Adjunctive use of netarsudil 0.02% in the treatment of refractory glaucoma: a one year analysis.

PURPOSE: This study evaluates the long-term adjunctive use of netarsudil ophthalmic solution 0.02% in lowering IOP in patients with refractory glaucoma. METHODS: This retrospective chart review study was conducted at a tertiary care center. Patients who were prescribed add-on netarsudil therapy and on ≥ 3 topical glaucoma medications from 01/01/2018 to 08/31/2020 were reviewed. 47 patients (69 eyes) met the inclusion criteria. Baseline IOPs prior to the addition of netarsudil were compared to IOPs measured at 3-, 6-, and 12-month intervals. Any patients with inadequate follow-up or who had glaucoma surgery after netarsudil initiation were excluded. RESULTS: Median baseline IOP (± SD) was 21 ± 5.8 mmHg (median of 2 visits prior to initiation of netarsudil). At 3-month follow-up, 64 eyes had a median IOP of 16 ± 6.7 mmHg (p < 0.01). At 6-month follow-up, 56 eyes had a median IOP of 18 ± 4.6 mmHg (p < 0.01). At 12-month follow-up, 44 eyes had a median IOP of 15 ± 6.8 mmHg (p < 0.01). At the conclusion of the study, 64% of eyes reached 1 year follow-up due to several reasons. CONCLUSIONS: Patients with refractory glaucoma showed statistically and clinically significant IOP reductions on netarsudil. IOP reduction was stable long-term with the largest decrease in IOP seen at 12 months. Although some patients will still go on to require further laser or incisional surgery, for most patients netarsudil is an effective treatment for adjunctive use in refractory glaucoma.

Socio-demographic determinants of myelofibrosis outcomes in an underserved center and the SEER national database.

The influence of demographic characteristics and social determinants on cancer outcomes is widely recognized in various malignancies but remains understudied in myelofibrosis (MF). This study aims to investigate social and demographic variables associated with MF survival. We retrospectively reviewed data of biopsy-proven MF patients from the Surveillance, Epidemiology and End Results (SEER) database (2000-2021) and Montefiore Medical Center (2000-2023), an underserved inner-city hospital. The SEER cohort included 5,403 MF patients and was predominantly Non-Hispanic (NH) White (82%) with a median age of 69 years. The age-adjusted incidence rate of MF was 0.32 cases per 100,000 person-years, increasing annually by 1.3% from 2000 to 2021. Two- and five- year overall survival rates were 69% and 42%, respectively. Worse cause-specific survival was associated with older age, male sex, and diagnosis before 2011 (year of Ruxolitinib approval). NH-Black ethnicity, unmarried status and lower median income were independent predictors of worse overall survival. The single-center analysis included 84 cases, with a median age of 66 years. NH-White patients comprised 37% of the sample, followed by NH-Black (28.5%). Two- and five- year overall survival rates were 90% and 61%, respectively, with NH-Black patients exhibiting the lowest median survival, although the difference was not statistically significant. Age was a significant predictor of worse survival in this cohort. NH-Black and Hispanic patients lived in areas with higher socioeconomic and demographic stress compared to NH-White patients. Overall, this study highlights the association of social and demographic factors with MF survival and emphasizes the need for equitable healthcare and further exploration of social-demographic factors affecting MF survival.

Rapid multi-attribute characterization of intact bispecific antibodies by a microfluidic chip-based integrated icIEF-MS technology.

