Correlation of limited-early-response status with 12-month CST, BVA, and machine learning-quantified retinal fluid in diabetic macular oedema in routine clinical practice.

BACKGROUND/OBJECTIVES: Anti-VEGF treatment response in DMO has been measured by changes in the central subfield thickness (CST) and best visual acuity (BVA) outcomes at 3 months after initial treatment, termed early or limited early response (ER/LER). This study correlates LER with 12-month BVA, CST, and retinal fluid volumes quantified by a machine learning algorithm on optical coherence tomography (OCT). SUBJECTS/METHODS: The study included treatment naïve DMO patients ≥ 18 years with OCT scans at baseline (M0), M3, M6, and M12. The 220 patients were categorized as limited early responders (LER) if they had ≤ 10% CST reduction and/or < 5 ETDRS letter gain at M3. BVA, CST, and subretinal (SRF), intraretinal (IRF), and total retinal (TRF) fluid volumes quantified by a machine learning algorithm were compared between groups and across time. RESULTS: At M12, the anatomic LER (aLER), defined solely by CST, had significantly worse BVA and CST versus the anatomic ER (aER) group (p < 0.001). Retinal fluid M12 outcomes did not significantly vary between all LER and ER groups. No significant BVA, CST, TRF, and IRF variance across time for LER was found (p > 0.1). CONCLUSIONS: BVA and CST M12 outcomes vary by aLER/aER status indicating that CST may be a strong predictor of treatment outcomes, while retinal fluid volumes were not predicted by LER status.

Macular Holes in Tractional Retinal Detachments Secondary to Diabetic Retinopathy.

Purpose: To characterize the visual outcomes and rate of macular hole (MH) closure with tractional retinal detachment (TRD) and proliferative diabetic retinopathy (PDR). Methods: Visit data of patients who had pars plana vitrectomy were retrospectively reviewed; patient demographics, other procedure(s), the MH closure rate, and visual outcomes were also collected. Paired t, Fisher exact, and Mann-Whitney U tests were performed. Results: Ten patients (10 eyes) developed a TRD MH; 3 distinct MH presentations were identified. At the 3-month follow-up, 90% of MHs remained closed without the need for further reoperation (n = 6, type 1 closure; n = 3, type 2 closure). All MHs were closed 12 months after the initial surgery, with 1 eye requiring a single reoperation. The mean visual acuity (VA) at baseline and at 12 months was 20/235 and 20/138, respectively. Conclusions: MHs in the setting of fibrovascular proliferation resulting from PDR present with varied morphology. There is a high rate of MH closure and a trend toward improved VA.

Real-world effects of anti-vascular endothelial growth factor injection frequency on visual outcomes in patients with diabetic macular oedema.

BACKGROUND AND OBJECTIVE: Anti-vascular endothelial growth factor (VEGF) injections are often administered less frequently in real-world treatment of diabetic macular oedema (DMO) than what was studied in clinical trials. This study aims to characterise real-world DMO treatment patterns and the effect of treatment intervals on patient outcomes. STUDY DESIGN/PATIENTS AND METHODS: This was a retrospective study of 291 patients with DMO treated with anti-VEGF therapy. 12- and 24-month best visual acuity (BVA) and central subfield thickness (CST) were compared between injection interval groups, which were determined by averaging the two most recent injection intervals. Multiple linear regressions were performed to identify factors associated with injection interval, BVA, and CST. RESULTS: 48.8% of patients received injections less than or equal to every 8 weeks (≤ q8w), 27.5% between every 8 to 12 weeks (q8-12w), and 23.7% greater than every 12 weeks (> q12w). Baseline CST was similar (p = 0.32), but BVA differed significantly in q8-12w patients (p = 0.0095). BVA and CST at 12 months were similar, but q8-12w patients experienced greater 12-month BVA improvement (7.36 ± 12.4 letters) than > q12w patients (1.26 ± 12.3 letters; p = 0.0056). 24-month BVA and CST changes were similar between groups (p = 0.30 and 0.87). Baseline BVA, HbA1c, and sex were associated with 12-month BVA, and baseline BVA and CST were associated with 12-month CST. CONCLUSION: Many patients experienced improvements in BVA and CST over 12 months of treatment despite receiving less frequent anti-VEGF therapy than recommended in the pivotal trials. The present study showed that extended treatment intervals with bevacizumab were effective in preserving vision of many individuals with high baseline BVA.

