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Reconstructing the absolute chronology of Jerusalem during the time it served as the Judahite Kingdom's capital is challenging due to its dense, still inhabited urban nature and the plateau shape of the radiocarbon calibration curve during part of this period. We present 103 radiocarbon dates from reliable archaeological contexts in five excavation areas of Iron Age Jerusalem, which tie between archaeology and biblical history. We exploit Jerusalem's rich past, including textual evidence and vast archaeological remains, to overcome difficult problems in radiocarbon dating, including establishing a detailed chronology within the long-calibrated ranges of the Hallstatt Plateau and recognizing short-lived regional offsets in atmospheric 14C concentrations. The key to resolving these problems is to apply stringent field methodologies using microarchaeological methods, leading to densely radiocarbon-dated stratigraphic sequences. Using these sequences, we identify regional offsets in atmospheric 14C concentrations c. 720 BC, and in the historically secure stratigraphic horizon of the Babylonian destruction in 586 BC. The latter is verified by 100 single-ring measurements between 624 to 572 BC. This application of intense 14C dating sheds light on the reconstruction of Jerusalem in the Iron Age. It provides evidence for settlement in the 12th to 10th centuries BC and that westward expansion had already begun by the 9th century BC, with extensive architectural projects undertaken throughout the city in this period. This was followed by significant damage and rejuvenation of the city subsequent to the mid-eight century BC earthquake, after which the city was heavily fortified and continued to flourish until the Babylonian destruction.
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BACKGROUND: Frequent anti-vascular endothelial growth factor A (VEGF-A) injections reduce the risk of rapid and severe vision loss in patients with neovascular age-related macular degeneration (nAMD); however, due to undertreatment, many patients lose vision over time. New treatments that provide sustained suppression of VEGF-A are needed. RGX-314 (currently known as ABBV-RGX-314) is an adeno-associated virus serotype 8 vector that expresses an anti-VEGF-A antigen-binding fragment, which provides potential for continuous VEGF-A suppression after a single subretinal injection. We report results on the safety and efficacy of subretinal injection of RGX-314 in patients with nAMD. METHODS: For this open-label, multiple-cohort, multicentre, phase 1/2a, dose-escalation study conducted at eight sites in the USA, we enrolled participants with nAMD aged 50-89 years who had previously been treated with anti-VEGF injections into five cohorts (with five different doses of RGX-314). To be eligible, participants had to have macular neovascularisation secondary to nAMD with subretinal or intraretinal fluid in the centre subfield, be pseudophakic (after cataract removal), and have a best-corrected visual acuity (BCVA) in the study eye between 20/63 and 20/400 for the first participant in each cohort and between 20/40 and 20/400 for others. Subretinal injection of RGX-314 was done without a pre-bleb by a wet-laboratory-trained vitreoretinal surgeon. Cohort 1 received 3 × 109 genome copies per eye, cohort 2 received 1 × 1010, and cohort 3 received 6 × 1010. Two additional dose cohorts (cohort 4: 1·6 × 1011; cohort 5: 2·5 × 1011) were added. Participants were seen 1 day and 1 week after administration of RGX-314, and then monthly for 2 years (up to week 106). The primary outcome was safety of RGX-314 delivered by subretinal injection up to week 26. This analysis includes all 42 patients enrolled in the study. This study is registered with ClinicalTrials.gov, NCT03066258. FINDINGS: Between May 12, 2017, and May 21, 2019, we screened 110 patients for eligibility and enrolled 68. 42 participants demonstrated the required anatomic response to intravitreal ranibizumab and then received a single RGX-314 injection (dose range 3 × 109 to 2·5 × 1011 genome copies per eye) and were followed up for 2 years. There were 20 serious adverse events in 13 participants, of which one was possibly related to RGX-314: pigmentary changes in the macula with severe vision reduction 12 months after injection of RGX-314 at a dose of 2·5 × 1011 genome copies per eye. Asymptomatic pigmentary changes were seen in the inferior retinal periphery several months after subretinal injection of RGX-314 most commonly at doses of 6 × 1010 genome copies per eye or higher. There were no clinically determined immune responses or inflammation beyond that expected following routine vitrectomy. Doses of 6 × 1010 genome copies or higher resulted in sustained concentrations of RGX-314 protein in aqueous humour and stable or improved BCVA and central retinal thickness with few or no supplemental anti-VEGF-A injections in most participants. INTERPRETATION: Subretinal delivery of RGX-314 was generally well tolerated with no clinically recognised immune responses. RGX-314 gene therapy provides a novel approach for sustained VEGF-A suppression in patients with nAMD that has potential to control exudation, maintain vision, and reduce treatment burden after a single administration. Results from this study informed the pivotal programme to evaluate RGX-314 in patients with nAMD. FUNDING: RegenxBio.