Rapid, direct identification and quantitation of protein charge variants, and assessment of critical quality attributes with high sensitivity are important drivers required to accelerate the development of biotherapeutics. We describe the use of an enhanced microfluidic chip-based integrated imaged capillary isoelectric focusing-mass spectrometry (icIEF-MS) technology to assess multiple quality attributes of intact antibodies in a single run. Results demonstrate comprehensive detection of multiple charge variants of an aglycosylated knob-into-hole bispecific antibody. Upfront, on-chip separation by icIEF coupled to MS provides the orthogonal separation required to resolve and identify acidic posttranslational modifications including difficult-to-detect deamidation and glycation events at the intact protein level. In addition, on-chip UV detection enables pI determination and relative quantitation of charge isoforms. Six charge variant peaks were resolved by icIEF, mobilized toward the on-chip electrospray tip and directly identified by in-line icIEF-MS using a connected quadrupole time-of-flight mass spectrometer. In addition to acidic charge variants, basic variants were identified as C-terminal lysine, N-terminal cyclization, proline amidation, and the combination of modifications (not typically identified by other intact methods), including lysine and one or two hexose additions. Nonspecific chain cleavages were also resolved, along with their acidic charge variants, demonstrating highly sensitive and comprehensive intact antibody multi-attribute characterization within a 15-min run time.

Epidemiology of ocular injuries associated with landscaping tools.

The purpose of this retrospective, cross-sectional study was to determine and analyze the trends in ocular injuries related to landscaping activities and equipment from 2010 to 2019. A total of 168,845 ocular injuries were associated with landscaping activities with the majority of cases occurring in men (80.4%) between the ages of 41-60 during the summer months of June, July, and August. The majority of ocular injuries did not require admission (97.8%) but of those that were admitted 42% had an open globe injury (n = 399). The results of this investigation provide useful information for emergency room physicians and ophthalmologists in understanding the prevalence of these landscaping-associated ocular injuries and further draw suspicion for the incidence of open globe injuries in this population.

Epidemiology of welding-associated ocular injuries.

PURPOSE: Currently, there exists a lack of recent epidemiological data concerning ocular injuries due to welding related activities. Our study analyzes trends in ocular injuries related to usage of welding equipment in the U.S. from 2010 to 2019. METHODS: Using the Consumer Product Safety Commission's National Electronic Injury Surveillance System (NEISS) Database, we queried data from January 1st 2010 to December 31st 2019 using the corresponding product code for welding equipment (896). Results were stratified by year, and standard descriptive statistical methods were applied to components including gender, age, diagnoses, and ED disposition. Circumstances leading up to the injuries were reviewed as well. RESULTS: Between 2010 and 2019 a total of 109,127 welding-associated ocular injuries occurred in the United States (95% CI, 86937-131,316). Estimates show a decreasing trend in cases from 13,415 (95% CI, 9979-16,851) in 2010 to 6944 (95% CI, 4868-9020) in 2019. A majority of cases occurred in men (98.2%) and in the 10-49 year age range (83.8%). 3.3% of cases involved spectators and 44% were bilateral. The top three ocular injury diagnoses were flash burns (62.1%), foreign body implantation (19.6%), and contusions/abrasions (11.1%). The number of radiation injuries trended down from 9286 in 2010 to 4023. With respect to a documented location, 38.9% occurred at home and 4.5% occurred in a school setting. Most patients (99.9%) were discharged from the ED; 0.1% were admitted to the hospital. CONCLUSIONS: The data suggests that number of ocular injuries related to welding has decreased significantly over the past 10 years. The most common injuries were radiation burns, foreign body disruption, and contusions/abrasions of the eye. Patients were predominantly men and between the ages of 10 and 49. Of note, almost half of all ocular injuries due to welding were bilateral, and 3% of ocular injuries were seen in spectators.

Association of CARD8 Activating Polymorphism With Bone Erosion in Cholesteatoma Patients.