Long-Term Outcomes in Early versus Limited Response to Anti-VEGF Treatment for Retinal Vein Occlusion.

OBJECTIVE: Macular edema secondary to retinal vein occlusion (RVO) is a sight-threatening condition. Previous studies showed that early responders (ERs) who respond well to anti-VEGF injections within 3 months of treatment have better outcomes, as measured by best visual acuity (BVA) and central subfield thickness (CST) at 12 months postinjection initiation compared with limited early responders (LERs). This study analyzed whether ER eyes continue to respond better than LER eyes over longer periods. This study also aimed to identify baseline comorbidities associated with response status. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients aged > 18 years with RVO-related macular edema treated with anti-VEGF injections. METHODS: Patients were categorized as ERs or LERs. Limited early responder eyes were defined as having CST reduction < 10%, BVA gain < 5 ETDRS letters, or both at 3 months after anti-VEGF initiation. Best visual acuity and CST changes over the 24- and 36-month period after the first anti-VEGF treatment were compared between ERs and LERs. Patient characteristics and systemic comorbidities were identified by chart review. Statistical analysis involved the Levene test, Welch t test, and Welch analysis of variance. MAIN OUTCOME MEASURES: Best visual acuity and CST changes over the initial 24-month and 36-month periods after treatment. RESULTS: The 24-month cohort included 68 ERs and 39 LERs, and the 36-month cohort included 58 ERs and 33 LERs. At the 24-month time point, there were significant differences in BVA and CST gains between ERs (+19.8 letters, -221.2 um) and LERs (-2.4 letters, -90.1 um; P < 0.001, P < 0.01). Similarly, at 36 months, there were significant differences in BVA and CST gains between ERs (+17.7 letters, -229.3 um) and LERs (+1.3 letters, -128 um; P < 0.001, P < 0.05). After controlling for differences in baseline BVA and CST, only the 24-month change in BVA remained significant (P < 0.001). There were no significant associations between response status and cardiopulmonary, endocrine, and oncologic comorbidities. CONCLUSIONS: Early responder eyes with branched retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO) have better functional responses to anti-VEGF injections at 24 months compared with LER eyes, even after controlling for baseline differences. Early identification of eyes as ERs or LERs in BRVO and CRVO may predict long-term functional prognoses. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Mechanism of the Multistep Catalytic Cycle of 6-Hydroxynicotinate 3-Monooxygenase Revealed by Global Kinetic Analysis.

The class A flavoenzyme 6-hydroxynicotinate 3-monooxygenase (NicC) catalyzes a rare decarboxylative hydroxylation reaction in the degradation of nicotinate by aerobic bacteria. While the structure and critical residues involved in catalysis have been reported, the mechanism of this multistep enzyme has yet to be determined. A kinetic understanding of the NicC mechanism would enable comparison to other phenolic hydroxylases and illuminate its bioengineering potential for remediation of N-heterocyclic aromatic compounds. Toward these goals, transient state kinetic analyses by stopped-flow spectrophotometry were utilized to follow rapid changes in flavoenzyme absorbance spectra during all three stages of NicC catalysis: (1) 6-HNA binding; (2) NADH binding and FAD reduction; and (3) O2 binding with C4a-adduct formation, substrate hydroxylation, and FAD regeneration. Global kinetic simulations by numeric integration were used to supplement analytical fitting of time-resolved data and establish a kinetic mechanism. Results indicate that 6-HNA binding is a two-step process that substantially increases the affinity of NicC for NADH and enables the formation of a charge-transfer-complex intermediate to enhance the rate of flavin reduction. Singular value decomposition of the time-resolved spectra during the reaction of the substrate-bound, reduced enzyme with dioxygen provides evidence for the involvement of C4a-hydroperoxy-flavin and C4a-hydroxy-flavin intermediates in NicC catalysis. Global analysis of the full kinetic mechanism suggests that steady-state catalytic turnover is partially limited by substrate hydroxylation and C4a-hydroxy-flavin dehydration to regenerate the flavoenzyme. Insights gleaned from the kinetic model and determined microscopic rate constants provide a fundamental basis for understanding NicC's substrate specificity and reactivity.