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Factor A de Crecimiento Endotelial Vascular , Degeneración Macular Húmeda , Humanos , Inhibidores de la Angiogénesis/uso terapéutico , Terapia Genética/métodos , Ranibizumab , Resultado del Tratamiento , Degeneración Macular Húmeda/tratamiento farmacológicoRESUMEN
BACKGROUND: A high-dose formulation of intravitreal aflibercept (8 mg) could improve treatment outcomes in diabetic macular oedema (DMO) by requiring fewer injections than the standard comparator, aflibercept 2 mg. We report efficacy and safety results of aflibercept 8 mg versus 2 mg in patients with DMO. METHODS: PHOTON was a randomised, double-masked, non-inferiority, phase 2/3 trial performed at 138 hospitals and specialty retina clinics in seven countries. Eligible patients were adults aged 18 years or older with type 1 or 2 diabetes and centre-involved DMO. Patients were randomly assigned (1:2:1) to intravitreal aflibercept 2 mg every 8 weeks (2q8), aflibercept 8 mg every 12 weeks (8q12), or aflibercept 8 mg every 16 weeks (8q16), following initial monthly dosing. From week 16, dosing intervals for the aflibercept 8 mg groups were shortened if patients met prespecified dose regimen modification criteria denoting disease activity. The primary endpoint was change from baseline in best-corrected visual acuity (BCVA) at week 48 (non-inferiority margin of 4 letters). Efficacy and safety analyses included all randomly assigned patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov (NCT04429503). FINDINGS: Between June 29, 2020, and June 28, 2021, 970 patients were screened for eligibility. After exclusions, 660 patients were enrolled and randomly assigned to receive aflibercept 8q12 (n=329), 8q16 (n=164), or 2q8 (n=167); two patients were randomly assigned in error and did not receive treatment. 658 (99·7%) patients were treated and included in the full analysis set and safety analysis set (8q12 n=328, 8q16 n=163, and 2q8 n=167). Mean patient age was 62·3 years (SD 10·4). 401 (61%) patients were male. 471 (72%) patients were White. Aflibercept 8q12 and 8q16 demonstrated non-inferior BCVA gains to aflibercept 2q8 (BCVA mean change from baseline 8·8 letters [SD 9·0] in the 8q12 group, 7·9 letters [8·4] in the 8q16 group, and 9·2 letters [9·0] in the 2q8 group). The difference in least squares means was -0·57 letters (95% CI -2·26 to 1·13, p value for non-inferiority <0·0001) between 8q12 and 2q8 and -1·44 letters (-3·27 to 0·39, p value for non-inferiority 0·0031) between aflibercept 8q16 and 2q8. Proportions of patients with ocular adverse events in the study eye were similar across groups (8q12 n=104 [32%], 8q16 n=48 [29%], and 2q8 n=46 [28%]). INTERPRETATION: Aflibercept 8 mg demonstrated efficacy and safety with extended dosing intervals and could decrease treatment burden in patients with DMO. FUNDING: Regeneron Pharmaceuticals and Bayer.
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Diabetes Mellitus , Retinopatía Diabética , Edema Macular , Adulto , Femenino , Humanos , Masculino , Inhibidores de la Angiogénesis , Diabetes Mellitus/tratamiento farmacológico , Edema Macular/etiología , Edema Macular/inducido químicamente , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/efectos adversos , Resultado del Tratamiento , Persona de Mediana Edad , AncianoRESUMEN
PURPOSE: This study was designed to investigate retinal nerve fiber layer circumpapillary optical coherence tomography to determine posterior vitreous detachment (PVD) status and to develop a clinically relevant PVD grading scale based on retinal nerve fiber layer circumpapillary optical coherence tomography to determine the incidence of PVD by age and association with vitreomacular traction disorders. METHODS: Ophthalmic images and medical records of patients with retinal diseases were retrospectively analyzed by three masked graders using retinal nerve fiber layer circumpapillary optical coherence tomography and macular optical coherence tomography. Based on PVD status, eyes were categorized into five newly defined PVD stages. RESULTS: Among 2002 eyes, PVD stages were as follows: A) 25 (1.25%); B) 725 (36.21%); C-) 248 (12.39%); C+) 151 (7.54%); D) 851 (42.51%); X) 2 (0.1%). Posterior vitreous detachment was correlated with advanced age (P < 0.0001). Limited separation or partial separation between lamella within the posterior vitreous cortex (Stage B) was noted early (68% of eyes <18 years). Overall, 34% of eyes >70 years did not exhibit complete PVD. Of 75 eyes with tractional vitreoretinal disorders, 64 (85.3%) were Stage C-/C+, identifying Stage C as the high-risk "complication" stage. CONCLUSION: Imaging analyses using retinal nerve fiber layer circumpapillary optical coherence tomography and macular optical coherence tomography scans in conjunction allow rapid assessment of the PVD stage. These techniques can assist clinicians and surgeons in counseling patients and planning surgical approaches. Observations confirmed the progression of PVD through predictable stages and the progression of PVD with age.