OBJECTIVES: We compared the incidence of polymorphisms activating the NLRP3 inflammasome between controls and patients with cholesteatoma and its potential association with bone erosion in patients with cholesteatoma. METHODS: This is a case-control study assessing the mutation rates in genes of interest in patients with and without cholesteatoma. A total of 133 saliva samples from control (n = 65) and cholesteatoma (n = 68) patients were collected for DNA extraction. Caspase recruitment domain family member 8 (CARD8) (AA: homozygous wild type, AT: heterozygous, TT: homozygous mutant polymorphism) and NLRP3 (CC: homozygous wild type, CA: heterozygous, AA: homozygous mutant) polymorphisms were analyzed with TaqMan single-nucleotide polymorphism (SNP) quantitative polymerase chain reaction (ThermoFisher Scientific, Waltham, MA). Mutation status was correlated with a novel bone erosion scoring model developed as a part of this study. Summary statistics, including frequencies (%) and median (Q1, Q3) were used to describe the sample. RESULTS: The presence of CARD8 and NLRP3 homozygous wild-type polymorphisms were generally similar for the control and cholesteatoma patient groups. CARD8 homozygous TT polymorphisms were an exception, occurring more frequently in patients who developed a cholesteatoma compared to the control group (29% vs. 10%, P = .009). Those patients with CARD8 homozygous TT polymorphism had higher median scores of bone erosion as compared to subjects with nonhomozygous mutant genotypes (median [interquartile range]: 4.0 [3.0, 5.5] vs. 2.5 [1.0, 3.5], P = .0142). CONCLUSION: Cholesteatoma patients have a significant, twofold higher incidence of CARD8 homozygous TT polymorphism. Furthermore, cholesteatoma patients with this homozygous polymorphism had greater bone erosion rates than controls. These findings suggest that genetic mutations may increase host susceptibility to cholesteatomas. Specifically, the CARD8 TT polymorphism may influence the severity of cholesteatoma-induced bone erosion. LEVEL OF EVIDENCE: 3B.

Serial Multimodality Imaging and 2-Year Clinical Outcomes of the Novel DESolve Novolimus-Eluting Bioresorbable Coronary Scaffold System for the Treatment of Single De Novo Coronary Lesions.

OBJECTIVES: This study sought to report the late multimodality imaging and clinical outcomes of the novel poly-l-lactic-acid-based DESolve novolimus-eluting bioresorbable coronary scaffold for the treatment of de novo coronary lesions. BACKGROUND: Bioresorbable scaffolds are an alternative to drug-eluting metallic stents and provide temporary vascular scaffolding, which potentially may allow vessel restoration and reduce the risk of future adverse events. METHODS: Overall, 126 patients were enrolled at 13 international sites between November 2011 and June 2012. The primary endpoint was in-scaffold late lumen loss at 6 months. Major adverse cardiac events, the main safety endpoint, were defined as the composite of cardiac death, target vessel myocardial infarction, or clinically indicated target lesion revascularization. All patients underwent angiography at 6 months. Serial intravascular ultrasound and optical coherence tomography were performed in a subset of patients. RESULTS: The scaffold device success rate was 97% (n = 122 of 126), and procedural success was 100% (n = 122 of 122). The major adverse cardiac event rate was 3.3% (n = 4 of 122) at 6 months and 7.4% (n = 9 of 122) at 24 months, including 1 probable stent thrombosis within the first month. At 6-month angiographic follow-up, in-scaffold late lumen loss was 0.20 ± 0.32 mm. Paired intravascular ultrasound analysis demonstrated a significant increase in vessel, lumen and scaffold dimensions between post-procedure and 6-month follow-up, and strut-level optical coherence tomography analysis showed full strut coverage in 99 ± 1.7%. CONCLUSIONS: Our results showed favorable performance of the DESolve scaffold, effective inhibition of neointimal hyperplasia, and for the first time, early luminal and scaffold growth at 6 months with sustained efficacy and safety through 2 years. (Elixir Medical Clinical Evaluation of the DESolve Novolimus Eluting Bioresorbable Coronary Scaffold System-The DESolve Nx Trial; NCT02086045).