Characterizing and Predicting Limited Early Response in Eyes With Retinal Vein Occlusion Using Machine Learning in Routine Clinical Practice.

OBJECTIVE: To characterize and predict limited early responders (LER) in eyes with retinal vein occlusion (RVO) treated with anti-vascular endothelial growth factor (anti-VEGF). PATIENTS AND METHODS: This retrospective cohort study of 116 eyes with edema secondary to RVO characterized early responders (ER) and LER 3 months after initiating anti-VEGF treatment. Baseline characteristics and 12-month outcomes were compared. A machine learning (ML) algorithm was developed to predict LER. RESULTS: At baseline, LER had higher best-corrected visual acuity (BCVA) than ER (P< 0.0001) and lower central subfield thickness (CST) than ER (P< 0.01). At 12 months, change in BCVA was + 0.8 and + 21.4 letters, and change in CST was -104.4 and -187.1 µm for LER and ER, respectively (P < 0.0001, P < 0.05). The ML algorithm achieved area under the receiver operating characteristic curve = 0.73. CONCLUSION: ER eyes experienced greater functional and anatomical improvements at 12 months in routine clinical practice than LER. The ML algorithm achieved moderately high performance predicting LER. [Ophthalmic Surg Lasers Imaging Retina 2023;54:231-237.].

Pharmacotherapy Considerations in Heart Failure with Mildly-Reduced Ejection Fraction.

Heart failure with mildly reduced ejection fraction (HFmrEF) has been classified using various definitions since its first mention in the literature in 2014. This group was most recently defined in the Universal Definition and Classification of Heart Failure (HF) as HF with a left ventricular ejection fraction of 41% to 49%. An increasing emphasis has been placed on HFmrEF over the past several years, with many recent publications suggesting that common therapies used in HF with reduced ejection fraction provide benefit in this population as well. Patients with HFmrEF comprise approximately one-quarter of all patients with HF. The lack of authoritative guidance concerning pharmacotherapeutic approaches in these patients leaves a significant portion of HF patients without an evidence-based approach. Although it remains unclear if HFmrEF is simply a transitional state from preserved to reduced ejection fraction, or a distinct phenotype requiring medical optimization, there are clear cardiovascular benefits to managing this subset appropriately. This publication was created to help serve as a resource for clinicians on this evolving subset of HF and aid in preventing the progression of this disease state through improved therapy optimization. The objective of this article is to briefly discuss the epidemiology and pathophysiology of HFmrEF and review the pharmacology and clinical application of therapies for the management of HFmrEF.

Reduced-Dose Apixaban in the Treatment of Left Ventricular Thrombus: A Report of 2 Cases.

