Efficacy and safety of avacincaptad pegol in patients with geographic atrophy (GATHER2): 12-month results from a randomised, double-masked, phase 3 trial.

BACKGROUND: Geographic atrophy is an advanced form of dry age-related macular degeneration that can lead to irreversible vision loss and high burden of disease. We aimed to assess efficacy and safety of avacincaptad pegol 2 mg in reducing geographic atrophy lesion growth. METHODS: GATHER2 is a randomised, double-masked, sham-controlled, 24-month, phase 3 trial across 205 retina clinics, research hospitals, and academic institutions globally. To be eligible, patients had to be aged 50 years or older with non-centrepoint-involving geographic atrophy and best corrected visual acuity between 20/25 and 20/320 in the study eye. Eligible patients were randomly assigned (1:1) to monthly avacincaptad pegol 2 mg administered as a 100 µL intravitreal injection or sham for the first 12 months. Randomisation was performed using an interactive response technology system with stratification by factors known to be of prognostic importance in age-related macular degeneration. Patients, investigators, study centre staff, sponsor personnel, and data analysts were masked to treatment allocation. The primary endpoint was geographic atrophy lesion size measured by fundus autofluorescence at baseline, month 6, and month 12. Efficacy and safety analyses were done in the modified intention-to-treat and safety populations, respectively. This trial is registered with ClinicalTrials.gov, NCT04435366. FINDINGS: Between June 22, 2020, and July 23, 2021, 1422 patients were screened for eligibility, of whom 448 were enrolled and randomly assigned to avacincaptad pegol 2 mg (n=225) or sham (n=223). One patient in the sham group did not receive study treatment and was excluded from analyses. There were 154 (68%) female patients and 71 (32%) male patients in the avacincaptad pegol 2 mg group, and 156 (70%) female patients and 66 (30%) male patients in the sham group. From baseline to month 12, the mean rate of square-root-transformed geographic atrophy area growth was 0·336 mm/year (SE 0·032) with avacincaptad pegol 2 mg and 0·392 mm/year (0·033) with sham, a difference in growth of 0·056 mm/year (95% CI 0·016-0·096; p=0·0064), representing a 14% difference between the avacincaptad pegol 2 mg group and the sham group. Ocular treatment-emergent adverse events in the study eye occurred in 110 (49%) patients in the avacincaptad pegol 2 mg group and 83 (37%) in the sham group. There were no endophthalmitis, intraocular inflammation, or ischaemic optic neuropathy events over 12 months. To month 12, macular neovascularisation in the study eye occurred in 15 (7%) patients in the avacincaptad pegol 2 mg group and nine (4%) in the sham group, with exudative macular neovascularisation occurring in 11 (5%) in the avacincaptad pegol 2 mg group and seven (3%) in the sham group. INTERPRETATION: Monthly avacincaptad pegol 2 mg was well tolerated and showed significantly slower geographic atrophy growth over 12 months than sham treatment, suggesting that avacincaptad pegol might slow disease progression and potentially change the trajectory of disease for patients with geographic atrophy. FUNDING: Iveric Bio, An Astellas Company.

Efficacy and safety of brolucizumab versus aflibercept in eyes with early persistent retinal fluid: 96-week outcomes from the HAWK and HARRIER studies.

OBJECTIVE: Post-hoc analysis to compare the outcomes of brolucizumab 6 mg vs. aflibercept 2 mg in neovascular age-related macular degeneration (nAMD) patients with early persistent retinal fluid in HAWK and HARRIER. METHODS: After 3 monthly loading doses, brolucizumab-treated eyes (N = 730) received injections every 12 weeks (q12w) or q8w if disease activity was detected. Aflibercept-treated eyes (N = 729) received fixed q8w dosing. Early persistent fluid was defined as the presence of subretinal fluid and/or intraretinal fluid up to Week 12. RESULTS: A lower proportion of brolucizumab patients had early persistent retinal fluid compared with aflibercept (11.2% (n = 82) vs. 19.2% (n = 140)). In these patients, 34.1% of the brolucizumab-treated group achieved a ≥ 15 ETDRS letter gain in best corrected visual acuity (BCVA) from baseline at Week 96 compared with 20.7% of the aflibercept-treated group. Brolucizumab achieved numerically better BCVA outcomes (Week 96: brolucizumab, +6.4 letters; aflibercept, +3.7 letters) and significantly greater central subfield thickness reductions versus aflibercept from baseline through Week 96 (Week 96: -202 µm vs. -145 µm; p = 0.0206). Brolucizumab demonstrated an overall favourable benefit/risk profile in this patient cohort. In their unmasked, post-hoc review, the Safety Review Committee identified two cases of retinal vasculitis and no cases of retinal vascular occlusion in the brolucizumab arm; no cases of retinal vasculitis or retinal vascular occlusion were identified in the aflibercept arm. CONCLUSION: In this analysis, anatomical and visual outcomes were better with brolucizumab compared with aflibercept. Brolucizumab may therefore achieve greater disease control than aflibercept in nAMD patients with early persistent retinal fluid.

