two-Week Outcomes.

Purpose: To report the 52-week real-world efficacy and safety outcomes of brolucizumab therapy for neovascular age-related macular degeneration (nAMD) in Indian eyes. Patients and Methods: A retrospective, multicentre chart analysis of 82 eyes of 82 patients with nAMD (switch therapy: 65 eyes; treatment-naïve: 17 eyes) with 52-week follow-up data was performed. Pro-re-nata re-treatment was offered based on visual and tomographic criteria. Changes in best-corrected visual acuity (BCVA), intraretinal fluid (IRF), subretinal fluid (SRF), central-subfield thickness (CST), and pigment epithelial detachment (PED) were the key outcome measures, coupled with the safety profile. Results: The mean age of the study population was 67.65 (±10.67) years, with 57 male patients (69.5%). The study's mean number of injections was 4.8 (± 0.77). After brolucizumab therapy, the BCVA improved significantly at weeks 4 (P<0.001), and maintained up to week 52 (P<0.001). The CST also reduced significantly at all the visits (Baseline: 413.6 ± 64.6 µm; 52-week: 292.37 ± 13.5 µm; P<0.001). Significantly fewer eyes demonstrated residual SRF (P<0.001) and IRF (P<0.001) at all visits, starting with week 12 and continuing until week 52. The PED resolution was significant from week 24 through week 52 (P=0.004). Each of the 82 eyes received four injections of brolucizumab, with 63.4% (52 eyes) receiving a fifth dose and only 17.1% requiring a sixth. Mild intraocular inflammation (IOI) was seen in three eyes (3.66%) that resolved conservatively. One patient (1.2%) developed mild fever that subsided with oral medications. Conclusion: The 52-week BRAILLE study demonstrates that brolucizumab is effective and safe in nAMD eyes in a real-world setting. Brolucizumab treatment can reduce the therapeutic burden in patients with nAMD due to its rapid, sustained efficacy and favourable safety profile.

Barth Syndrome: Psychosocial Impact and Quality of Life Assessment.

BACKGROUND: Barth syndrome (BTHS) is a rare X-linked genetic disease that affects multiple systems and leads to complex clinical manifestations. Although a considerable amount of research has focused on the physical aspects of the disease, less has focused on the psychosocial impact and quality of life (QoL) in BTHS. METHODS: The current study investigated caregiver- (n = 10) and self-reported (n = 16) psychological well-being and QoL in a cohort of BTHS-affected patients and families. Participants completed the depression and anxiety components of the Patient-Reported Outcomes Information System (PROMIS) Short Form 8A and Health-related quality of life (HRQoL) surveys at enrollment and again during a follow-up period ranging from 6 to 36 months after baseline. RESULTS: Quality of life changed significantly over time and the various domains with some improvement and some decline. Among the available caregiver-patient dyad data, there was a trend toward discordance between caregiver and self-reported outcomes. Most notably, patients reported improvement in HRQoL, while caregivers reported declines. This suggests that there may be differences in perceived quality of life between the patients and parents, though our study is limited by small sample size. CONCLUSION: Our study provides valuable insights into the impacts of psychosocial and mental health aspects of BTHS. Implications of these findings include incorporating longitudinal assessment of QoL and screening for psychological symptoms in BTHS care to identify interventions that may drastically impact health status and the course of the disease.

Synthesis of Phosphorodiamidate Morpholino Oligonucleotides Using Trityl and Fmoc Chemistry in an Automated Oligo Synthesizer.

Phosphorodiamidate morpholino oligonucleotides (PMOs) constitute 3 out of the 11 FDA-approved oligonucleotide-based drugs in the last 6 years. PMOs can effectively silence disease-causing genes and modify splicing. However, PMO synthesis has remained challenging for a variety of reasons: inefficient deprotection and coupling methods and instability of monomers. Here, we report the development of a suitable combination of resin supports, deblocking and coupling reagents for synthesizing PMOs using either trityl or Fmoc-protected chlorophosphoramidate monomers. The synthesized PMOs using both the methods on a solid support have been validated for gene silencing in a zebrafish model. The protocol was successfully transferred into an automated DNA synthesizer to make several sequences of PMOs, demonstrating for the first time the adaptation of regular PMOs in a commercial DNA synthesizer. Moreover, PMOs with longer than 20-mer sequences, including FDA-approved Eteplirsen (30-mer), were achieved in >20% overall yield that is superior to previous reports. Hybridization study shows that PMOs exhibit a higher binding affinity toward complementary DNA relative to the DNA/DNA duplex (>6 °C). Additionally, the introduction of Fmoc chemistry into PMOs opens up the possibility for PMO synthesis in commercial peptide synthesizers for future development.

Comparison of Innovator vs. Biosimilar Ranibizumab in Treating Diabetic Macular Edema: A Multicenter Retrospective Study.