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Mácula Lútea , Fibras Nerviosas , Tomografía de Coherencia Óptica , Desprendimiento del Vítreo , Humanos , Tomografía de Coherencia Óptica/métodos , Desprendimiento del Vítreo/diagnóstico , Desprendimiento del Vítreo/diagnóstico por imagen , Estudios Retrospectivos , Persona de Mediana Edad , Femenino , Masculino , Anciano , Adulto , Fibras Nerviosas/patología , Mácula Lútea/patología , Mácula Lútea/diagnóstico por imagen , Anciano de 80 o más Años , Adolescente , Células Ganglionares de la Retina/patología , Adulto Joven , Niño , Cuerpo Vítreo/patología , Cuerpo Vítreo/diagnóstico por imagenRESUMEN
PURPOSE: To develop professional guidelines for best practices for suprachoroidal space (SCS) injection, an innovative technique for retinal therapeutic delivery, based on current published evidence and clinical experience. METHODS: A panel of expert ophthalmologists reviewed current published evidence and clinical experience during a live working group meeting to define points of consensus and key clinical considerations to inform the development of guidelines for in-office SCS injection. RESULTS: Core consensus guidelines for in-office SCS injection were reached and reported by the expert panel. Current clinical evidence and physician experience supported SCS injection as a safe and effective method for delivering retinal and choroidal therapeutics. The panel established consensus on the rationale for SCS injection, including potential benefits relative to other intraocular delivery methods and current best practices in patient preparation, pre- and peri-injection management, SCS-specific injection techniques, and postinjection management and follow-up. CONCLUSION: These expert panel guidelines may support and promote standardization of SCS injection technique, with the goal of optimizing patient safety and outcomes. Some aspects of the procedure may reasonably be modified based on the clinical setting and physician judgment, as well as additional study.
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Coroides , Humanos , Inyecciones Intraoculares , Enfermedades de la Retina , Guías de Práctica Clínica como AsuntoRESUMEN
BACKGROUND/PURPOSE: To determine and compare the efficacy of a surgical internal limiting membrane (ILM) flap technique with the traditional ILM peel on long-term visual and anatomical outcomes for large (>400 µm) full-thickness macular holes. METHODS: From October 2016 to July 2022, patients undergoing initial full-thickness macular hole repair with the ILM flap or ILM peel technique were reviewed. Final outcomes were recorded and based on size in microns: 401 to 800, 801 to 1,200, and >1,200. RESULTS: Patients treated with ILM flap (n = 52, 94.2% closure rate) or ILM peel (n = 407, 93.6% closure rate) were followed with a mean follow-up time of 15.0 ± 10.2 and 20.0 ± 13.4 months, respectively. Success rates for ILM flaps and ILM peels were compared for full-thickness macular holes of 401 to 800 (100%, 95.8%, P = 0.39), 801 to 1,200 (95%, 93%, P = 0.74), and >1,200 (86.7%, 86.7%, P = 1.0) µm. Mean best-recorded logarithm of the minimal angle of resolution visual acuity for ILM flaps and ILM peels, respectively, was 1.02 ± 0.46 and 0.87 ± 0.47 preoperatively, with follow-up acuity of 0.48 ± 0.32 (P < 0.03) and 0.39 ± 0.42 (P < 0.01) at Year 3. CONCLUSION: Both techniques provide a similar anatomical closure rate and functional improvement in vision. Comparisons should be cautiously made based on difference in preoperative hole size.