RETINAL FLUID AND THICKNESS AS MEASURES OF DISEASE ACTIVITY IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: Retinal fluid and thickness are important anatomical features of disease activity in neovascular age-related macular degeneration, as evidenced by clinical trials that have used these features for inclusion criteria, retreatment criteria, and outcome measures of the efficacy of intravitreal injections of anti-vascular endothelial growth factor agents. METHODS: A literature review of anatomical measures of disease activity was conducted. RESULTS: Treatment goals for neovascular age-related macular degeneration include improving/maintaining vision by drying the retina, and several analyses have evaluated the relationship between visual function and anatomy. The change in retinal thickness has been found to correlate with the change in the visual acuity, and variation in retinal thickness may predict visual acuity outcomes. In addition, specific fluid compartments may have different prognostic values. For example, the presence of intraretinal fluid has been associated with poorer visual acuity, whereas the presence of subretinal fluid has been associated with better visual acuity. Retinal fluid and thickness are important for selecting dosing interval durations in clinical trials and clinical practice. CONCLUSION: Retinal thickness and retinal fluid are common anatomical measures of disease activity in neovascular age-related macular degeneration. Further research is required to fully elucidate the relationship between anatomical features and visual outcomes in neovascular age-related macular degeneration.

Variations in Interlaminar Epidural Steroid Injection Practice Patterns by Interventional Pain Management Physicians in the United States.

BACKGROUND: Previous surveys have identified variations in practice patterns related to epidural steroid injections. Since then, the United States Food and Drug Administration (FDA) has required the addition of drug warning labels for injectable corticosteroids. Updated evidence, as well as scrutiny from regulatory agencies, may affect practice patterns. OBJECTIVE: To provide an update on interlaminar epidural steroid injection (ILESI) practice patterns, we surveyed interventional pain management (IPM) physicians in the United States. STUDY DESIGN AND SETTING: This was a cross-sectional survey of IPM physicians in the United States. METHODS: A web-based survey was distributed to IPM physicians in the United States selected from the Accreditation Council for Graduate Medical Education accredited pain medicine fellowship program list as well as the American Society of Interventional Pain Physicians membership database. Physicians were queried about ILESI practices, including needle size, use of image guidance, level of injection, identification of the epidural space, and preference for injectate. RESULTS: A total of 249 responses were analyzed. All respondents used image guidance for ILESI. There were variations in needle size, use of contrast, number of fluoroscopic views utilized, technique for identifying the epidural space, and choice of injectate. LIMITATIONS: The response rate is a limitation, thus the results may not be representative of all United States IPM physicians. CONCLUSIONS: Though all respondents used image guidance for ILESI, variations in other ILESI practices still exist. Since the closure of this survey, a multi-society pain workgroup published recommendations regarding ESI practices. Our survey findings support the need for more evidence-based guidelines regarding ESI. KEY WORDS: Epidural injection, epidural steroids, survey, low back pain, neck pain, technique.

Association Between Unruptured Intracranial Aneurysms and Downstream Stroke.

Background and Purpose- Case reports suggest that unruptured intracranial aneurysms may serve as a nidus for thrombus formation and downstream embolic stroke. However, few data exist to support an association between unruptured aneurysms and ischemic stroke. Methods- We conducted a within-subjects case-control study of acute ischemic stroke patients prospectively enrolled in the Cornell Acute Stroke Academic Registry who had magnetic resonance imaging of the brain and arterial imaging of the head within 14 days of admission. Reviewers blinded to the study hypothesis ascertained the presence of aneurysms from the neuroradiologist's clinical report of the arterial imaging findings. McNemar test for paired data was used to compare the prevalence of unruptured aneurysms ipsilateral versus contralateral to the side of anterior circulation infarcts. Aneurysms of the anterior communicating artery or in the posterior circulation were not counted in the analysis. Results- Among 2116 patients registered in the Cornell Acute Stroke Academic Registry during 2011 to 2016, 1541 met our inclusion criteria, of whom 176 (11.4%; 95% CI, 9.8-13.0%) had an intracranial aneurysm. The prevalence of aneurysms did not differ on the side ipsilateral versus contralateral to the infarction (risk ratio [RR], 1.2; 95% CI, 0.9-1.5). There was no significant association between aneurysms and ipsilateral stroke in secondary analyses of the 1244 patients with stroke in a single anterior circulation territory (RR, 1.2; 95% CI, 0.8-1.9), the 619 patients with cryptogenic stroke (RR, 1.4; 95% CI, 0.9-2.0), or the 485 patients with cryptogenic stroke in a single anterior circulation territory (RR, 1.7; 95% CI, 0.8-3.3). Results were unchanged when counting only aneurysms >3 mm (RR, 1.2; 95% CI, 0.8-1.9) or 5 mm in diameter (RR, 1.2; 95% CI, 0.9-1.5). Conclusions- Contrary to our hypothesis, we found no significant association between unruptured intracranial aneurysms and ipsilateral ischemic stroke.