INTRODUCTION: To compare the efficacy of innovator ranibizumab (iRBZ-Accentrix, Novartis, India) vs. biosimilar ranibizumab (bRBZ, Razumab-Intas, India) in eyes with diabetic macular edema (DME) in an Indian population. METHODS: Data of patients with DME who underwent at least three injections of iRBZ or bRBZ and had a minimum of 6 months follow-up were obtained from an electronic database. Choice of injection depended upon the patient. Pro re nata (PRN) protocol from baseline was used with reinjections advised if the central macular thickness (CMT) was at least 300 µm and best corrected visual acuity (BCVA) was 20/40 or worse. Primary outcome measure was comparison of change in BCVA at 6 months between iRBZ and bRBZ. RESULTS: We included 264 eyes in the iRBZ group and 69 eyes in bRBZ group, which were comparable for baseline characteristics. Mean BCVA improved from 0.64 ± 0.39 logMAR to 0.47 ± 0.31 logMAR (p < 0.001) in the iRBZ group and from 0.71 ± 0.42 logMAR to 0.50 ± 0.29 logMAR in the bRBZ group (p < 0.001) at 6 months. There were no differences in BCVA between the two groups (p > 0.05 for all time points). The CMT reduction in the iRBZ group (120 ± 196 µm) was comparable to that in the bRBZ group at 6 months (105 ± 187 µm) (p = 0.69). There was no difference in the mean number of injections taken (3.81 ± 1.2 in iRBZ vs. 3.55 ± 1.2 in bRBZ) (p > 0.05) between groups. Vision at baseline was the only factor associated with vision at last follow-up after adjusting for CMT at baseline, type of injection, and number of injections. CONCLUSIONS: Biosimilar RBZ is similar to innovator RBZ in improving vision and reducing CMT in eyes with DME in the short term.

Statistical mechanics of Floquet quantum matter: exact and emergent conservation laws.

Equilibrium statistical mechanics rests on the assumption of chaotic dynamics of a system modulo the conservation laws of local observables: extremization of entropy immediately gives Gibbs' ensemble (GE) for energy conserving systems and a generalized version of it (GGE) when the number of local conserved quantities is more than one. Through the last decade, statistical mechanics has been extended to describe the late-time behaviour of periodically driven (Floquet) quantum matter starting from a generic state. The structure built on the fundamental assumptions of ergodicity and identification of the relevant conservation laws in this inherently non-equilibrium setting. More recently, it has been shown that the statistical mechanics of Floquet systems has a much richer structure due to the existence ofemergentconservation laws: these are approximate but stable conservation laws arisingdue to the drive, and are not present in the undriven system. Extensive numerical and analytical results support perpetual stability of these emergent (though approximate) conservation laws, probably even in the thermodynamic limit. This banks on the recent finding of a sharp threshold for Floquet thermalization in clean, interacting non-integrable Floquet systems. This indicates to the possibility of stable Floquet phases of matter in disorder-free systems. This review intends to give a self-contained theoretical overview of these developments for a broad physics audience. We conclude by briefly surveying the current experimental scenario.

Inhibition of extracellular vesicle-associated MMP2 abrogates intercellular hepatic miR-122 transfer to liver macrophages and curtails inflammation.

Hepatic miRNA, miR-122, plays an important role in controlling metabolic homeostasis in mammalian liver. Intercellular transfer of miR-122 was found to play a role in controlling tissue inflammation. miR-122, as part of extracellular vesicles released by lipid-exposed hepatic cells, are taken up by tissue macrophages to activate them and produce inflammatory cytokines. Matrix metalloprotease 2 or MMP2 was found to be essential for transfer of extracellular vesicles and their miRNA content from hepatic to non-hepatic cells. MMP2 was found to increase the movement of the extracellular vesicles along the extracellular matrix to enhance their uptake in recipient cells. Inhibition of MMP2 restricts functional transfer of hepatic miRNAs across the hepatic and non-hepatic cell boundaries, and by targeting MMP2, we could reduce the innate immune response in mammalian liver by preventing intra-tissue miR-122 transfer. MMP2 thus could be a useful target to restrict high-fat-diet-induced obesity-related metaflammation.

Brolucizumab in Neovascular Age-Related Macular Degeneration - Indian Real-World Experience: The BRAILLE Study.

PURPOSE: To assess the short-term efficacy and safety profile of intravitreal brolucizumab injection in Indian eyes with neovascular age-related macular degeneration (nAMD) under real-world conditions. PATIENTS AND METHODS: This was a multicenter, retrospective chart review of 94 eyes of 94 patients with nAMD (treatment-naïve and switch-therapy) undergoing brolucizumab therapy. Re-treatment as per pro-re-nata protocol was performed based on fixed visual and tomographic criteria. The main outcome measures were changes in the best-corrected visual acuity (BCVA), intraretinal fluid (IRF), subretinal fluid (SRF), central subfield thickness (CST), and pigment epithelial detachment (PED) along with safety analysis. RESULTS: Of the 94 eyes, 20 eyes (21.3%) were treatment-naïve, whereas the rest 74 eyes (78.7%) underwent switch therapy. One hundred and twenty-six injections were given over a mean follow-up of 7.3 ± 2.2 (range 5-30) weeks. The BCVA improved significantly from 0.82 ± 0.5 LogMAR at baseline to 0.66 ± 0.5 LogMAR at the final visit (p < 0.0001). Significant reduction in CST was simultaneously noted (Baseline: 408.45 ± 65.63 µm; Final: 281.14 ± 37.74 µm; p < 0.0001). On qualitative analysis, resolution of subretinal fluid (SRF), intraretinal fluid (IRF), and pigment epithelial detachment (PED) was observed in 15.5%, 39.29%, and 23.81% of the eyes, respectively. The mean interval of repeat injection was 10.2 ± 2.1 weeks. Three episodes of ocular adverse drug reaction were reported, including two patients developing subretinal hemorrhage while one having a retinal pigment epithelial (RPE) tear. Notably, no intraocular inflammation (IOI) was seen in any of the eyes, and no systemic side effects were identified. CONCLUSION: In a real-world scenario, brolucizumab therapy is efficacious and safe in the management of nAMD over the short term. Further long-term studies are warranted to validate these findings. Additionally, lack of ocular inflammation after 126 brolucizumab injections in our Indian data is peculiar and underlines the necessity to explore the role of race and genetics in predisposing to/safeguarding against brolucizumab-related IOIs.