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Membrana Basal , Perforaciones de la Retina , Colgajos Quirúrgicos , Tomografía de Coherencia Óptica , Agudeza Visual , Vitrectomía , Humanos , Perforaciones de la Retina/cirugía , Perforaciones de la Retina/fisiopatología , Femenino , Membrana Basal/cirugía , Masculino , Agudeza Visual/fisiología , Vitrectomía/métodos , Estudios Retrospectivos , Anciano , Estudios de Seguimiento , Persona de Mediana Edad , Resultado del Tratamiento , Endotaponamiento/métodos , Factores de Tiempo , Membrana Epirretinal/cirugíaRESUMEN
PURPOSE: To evaluate the association of posterior vitreous opacities (PVOs) on optical coherence tomography with retinal tears identified on examination in patients with acute, symptomatic posterior vitreous detachment (PVD). METHODS: Data were retrospectively collected from the medical records of 388 patients with acute, symptomatic PVD between January 1, 2021, and June 30, 2021. Included patients had received a primary diagnosis of PVD and presented with flashes and/or floaters. Optical coherence tomography scans were reviewed by two separate readers for the presence of PVOs. The primary outcome was the presence of retinal tear on fundus photograph and on examination. RESULTS: Of 388 patients who presented with acute PVD symptoms, 90 (23.2%) were found to have a retinal tear on dilated fundus examination. Among these patients, 78 (86.7%) were found to have PVOs on optical coherence tomography. Statistical analysis demonstrated a significant relationship between the presence of PVOs and retinal tear ( P < 0.01). The sensitivity and specificity of this finding was 86.7% and 72.5%, respectively. Further analysis included area under the curve from receiver operating characteristic curve which was found to be 0.80. CONCLUSION: The presence of PVOs on optical coherence tomography is suggestive of a retinal tear in patients with acute, symptomatic PVD.
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Desprendimiento de Retina , Perforaciones de la Retina , Desprendimiento del Vítreo , Humanos , Perforaciones de la Retina/diagnóstico , Desprendimiento del Vítreo/diagnóstico , Estudios Retrospectivos , Tomografía de Coherencia Óptica/métodos , Cuerpo Vítreo/diagnóstico por imagen , Trastornos de la Visión , Desprendimiento de Retina/diagnósticoRESUMEN
PURPOSE: To assess the effect of the total number of fluid-free months after loading on visual and anatomical outcomes in neovascular age-related macular degeneration patients receiving anti-vascular endothelial growth factor therapy. METHODS: This post hoc analysis pooled patient-level data from the brolucizumab 6 mg (n = 718) and aflibercept 2 mg (n = 715) arms of the HAWK and HARRIER randomized clinical trials. Based on data from Weeks 12 to 96, patients were assigned to one of five categories based on fluid-free visits (FFVs; the total number of monthly visits at which they were observed to be without retinal fluid). Three definitions of "fluid-free" were explored based on the location of the fluid observed. RESULTS: Patients allocated to Categories 4 (15-21 FFV) and 5 (22 FFV, always dry) consistently had the best visual and anatomical outcomes at Week 96, whereas patients allocated to Categories 1 (0 FFV, never dry) and 2 (1-7 FFV) consistently had the worst visual and anatomical outcomes. Variability in retinal thickness over time was lowest in Categories 4 and 5. CONCLUSION: Absence of retinal fluid at more visits after loading has a positive association with visual and anatomic outcomes in neovascular age-related macular degeneration patients, regardless of fluid type.