According to the American College of Cardiology and the American Heart Association, warfarin has historically been the standard of care anticoagulant for the treatment of left ventricular thrombus. The use of direct oral anticoagulants (DOACs) has become more prevalent, as they require less frequent laboratory monitoring, offer fixed-dose regimens, are associated with fewer drug-drug and drug-food interactions, and provide more favorable safety profiles when compared to warfarin. However, DOACs are not currently FDA-indicated in the treatment of left ventricular (LV) thrombus. Numerous recent studies have reported and evaluated the use of DOACs for treatment of LV thrombus. Recently, a prospective, open-label, multicenter study evaluated warfarin compared to DOACs for LV thrombus treatment. The AHA recently published a scientific statement regarding the management of patients at risk for and with left ventricular thrombus, which included DOACs as a reasonable alternative to warfarin. This report describes two patients treated with DOACs following LV thrombus diagnosis. The first case is a 71-year-old male admitted for cerebrovascular accident and non-ST-elevation myocardial infarction complicated by a LV thrombus. The second case is an 83-year-old female admitted for acute myocardial infarction complicated with an LV thrombus. Both patients were prescribed apixaban 2.5 mg twice daily. Neither patient has experienced LV thrombus or DOAC treatment related complications. This case series serves as evidence for reduced-dose DOACs as an alternative to warfarin in the treatment of LV thrombus.

Anti-Vascular Endothelial Growth Factor Treatment Patterns and Outcomes in Retinal Vein Occlusion in Routine Clinical Practice.

BACKGROUND AND OBJECTIVE: To characterize treatment patterns for retinal vein occlusion (RVO)-related macular edema (ME) in routine clinical practice and its impact on long-term best-corrected visual acuity (BCVA) and central subfield thickness (CST). PATIENTS AND METHODS: Retrospective study of 365 eyes with branch RVO (BRVO) or central/hemi-RVO (CRVO/HRVO)-related ME between 2003 and 2020. Regression analysis identified factors associated with maintenance injection interval (MII). Subgroup analysis compared outcomes between different MIIs. RESULTS: 51.3% of BRVO patients received injections ≤q8 weeks, 26.4% received injections q8-12 weeks, and 22.3% received injections >q12 weeks. 45.2% of CRVO/HRVO patients received injections ≤q8 weeks, 32.1% received injections q8-12 weeks, and 22.6% received injections >q12 weeks. Age, diabetes, and baseline CST were found to predict MII. There was no significant difference in BCVA and CST at baseline, 12, or 24 months in all MII groups in BRVO and CRVO/HRVO. CONCLUSION: There exists a significant heterogeneity in anti-VEGF treatment frequency for RVO-associated ME in routine clinical practice. [Ophthalmic Surg Lasers Imaging Retina 2022;53:626-633.].

Predictors of limited early response to anti-vascular endothelial growth factor therapy in neovascular age-related macular degeneration with machine learning feature importance.

PURPOSE: Patients with neovascular age-related macular degeneration (nAMD) have varying responses to anti-vascular endothelial growth factor injections. Limited early response (LER) after three monthly loading doses is associated with poor long-term vision outcomes. This study predicts LER in nAMD and uses feature importance analysis to explain how baseline variables influence predicted LER risk. METHODS: Baseline age, best visual acuity (BVA), central subfield thickness (CST), and baseline and 3 months intraretinal fluid (IRF) and subretinal fluid (SRF) for 286 eyes were collected in a retrospective clinical chart review. At month 3, LER was defined as the presence of fluid, while early response (ER) was the absence thereof. Decision tree classification and feature importance methods determined the influence of baseline age, BVA, CST, IRF, and SRF, on predicted LER risk. RESULTS: One hundred and sixty-seven eyes were LERs and 119 were ERs. The algorithm achieved area under the curve = 0.66 in predicting LER. Baseline SRF was most important for predicting LER while age, BVA, CST, and IRF were somewhat less important. Nonlinear trends were observed between baseline variables and predicted LER risk. Zones of increased predicted LER risk were identified, including age <74 years, and CST <290 or >350 µm, IRF >750 nL, and SRF >150 nL. CONCLUSION: These findings explain baseline variable importance for predicting LER and show SRF to be the most important. The nonlinear impact of baseline variables on predicted risk is shown, increasing understanding of LER and aiding clinicians in assessing personalized LER risk.