Serial multimodality imaging and 2-Year clinical outcomes of the novel DESolve novolimus-eluting bioresorbable coronary scaffold system for the treatment of single de novo coronary lesions

OBJECTIVES:This study sought to report the late multimodality imaging and clinical outcomes of the novel poly-l-lactic-acid-based DESolve novolimus-eluting bioresorbable coronary scaffold for the treatment of de novo coronary lesions. BACKGROUND: Bioresorbable scaffolds are an alternative to drug-eluting metallic stents and provide temporary vascular scaffolding, which potentially may allow vessel restoration and reduce the risk of future adverse events...

Redox metabolites signal polymicrobial biofilm development via the NapA oxidative stress cascade in Aspergillus.

BACKGROUND: Filamentous fungi and bacteria form mixed-species biofilms in nature and diverse clinical contexts. They secrete a wealth of redox-active small molecule secondary metabolites, which are traditionally viewed as toxins that inhibit growth of competing microbes. RESULTS: Here, we report that these "toxins" can act as interspecies signals, affecting filamentous fungal development via oxidative stress regulation. Specifically, in coculture biofilms, Pseudomonas aeruginosa phenazine-derived metabolites differentially modulated Aspergillus fumigatus development, shifting from weak vegetative growth to induced asexual sporulation (conidiation) along a decreasing phenazine gradient. The A. fumigatus morphological shift correlated with the production of phenazine radicals and concomitant reactive oxygen species (ROS) production generated by phenazine redox cycling. Phenazine conidiation signaling was conserved in the genetic model A. nidulans and mediated by NapA, a homolog of AP-1-like bZIP transcription factor, which is essential for the response to oxidative stress in humans, yeast, and filamentous fungi. Expression profiling showed phenazine treatment induced a NapA-dependent response of the global oxidative stress metabolome, including the thioredoxin, glutathione, and NADPH-oxidase systems. Conidiation induction in A. nidulans by another microbial redox-active secondary metabolite, gliotoxin, also required NapA. CONCLUSIONS: This work highlights that microbial redox metabolites are key signals for sporulation in filamentous fungi, which are communicated through an evolutionarily conserved eukaryotic stress response pathway. It provides a foundation for interspecies signaling in environmental and clinical biofilms involving bacteria and filamentous fungi.

A next-generation bioresorbable coronary scaffold system: from bench to first clinical evaluation: 6- and 12-month clinical and multimodality imaging results.

OBJECTIVES: This study sought to perform clinical and imaging assessments of the DESolve Bioresorbable Coronary Scaffold (BCS). BACKGROUND: BCS, which is drug eluting, may have potential advantages compared with conventional metallic drug-eluting stents. The DESolve system, designed to provide vessel support and neointimal suppression, combines a poly-l-lactic acid-based scaffold with the antiproliferative myolimus. METHODS: The DESolve First-in-Man (a non-randomized, consecutive enrollment evaluation of the DESolve myolimus eluting bioresorbable coronary stent in the treatment of patients with de novo native coronary artery lesions) trial was a prospective multicenter study enrolling 16 patients eligible for treatment. The principal safety endpoint was a composite of cardiac death, myocardial infarction, and clinically indicated target lesion revascularization. The principal imaging endpoint was in-scaffold late lumen loss (LLL) assessed by quantitative coronary angiography (QCA) at 6 months. Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) imaging was performed at baseline and 6 months; multislice computed tomography (MSCT) was performed at 12 months. RESULTS: Acute procedural success was achieved in 15 of 15 patients receiving a study scaffold. At 12 months, there was no scaffold thrombosis and no major adverse cardiac events directly attributable to the scaffold. At 6 months, in-scaffold LLL (by QCA) was 0.19 ± 0.19 mm; neointimal volume (by IVUS) was 7.19 ± 3.56%, with no evidence of scaffold recoil or late malapposition. Findings were confirmed with OCT and showed uniform, thin neointimal coverage (0.12 ± 0.04 mm). At 12 months, MSCT demonstrated excellent vessel patency. CONCLUSIONS: This study demonstrated the feasibility and efficacy of the DESolve BCS. Results showing low in-scaffold LLL, low % neointimal volume at 6 months, no chronic recoil, and maintenance of lumen patency at 12 months prompt further study. (DESolve First-in-Man; EudraCT number 2011-000027-32).