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Halcones , Degeneración Macular , Degeneración Macular Húmeda , Humanos , Animales , Inhibidores de la Angiogénesis/uso terapéutico , Agudeza Visual , Inyecciones Intravítreas , Tomografía de Coherencia Óptica , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Aves , Degeneración Macular/tratamiento farmacológico , Proteínas Recombinantes de Fusión/uso terapéutico , Degeneración Macular Húmeda/diagnóstico , Degeneración Macular Húmeda/tratamiento farmacológicoRESUMEN
PURPOSE: To assess the 52-week efficacy and safety of brolucizumab 6 mg administered every 4 weeks compared with aflibercept 2 mg dosed every 4 weeks in eyes with neovascular age-related macular degeneration (nAMD) and persistent retinal fluid. DESIGN: Multicenter, randomized, double-masked phase 3a study. PARTICIPANTS: Participants with recalcitrant nAMD (persistent residual retinal fluid despite previous frequent anti-vascular endothelial growth factor treatment). METHODS: Eyes were randomized (2:1) to intravitreal brolucizumab 6 mg or aflibercept 2 mg every 4 weeks up to and including week 100. MAIN OUTCOME MEASURES: The primary end point was analysis of noninferiority in mean best-corrected visual acuity (BCVA) change from baseline to week 52 (margin, 4 letters). Other key end points included change in central subfield thickness (CST) from baseline to week 52, fluid-free status (no intraretinal fluid and no subretinal fluid), and safety. RESULTS: At week 52, brolucizumab was noninferior to aflibercept in BCVA change from baseline (least squares mean difference, -0.6 Early Treatment Diabetic Retinopathy Study letters; 95% confidence interval [CI], -2.1 to 0.9; P < 0.001). A total of 4.8% and 1.7% of participants reported a 15-letter or more BCVA loss from baseline at week 52 in the brolucizumab and aflibercept groups, respectively. In eyes treated with brolucizumab compared with those treated with aflibercept, the CST was reduced significantly (P < 0.001), and a significantly greater proportion of eyes were fluid free at week 52 (40.4% brolucizumab vs. 19.0% aflibercept; 95% CI, 13.9-29.0; P < 0.001). Incidence of intraocular inflammation (IOI), including retinal vasculitis and retinal vascular occlusion, were 9.3% (0.8% and 2.0%) for brolucizumab versus 4.5% (0% and 0%) for aflibercept, respectively. CONCLUSIONS: Visual acuity outcomes in previously treated participants with nAMD and persistent retinal fluid receiving brolucizumab 6 mg dosed every 4 weeks were noninferior to aflibercept 2 mg dosed every 4 weeks, with superior anatomic outcomes. However, incidences of IOI, including retinal vasculitis and retinal vascular occlusion, also were higher, leading to study termination.
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Degeneración Macular , Vasculitis Retiniana , Degeneración Macular Húmeda , Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados , Humanos , Inyecciones Intravítreas , Degeneración Macular/tratamiento farmacológico , Neurofibromina 2 , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Vasculitis Retiniana/tratamiento farmacológico , Resultado del Tratamiento , Degeneración Macular Húmeda/diagnóstico , Degeneración Macular Húmeda/tratamiento farmacológicoRESUMEN
PURPOSE: To quantify changes of the retinal vascular bed area (RVBA) in mm2 on stereographically projected ultrawide field fluorescein angiography images in eyes with proliferative diabetic retinopathy after antivascular endothelial growth factor injection. METHODS: This is a prospective, observational study. The early-phase ultrawide field fluorescein angiography images (Optos 200Tx) of 40 eyes with proliferative diabetic retinopathy and significant nonperfusion obtained at baseline and after six months (NCT02863354) were stereographically projected by correcting peripheral distortion. The global retinal vasculature on ultrawide field fluorescein angiography was extracted for calculating RVBA by summing the real size (mm2) of all the pixels automatically. RESULTS: For the entire cohort, the global RVBA for the entire retina decreased from 67.1 ± 15.5 to 43.6 ± 18.8 mm2 after anti-VEGF treatment at six months (P < 0.001). In the subgroup receiving monthly anti-VEGF injections, the global RVBA decreased from 68.7 ± 16.2 to 33.9 ± 13.3 mm2 (P < 0.001). In the subgroup receiving anti-VEGF every three months, the global RVBA decreased from 65.6 ± 15.1 to 50.8 ± 19.3 mm2 (P = 0.004). CONCLUSION: RVBA seems to be a new biomarker to indicate efficiency of retinal vascular changes after anti-VEGF injection. Eyes with proliferative diabetic retinopathy and significant nonperfusion demonstrate reduced RVBA after anti-VEGF treatment.