Image Quality on Dual-energy CTPA Virtual Monoenergetic Images: Quantitative and Qualitative Assessment.

RATIONALE AND OBJECTIVES: This study aims to determine the optimal photon energy for image quality of the pulmonary arteries (PAs) on dual-energy computed tomography (CT) pulmonary angiography (CTPA) utilizing low volumes of iodinated contrast. MATERIALS AND METHODS: The study received institutional review board exemption and was Health Insurance Portability and Accountability Act compliant. Adults (n = 56) who underwent dual-energy CTPA with 50-60 cc of iodinated contrast on a third-generation dual-source multidetector CT were retrospectively and consecutively identified. Twelve virtual monoenergetic kiloelectron volt (keV) image data sets (40-150 keV, 10-keV increments) were generated with a second-generation noise-reducing algorithm. Standard regions of interest were placed on main, right, left, and right interlobar pulmonary arteries; pectoralis muscle; and extrathoracic air. Attenuation [mean CT number (Hounsfield unit, HU)], noise [standard deviation (HU)], signal to noise (SNR), and contrast to noise ratio were evaluated. Three blinded chest radiologists rated (from 1 to 5, with 5 being the best) randomized monoenergetic and weighted-average images for attenuation and noise. P <.05 was considered significant. RESULTS: Region of interest mean CT number increased as keV decreased, with 40 keV having the highest value (P < .001). Mean SNR was highest for 40-60 keV (P <.05) (14.5-14.7) and was higher (P <.05) than all remaining energies (90-150 keV) for all vessel regions combined. Contrast to noise ratio was highest for 40 keV (P <.001) and decreased as keV increased. SNR was highest at 60 and 70 keV, only slightly higher than 40-50 keV (P <.05). Reader scores for 40-50 keV were greater than other energies and weighted-average images (P <.05). CONCLUSIONS: Kiloelectron volt images of 40-50 keV from the second-generation algorithm optimize attenuation on dual-energy CTPA and can potentially aid in interpretation and avoiding nondiagnostic examinations.

Diagnosis of Normal-Pressure Hydrocephalus: Use of Traditional Measures in the Era of Volumetric MR Imaging.

Purpose To assess the diagnostic performance of the callosal angle (CA) and Evans index (EI) measures and to determine their role versus automated volumetric methods in clinical radiology. Materials and Methods Magnetic resonance (MR) examinations performed before surgery (within 1-5 months of the MR examination) in 36 shunt-responsive patients with normal-pressure hydrocephalus (NPH; mean age, 75 years; age range, 58-87 years; 26 men, 10 women) and MR examinations of age- and sex-matched patients with Alzheimer disease (n = 34) and healthy control volunteers (n = 36) were studied. Three blinded observers independently measured EI and CA for each patient. Volumetric segmentation of global gray matter, white matter, ventricles, and hippocampi was performed by using software. These measures were tested by using multivariable logistic regression models to determine which combination of metrics is most accurate in diagnosis. Results The model that used CA and EI demonstrated 89.6%-93.4% accuracy and average area under the curve of 0.96 in differentiating patients with NPH from patients without NPH (ie, Alzheimer disease and healthy control). The regression model that used volumetric predictors of gray matter and white matter was 94.3% accurate. Conclusion CA and EI may serve as a screening tool to help the radiologist differentiate patients with NPH from patients without NPH, which would allow for designation of patients for further volumetric assessment. © RSNA, 2017.

General anesthesia in a patient with citrullinemia using Precedex as an adjunct to prevent delayed emergence.