A Next-Generation Bioresorbable CoronaryScaffold System: From Bench toFirst Clinical Evaluation

This study sought to perform clinical and imaging assessments of the DESolveBioresorbable Coronary Scaffold (BCS).Background BCS, which is drug eluting, may have potential advantages compared with conventionalmetallic drug-eluting stents. The DESolve system, designed to provide vessel support and neointimalsuppression, combines a poly-L-lactic acid–based scaffold with the antiproliferative myolimus.Methods The DESolve First-in-Man (A NON-RANDOMIZED, CONSECUTIVE ENROLLMENT EVALUATIONOF THE DESolve MYOLIMUS ELUTING BIORESORBABLE CORONARY STENT IN THE TREATMENT OFPATIENTS WITH DE NOVO NATIVE CORONARY ARTERY LESIONS) trial was a prospective multicenterstudy enrolling 16 patients eligible for treatment. The principal safety endpoint was a composite ofcardiac death, myocardial infarction, and clinically indicated target lesion revascularization. Theprincipal imaging endpoint was in-scaffold late lumen loss (LLL) assessed by quantitative coronaryangiography (QCA) at 6 months. Intravascular ultrasound (IVUS) and optical coherence tomography(OCT) imaging was performed at baseline and 6 months; multislice computed tomography (MSCT) wasperformed at 12 months.Results Acute procedural success was achieved in 15 of 15 patients receiving a study scaffold. At12 months, there was no scaffold thrombosis and no major adverse cardiac events directly attributableto the scaffold. At 6 months, in-scaffold LLL (by QCA) was 0.19 0.19 mm; neointimal volume (by IVUS)was 7.19 3.56%, with no evidence of scaffold recoil or late malapposition. Findings were confirmedwith OCT and showed uniform, thin neointimal coverage (0.12 0.04 mm). At 12 months, MSCTdemonstrated excellent vessel patency.

Functional modular dissection of DEBS1-TE changes triketide lactone ratios and provides insight into Acyl group loading, hydrolysis, and ACP transfer.

The DEBS1-TE fusion protein is comprised of the loading module, the first two extension modules, and the terminal TE domain of the Saccharopolyspora erythraea 6-deoxyerythronolide B synthase. DEBS1-TE produces triketide lactones that differ on the basis of the starter unit selected by the loading module. Typical fermentations with plasmid-based expression of DEBS1-TE produce a 6:1 ratio of propionate to isobutyrate-derived triketide lactones. Functional dissection of the loading module from the remainder of DEBS1-TE results in 50% lower titers of triketide lactone and a dramatic shift in the production to a 1:4 ratio of propionate to isobutyrate-derived products. A series of radiolabeling studies of the loading module has shown that transfer from the AT to the ACP occurs much faster for propionate than for isobutyrate. However, the equilibrium occupancy of the AT favors isobutyrate such that propionate is outcompeted for ACP occupancy. Thus, propionyl-ACP is the kinetic product, while isobutyryl-ACP is the thermodynamic product. A slowed transfer from the loading domain ACP to first-extension module KS due to functional dissection of DEBS1-TE allows this isobutyryl-ACP-favored equilibrium to be realized and likely accounts for the observed shift in triketide lactone products.

An unpowered, wireless contact lens pressure sensor for point-of-care glaucoma diagnosis.

The development of a wireless, microfluidic pressure sensor composed of Polydimethylsiloxane (PDMS) and dyed glycerol is presented for point-of-care glaucoma diagnosis. Design, fabrication and test results are presented.

Functional dissection of a multimodular polypeptide of the pikromycin polyketide synthase into monomodules by using a matched pair of heterologous docking domains.