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Inhibidores de la Angiogénesis/uso terapéutico , Biomarcadores , Retinopatía Diabética/diagnóstico , Retinopatía Diabética/tratamiento farmacológico , Angiografía con Fluoresceína , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Vasos Retinianos/patología , Adulto , Femenino , Humanos , Inyecciones Intravítreas , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
PURPOSE: To compute retinal vascular bed area (RVBA) in square millimeters on distortion corrected ultra-widefield fluorescein angiography images in eyes with retinal vein occlusion (RVO). METHODS: Prospective observational study. The peripheral distortion of baseline ultra-widefield fluorescein angiography (Optos 200Tx) images of 30 patients with RVO from the WAVE study (NCT01710839) and 13 control eyes of normal subjects was corrected using the stereographic projection method to compute RVBA in square millimeters. RESULTS: In comparison with age- and sex-matched normal control eyes, eyes with RVO had a decreased global RVBA for the entire retina (50.5 ± 20.4 mm 2 vs. 62.6 ± 12.2 mm 2 , P = 0.023). Eyes with RVO and the unaffected fellow eye had a similar RVBA globally (50.5 ± 20.4 mm 2 vs. 46.2 ± 18.9 mm 2 , P = 0.523). The RVBA was observed to negatively correlate with nonperfusion area (R = -0.47, P = 0.009). However, RVBA was not related to the severity of macular edema ( P > 0.05). CONCLUSION: Eyes with RVO have a similar RVBA to the unaffected fellow eyes but with a reduction when compared with normal control eyes. Retinal vascular bed area appears to be a surrogate biomarker of retinal ischemia on ultra-widefield fluorescein angiography but not the extent of macular edema.
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Edema Macular , Oclusión de la Vena Retiniana , Vena Retiniana , Angiografía con Fluoresceína/métodos , Humanos , Retina , Oclusión de la Vena Retiniana/diagnóstico , Vasos Retinianos , Tomografía de Coherencia Óptica/métodosRESUMEN
PURPOSE: The purpose of this study was to compare intravitreal nesvacumab (anti-angiopoietin 2) plus aflibercept with intravitreal aflibercept injection (IAI) in diabetic macular edema. METHODS: The eyes (n = 302) were randomized (1:2:3) to nesvacumab 3 mg + aflibercept 2 mg (LD combo), nesvacumab 6 mg + aflibercept 2 mg (HD combo), or IAI 2 mg at baseline, Weeks 4 and 8. LD combo continued every 8 weeks (q8w). HD combo was rerandomized at Week 12 to q8w or every 12 weeks (q12w); IAI to q8w, q12w, or HD combo q8w through Week 32. RESULTS: Week 12 best-corrected visual acuity gains for LD and HD combo versus IAI were 6.8, 8.5, and 8.8 letters; Week 36 changes were similar. Central subfield retinal thickness reductions at Week 12 were -169.4, -184.0, and -174.6 µm (nominal P = 0.0183, HD combo vs. IAI); Week 36 reductions for LD combo and HD combo q8w and q12w versus IAI were -210.4, -223.4, and -193.7 versus -61.9 µm (nominal P < 0.05). At Week 12, 13.3% and 21.3% versus 15.2% had ≥2-step Diabetic Retinopathy Severity Scale improvement (LD and HD combos vs. IAI) and 59.6% and 66.3% versus 53.7% had complete foveal center fluid resolution. Safety was comparable across groups. CONCLUSION: Nesvacumab + aflibercept demonstrated no additional visual benefit over IAI. Anatomic improvements with HD combo may warrant further investigation.
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Diabetes Mellitus , Retinopatía Diabética , Edema Macular , Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Retinopatía Diabética/complicaciones , Retinopatía Diabética/diagnóstico , Retinopatía Diabética/tratamiento farmacológico , Método Doble Ciego , Humanos , Inyecciones Intravítreas , Edema Macular/diagnóstico , Edema Macular/tratamiento farmacológico , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Factor A de Crecimiento Endotelial Vascular , Agudeza VisualRESUMEN
A laser-illuminated differential image motion monitor (DIMM) is presented that is able to measure the atmospheric coherence length r 0 along horizontal ground paths. This is accomplished by implementing a mono-static setup in which the transmitter and receiver are co-located and transmit to a retroreflective target. The impact of propagating along a folded path through the same volume of turbulent atmosphere is investigated in detail and the overall impact to angle-of-arrival measurements described. In addition, an outdoor test campaign was conducted to validate the findings by testing two commercial scintillometers and the laser DIMM side by side in both bi-static and mono-static configurations. Both analytical and experimental results show that under certain conditions, folded-path propagation can be treated identically to traditional single-path propagation.
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Measurements of atmospheric turbulence along a path can be quantified by scintillometers and differential image motion monitors (DIMMs). The two instruments often measure different levels of turbulence, sometimes varying by nearly an order of magnitude. A high-fidelity numerical simulation was leveraged to assess the measurement performance of both a scintillometer and a DIMM system. When a non-ideal detector is combined with range-dependent turbulence, significant differences between the scintillometer and DIMM are observed. The difference in measurements obtained with the numerically simulated scintillometer and DIMM was consistent with those observed in side-by-side measurements with the instruments.