The Impact of Early Residual Fluid After Anti-Vascular Endothelial Growth Factor Initiation in Patients With Neovascular Age-Related Macular Degeneration: A Meta-Analysis Review.

Fluid in neovascular age-related macular degeneration is often used to assess patient response to anti-vascular endothelial growth factor therapy. Various studies theorize that early residual fluid (ERF), noted as persistence of intraretinal fluid and subretinal fluid after the anti-vascular endothelial growth factor loading phase (LP), may be predictive of visual outcomes. This meta-analysis examined the existing literature on the relationship between ERF and long-term visual acuity (VA) and found that those who were fluid-free after the LP tended to have the highest VA gains overall. Early intraretinal fluid appeared to be associated with reduced VA gains, whereas the impact of early sub-retinal fluid was more debated. For those with ERF, monthly or more frequent dosing regimens following the LP appeared most optimal for VA. As most studies in this review were post hoc analyses, this highlights the need for real-world studies investigating ERF and its effect on visual outcomes in neovascular age-related macular degeneration. [Ophthalmic Surg Lasers Imaging Retina 2022;53:506-513.].

Characterizing Early Residual Fluid in Neovascular Age-Related Macular Degeneration using Machine Learning in Routine Clinical Practice.

PURPOSE: Neovascular age-related macular degeneration (nAMD) often requires intensive therapy with anti-VEGF injections. In prior post hoc studies, early residual fluid (ERF) after the loading phase was associated with poorer treatment outcomes. This retrospective study examined the impact of ERF on vision using machine learning (ML) methods in routine clinical practice. DESIGN: Retrospective cohort. PARTICIPANTS: This study included treatment-naïve patients with nAMD who were initiated on anti-VEGF between 2012 and 2018, with at least 1 year of follow-up. METHODS: Overall, 286 patients with nAMD were included. An ML algorithm quantified intraretinal fluid (IRF), subretinal fluid (SRF), and total retinal fluid from OCTs. The ERF group included those with fluid at week 12 and was further stratified by fluid subtype. Paired t tests and analysis of variance compared best visual acuity (BVA) and fluid among subgroups, and a quartile analysis correlated fluid volumes to week 52 BVA. The risk of ERF was predicted from baseline factors using 3 ML methods: Ridge logistic regression, k nearest neighbors classification, and support vector classification. MAIN OUTCOME MEASURES: Mean change in BVA from baseline to week 52 according to week 12 fluid status. RESULTS: At week 12, 58.4% of patients had ERF. The breakdown of those in the ERF group included SRF-only (45.5%), IRF-only (21.6%), and IRF and SRF (32.9%). The ERF and ERF-free groups had similar BVA gains from baseline to week 52 (+5.7 ± 15.4 vs. +4.9 ± 18; P = 0.69). Examining specific ERF subgroups revealed no significant differences among the IRF-only (+4.6 ± 16.4), SRF-only (+5.6 ± 12.5), and IRF and SRF (+6.6 ± 18.5, P = 0.93) groups. Quartile analysis of week 12 fluid revealed no predictive pattern for BVA gains. Three ML methods were developed to predict those at risk for ERF achieved equivalent performance, with F1 score of 0.73 to 0.76. CONCLUSIONS: These results diverge from prior post hoc studies, in that there was no significant difference in long-term BVA gains between ERF and ERF-free cohorts, as well as between the week 12 fluid subgroups.

Performance and Consistency of Circulating Warm Water Blankets for Rodents.