The pikromyin polyketide synthase (PKS) in Streptomyces venezulae is comprised of a loading module and six extension modules, which generate the corresponding 14-membered macrolactone product. PikAI is a multimodular component of this PKS and houses both the loading domain and the first two extension modules, joined by short intraprotein linkers. We have shown that PikAI can be separated into two proteins at either of these linkers, only when matched pairs of docking domains (DDs) from a heterologous modular phoslactomycin PKS are used in place of the intraprotein linker. In both cases the yields of pikromycin produced by the S. venezuelae mutant were 50% of that of a S. venezuelae strain expressing the native trimodular PikAI. This observation provides the first demonstration that such separations do not dramatically impact the efficiency of the entire in vivo biosynthetic process. Expression of module 2 as a monomodular protein fused to a heterologous N-terminal docking domain was also observed to give almost a tenfold improvement in the in vivo generation of pikromycin from a synthetic diketide intermediate. These results demonstrate the utility of DDs to manipulate biosynthetic processes catalyzed by modular PKSs and the quest to generate novel polyketide products.

EXCELLA First-in-Man (FIM) study: safety and efficacy of novolimus-eluting stent in de novo coronary lesions.

AIMS: First generation DES have markedly reduced restenosis. However, there is a major interest in developing new DES with greater flexibility, radiopacity and safety profile. The Elixir Medical drug eluting stent is a novel DES that combines a chromium-cobalt platform with novolimus (an antiproliferative sirolimus-analogue drug) and a polymer from the methacrylate family. As potential advantages, it provides a lower drug dose as compared to Cypher (85 microg of novolimus vs. 140 microg of sirolimus) and therefore has a lower polymer load. We sought to evaluate the safety and efficacy of this novel device in reducing neointimal hyperplasia as assessed by QCA and IVUS. METHODS AND RESULTS: In April 2007 a consecutive cohort of patients with de novo lesions < or = 14 mm in length, located in native coronaries of diameter from 3.0 to 3.5 mm were consecutively enrolled in this First-in-Man study (FIM). By protocol, angiography and IVUS would be done at baseline and repeated at four and eight months. Dual anti-platelet therapy was maintained for a minimum of 12 months. The primary endpoint was QCA lumen loss at 4-month follow-up. Secondary endpoints included MACE, in-stent neointimal obstruction by IVUS and device success. A total of 15 patients were included with 67% female patients and diabetes was detected in 47% of the cohort. Angiographic and procedural success was achieved in all patients. At 4-month angiographic follow-up there was in-stent late lumen loss (0.15 +/- 0.29 mm) by QCA and % volume obstruction (2.6 +/- 2.6) by IVUS. The angiographic in-stent late lumen loss results at eight months were 0.31 +/- 0.25 mm and % volume obstruction by IVUS was 6.0 +/- 4.4%. Late incomplete stent apposition (ISA) were not observed among these patients and no MACE was evidenced through nine month clinical follow-up. CONCLUSIONS: In this FIM study, implantation of the novolimus-eluting stent was proven to be feasible, safe and elicited minimum neointimal proliferation. Additional large clinical trials should be considered to confirm these promising results.

Excella First-in-man (FIM) study: safety and efficacy off novolimus-eluting stent in de novo coronary lesions / Excella First-in-man (FIM) study: safety and efficacy off novolimus-eluting stent in de novo coronary lesions

First degeration DES have markdly reduced restenosis. However , there is a major interest in developing a new DES with greater flexibility , radiopacity and safety profile. The elixir medical drug eluting stents is a novel DES combines a chromium-cobalt platform with novolimus (an atiproliferative sirolimos-analogue drug) and a polimer from the metacrylate family. As potential advantages , it provides a lower drug dose as compared to Cypher (85hg of novolimus vs 140 hg of sirolimus) and therefore has a lower polymer load. We sought to evaluated the safety and efficacy of this novel device in reducing neointimal hyperplasia as assessed by QCA and IVUS...