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The COVID-19 pandemic created significant challenges for the British pub industry, due to the uncertain conditions caused by the virus, changes in consumption patterns and government measures. Studies recommend that organisations adopt innovative and flexible business models to generate added value for customers and other stakeholders as a survival and growth strategy. However, such measures require business ecosystems which encourage co-creative engagement. This qualitative study extends the concept of value co-creation beyond its current boundary as a customer-driven experiential paradigm, reconceptualising it as a driver for societal benefits. Over the period March - December 2020, we carried out in-depth interviews with pub and brewery owners, managers, and customers, combined with netnographic and offline observations of pubs' engagement with customers. We uncovered three stages of strategies and innovation during this period, which we term 'survive', 'secure', and 'sustain'. We demonstrate how multiple stakeholders benefit from the innovations of pubs and breweries negotiating each stage, advancing current scholarship on sustainable value co-creation.
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In the near twenty-year existence of the human and mammalian artificial chromosome field, the technologies for artificial chromosome construction and installation into desired cell types or organisms have evolved with the rest of modern molecular and synthetic biology. Medical, industrial, pharmaceutical, agricultural, and basic research scientists seek the as yet unrealized promise of human and mammalian artificial chromosomes. Existing technologies for both top-down and bottom-up approaches to construct these artificial chromosomes for use in higher eukaryotes are very different but aspire to achieve similar results. New capacity for production of chromosome sized synthetic DNA will likely shift the field towards more bottom-up approaches, but not completely. Similarly, new approaches to install human and mammalian artificial chromosomes in target cells will compete with the microcell mediated cell transfer methods that currently dominate the field.
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Cromosomas Artificiales de los Mamíferos , Cromosomas de los Mamíferos/genética , Técnicas de Transferencia de Gen , Terapia Genética , Vectores Genéticos , Animales , HumanosRESUMEN
PURPOSE: Two similarly designed phase 3 trials (HAWK and HARRIER) compared brolucizumab, a single-chain antibody fragment that inhibits vascular endothelial growth factor-A, with aflibercept to treat neovascular age-related macular degeneration (nAMD). DESIGN: Double-masked, multicenter, active-controlled, randomized trials. PARTICIPANTS: Patients (N = 1817) with untreated, active choroidal neovascularization due to age-related macular degeneration in the study eye. INTERVENTION: Patients were randomized to intravitreal brolucizumab 3 mg (HAWK only) or 6 mg or aflibercept 2 mg. After loading with 3 monthly injections, brolucizumab-treated eyes received an injection every 12 weeks (q12w) and were interval adjusted to every 8 weeks (q8w) if disease activity was present; aflibercept-treated eyes received q8w dosing. MAIN OUTCOME MEASURES: The primary hypothesis was noninferiority in mean best-corrected visual acuity (BCVA) change from baseline to Week 48 (margin: 4 letters). Other key end points included the percentage of patients who maintained q12w dosing through Week 48 and anatomic outcomes. RESULTS: At Week 48, each brolucizumab arm demonstrated noninferiority to aflibercept in BCVA change from baseline (least squares [LS] mean, +6.6 [6 mg] and +6.1 [3 mg] letters with brolucizumab vs. +6.8 letters with aflibercept [HAWK]; +6.9 [brolucizumab 6 mg] vs. +7.6 [aflibercept] letters [HARRIER]; P < 0.001 for each comparison). Greater than 50% of brolucizumab 6 mg-treated eyes were maintained on q12w dosing through Week 48 (56% [HAWK] and 51% [HARRIER]). At Week 16, after identical treatment exposure, fewer brolucizumab 6 mg-treated eyes had disease activity versus aflibercept in HAWK (24.0% vs. 34.5%; P = 0.001) and HARRIER (22.7% vs. 32.2%; P = 0.002). Greater central subfield thickness reductions from baseline to Week 48 were observed with brolucizumab 6 mg versus aflibercept in HAWK (LS mean -172.8 µm vs. -143.7 µm; P = 0.001) and HARRIER (LS mean -193.8 µm vs. -143.9 µm; P < 0.001). Anatomic retinal fluid outcomes favored brolucizumab over aflibercept. Overall, adverse event rates were generally similar with brolucizumab and aflibercept. CONCLUSIONS: Brolucizumab was noninferior to aflibercept in visual function at Week 48, and >50% of brolucizumab 6 mg-treated eyes were maintained on q12w dosing interval through Week 48. Anatomic outcomes favored brolucizumab over aflibercept. Overall safety with brolucizumab was similar to aflibercept (ClinicalTrials.gov; NCT02307682, NCT02434328).