General anesthesia as used for rodent research can have adverse effects on physiologic mechanisms. Thermoregulation is often greatly inhibited, with resultant deleterious effects on cardiac and respiratory function. These potential effects can be mitigated by providing external heat support. The circulating warm water blanket and associated heat pump are often used in rodent procedures. The current study demonstrated that the heating pump and water blanket require quality control assessment to ensure adequate function. Our data showed that of the 6 pumps tested, 5 were able to achieve a temperature that met or exceeded the documented thermoneutral zone for mice. Pumps required 20 min of warming to reach their maximal attainable temperatures for the designated user setting. Although the pumps reached a temperature that was sufficient to provide external thermal support, only 1 of the 6 pumps reached the temperature that was set by the user during the trial. Surface temperatures across the water blanket were recorded to analyze whether a difference in heat support was influenced by animal placement along the water blanket; however, the location points did not yield statistically different results. Two pumps were eliminated from the study due to failure to pass the preparation phase of the trial. The results of this study support the need for facilities to establish quality control measures to ensure that heat support systems are functioning at a level required to maintain normothermia during anesthetic procedures.

Comparison of Student Pharmacists' Knowledge Retention Utilizing Electronic Health Records Versus Simultaneously Completing Simulated Experiences.

Objective. The purpose of this study was to determine whether the addition of standardized patients or the addition of interprofessional student teams with standardized patients to the use of a simulated electronic health record improved student knowledge retention and perceptions.Methods. This was a prospective cohort study assessing three cohorts of first-year student pharmacists in pharmacy skills laboratory activities that occurred in 2018, 2019, and 2021. The primary objective of the study was to compare knowledge retention of the case material between groups at one month. Each year, an element of simulated experience was added onto the previous year's case. In 2018, students completed the case using only the electronic health record web application. In 2019, the previous year's experience was combined with an objective structured clinical examination (OSCE) with standardized patients. In 2021, the 2019 experience was supplemented with student physician assistants. Case scores and student perceptions were also compared between groups.Results. Of the 260 potential participants, 238 students were included in the primary analysis. Results showed that with the addition of interprofessional team-based care and standardized patients, significant improvement was demonstrated in knowledge retention assessments at one month. Mean knowledge retention assessment scores for the 2018, 2019, and 2021 groups were 63.8%, 71.7%, and 76.1%, respectively. Significant improvement was also found in student perceptions.Conclusion. Adding standardized patients and interprofessional team-based care to a pharmacy skills laboratory that uses a simulated electronic health record significantly improved student knowledge retention and perceptions.

Implementation and justification of a curriculum-wide electronic health record platform.

BACKGROUND AND PURPOSE: In order to develop practice-ready pharmacists as mandated by the Accreditation Council for Pharmacy Education Accreditation Standards, exposing students to health information technologies used in clinical practice, like electronic health records (EHRs), is imperative. While the benefits of using EHRs have been described in the literature, limited information or guidance exists on how these tools can incorporate various activities and topics to be implemented throughout an entire curriculum. The purpose of this report is to describe the curriculum-wide implementation of a simulated EHR software, including the novel learning experiences and costs incurred by the college. EDUCATIONAL ACTIVITY AND SETTING: The EHR was implemented in various courses across the pharmacy school curriculum in the first, second, and third professional years. FINDINGS: During the final year of implementation, the EHR platform was utilized in each of the three didactic years of the pharmacy program. Twenty-two faculty members created cases using the EHR platform. These cases were used across 16 courses and were accessed by students 7191 times during the implementation process. The cost per use of the EHR platform was approximately half that of the most frequently used electronic learning database used in the program. SUMMARY: In the three years since its inception, the EHR has been highly utilized as evidenced by the overall number of experiences for students, the variety of experiences, and the number of faculty who used the EHR in their course.

Endovascular treatment of postpartum haemorrhage in a woman with genitourinary and vascular congenital malformations.

A 43-year-old woman presented with postpartum haemorrhage necessitating uterine artery embolisation. Prior to embolisation, angiography demonstrated the presence of a persistent sciatic artery (PSA). Due to the possibility of embolic particles inadvertently traveling to the lower extremity via this variant arterial pathway, care was taken to only embolise the uterine artery. PSAs are uncommon but important vascular pathways to screen for during pelvic intervention and are associated with other genitourinary anomalies.