Citrullinemia type I is a rare autosomal recessive genetic condition that causes reduced activity of the enzyme, argininosuccinate synthase, which is needed for proper urea metabolism. The end result is hyperammonemia which can cause life-threatening neurologic symptoms and global developmental delay. Previous case reports of the anesthetic management of patients with citrullinemia describe delayed recovery possibly related to elevated ammonia levels postoperatively or choice of intraoperative anesthetics which have included narcotics. In this case report, we present the anesthetic management of a 16-year-old adolescent girl with citrullinemia type I undergoing a vagus nerve stimulator revision. We used the α-2-adrenergic agonist, dexmedetomidine, as an adjunct to avoid narcotics to prevent delayed emergence. She was admitted for hydration the night before the procedure and had a baseline ammonia level of 33 µmol/L (reference, 9-33 µmol/L). Anesthetic maintenance consisted of 2% sevoflurane, dexmedetomidine 0.5 µg/kg per hour, and intravenous acetaminophen given toward the conclusion of the surgery. The patient awoke immediately at the end of the procedure and was extubated in the operating room. Postprocedure, her ammonia level was less than 9 µmol/L. She appeared to be free of pain, was tolerating gastric tube feeds postprocedure, and was discharged to home on the day of surgery. Effective management of ammonia levels in this patient using preoperative hydration and dexmedetomidine as an adjunct to general anesthesia may have helped to prevent delayed emergence.

Quantifying Maternal and Paternal Disease History Using Log-Rank Score with an Application to a National Cohort Study.

Both maternal and paternal disease history can be important predictors of the risk of common conditions such as heart disease or cancer because of shared environmental and genetic risk factors. Sometimes maternal and paternal history can have remarkably different effects on offspring's status. The results are often affected by how the maternal and paternal disease histories are quantified. We proposed using the log-rank score (LRS) to investigate the separate effect of maternal and paternal history on diseases, which takes parental disease status and the age of their disease onset into account. Through simulation studies, we compared the performance of the maternal and paternal LRS with simple binary indicators under two different mechanisms of unbalanced parental effects. We applied the LRS to a national cohort study to further segregate family risks for heart diseases. We demonstrated using the LRS rather than binary indicators can improve the prediction of disease risks and better discriminate the paternal and maternal histories. In the real study, we found that the risk for stroke is closely related with maternal history but not with paternal history and that maternal and paternal disease history have similar impact on the onset of myocardial infarction.

Virus reactivation: a panoramic view in human infections.

Viruses are obligate intracellular parasites, relying to a major extent on the host cell for replication. An active replication of the viral genome results in a lytic infection characterized by the release of new progeny virus particles, often upon the lysis of the host cell. Another mode of virus infection is the latent phase, where the virus is 'quiescent' (a state in which the virus is not replicating). A combination of these stages, where virus replication involves stages of both silent and productive infection without rapidly killing or even producing excessive damage to the host cells, falls under the umbrella of a persistent infection. Reactivation is the process by which a latent virus switches to a lytic phase of replication. Reactivation may be provoked by a combination of external and/or internal cellular stimuli. Understanding this mechanism is essential in developing future therapeutic agents against viral infection and subsequent disease. This article examines the published literature and current knowledge regarding the viral and cellular proteins that may play a role in viral reactivation. The focus of the article is on those viruses known to cause latent infections, which include herpes simplex virus, varicella zoster virus, Epstein-Barr virus, human cytomegalovirus, human herpesvirus 6, human herpesvirus 7, Kaposi's sarcoma-associated herpesvirus, JC virus, BK virus, parvovirus and adenovirus.

Cardiac myocyte remodeling mediated by N-cadherin-dependent mechanosensing.

Cell-to-cell adhesions are crucial in maintaining the structural and functional integrity of cardiac cells. Little is known about the mechanosensitivity and mechanotransduction of cell-to-cell interactions. Most studies of cardiac mechanotransduction and myofibrillogenesis have focused on cell-extracellular matrix (ECM)-specific interactions. This study assesses the direct role of intercellular adhesion, specifically that of N-cadherin-mediated mechanotransduction, on the morphology and internal organization of neonatal ventricular cardiac myocytes. The results show that cadherin-mediated cell attachments are capable of eliciting a cytoskeletal network response similar to that of integrin-mediated force response and transmission, affecting myofibrillar organization, myocyte shape, and cortical stiffness. Traction forces mediated by N-cadherin were shown to be comparable to those sustained by ECM. The directional changes in predicted traction forces as a function of imposed loads (gel stiffness) provide the added evidence that N-cadherin is a mechanoresponsive adhesion receptor. Strikingly, the mechanical sensitivity response (gain) in terms of the measured cell-spread area as a function of imposed load (adhesive substrate rigidity) was consistently higher for N-cadherin-coated surfaces compared with ECM protein-coated surfaces. In addition, the cytoskeletal architecture of myocytes on an N-cadherin adhesive microenvironment was characteristically different from that on an ECM environment, suggesting that the two mechanotransductive cell adhesion systems may play both independent and complementary roles in myocyte cytoskeletal spatial organization. These results indicate that cell-to-cell-mediated force perception and transmission are involved in the organization and development of cardiac structure and function.