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Neovascularización Coroidal/tratamiento farmacológico , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Degeneración Macular Húmeda/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Neovascularización Coroidal/fisiopatología , Método Doble Ciego , Femenino , Humanos , Inyecciones Intravítreas , Masculino , Persona de Mediana Edad , Proteínas Recombinantes de Fusión/efectos adversos , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Agudeza Visual/fisiología , Degeneración Macular Húmeda/fisiopatologíaRESUMEN
PURPOSE: To compare the efficacy and safety of intravitreal aflibercept + anti-platelet-derived growth factor receptor ß (PDGFRß) combination with intravitreal aflibercept injection (IAI) monotherapy in patients with treatment-naïve neovascular age-related macular degeneration (nAMD). DESIGN: Phase 2, randomized, double-masked study. PARTICIPANTS: A total of 505 patients (eyes) with nAMD. METHODS: Patients were randomized 1:2:2 to low-dose combination intravitreal anti-PDGFRß 1 mg and aflibercept 2 mg (LD combo), high-dose combination intravitreal anti-PDGFRß 3 mg and aflibercept 2 mg (HD combo), or IAI alone every 4 weeks through week 12. At week 12, patients in the HD combo and IAI groups were re-randomized to continue as assigned or switch to HD combo â IAI or IAI â HD combo and dosed every 4 weeks through week 28. During weeks 28 to 52, patients received treatment as needed per prespecified criteria. This report presents efficacy through week 28 and safety through week 52. MAIN OUTCOME MEASURES: Mean best-corrected visual acuity (BCVA) change from baseline at week 12 (primary end point). RESULTS: At week 12, mean BCVA gains from baseline were 5.8, 5.8, and 7.5 letters with LD combo, HD combo, and IAI, respectively (P = 0.21 for LD combo and P = 0.10 for HD combo vs. IAI). The corresponding proportions of eyes that gained ≥15 letters were 12%, 19%, and 22%, respectively. Mean reductions in central retinal thickness from baseline were 126.1, 127.1, and 126.9 µm, respectively. Proportions of eyes with complete resolution of fluid from baseline were 35%, 24%, and 42%, respectively. Vision and anatomic outcomes at week 28 were consistent with the week 12 results. Through week 52, the incidence of intraocular inflammation was 1.0%, 7.5%, 2.1%, 2.1%, and 0%, respectively. The incidence of Anti-Platelet Trialists' Collaboration-defined arterial thromboembolic events was 1.9%, 0.9%, 1.1%, 2.1%, and 1.9%, respectively. CONCLUSIONS: Intravitreal aflibercept + anti-PDGFRß did not improve BCVA over IAI alone. Anatomic outcomes evaluating complete fluid resolution favored IAI. Adverse events were consistent with the reported IAI safety profile, except for a higher frequency of intraocular inflammation in the HD combo group.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Neovascularización Coroidal/tratamiento farmacológico , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Degeneración Macular Húmeda/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Neovascularización Coroidal/diagnóstico , Neovascularización Coroidal/fisiopatología , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Inyecciones Intravítreas , Masculino , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Agudeza Visual/fisiología , Degeneración Macular Húmeda/diagnóstico , Degeneración Macular Húmeda/fisiopatologíaRESUMEN
PURPOSE: Geographic atrophy (GA), a late stage of age-related macular degeneration (AMD), is a major cause of blindness. Even while central visual acuity remains relatively well preserved, GA often causes considerable compromise of visual function and quality of life. No treatment currently exists. We evaluated the safety and efficacy of pegcetacoplan, a complement C3 inhibitor, for treatment of GA. DESIGN: Prospective, multicenter, randomized, sham-controlled phase 2 study. PARTICIPANTS: Two hundred forty-six patients with GA. METHODS: Patients with GA were assigned randomly in a 2:2:1:1 ratio to receive intravitreal injections of 15 mg pegcetacoplan monthly or every other month (EOM) or sham intravitreal injections monthly or EOM for 12 months with follow-up at months 15 and 18. Area and growth of GA were measured using fundus autofluorescence imaging. MAIN OUTCOME MEASURES: The primary efficacy end point was mean change in square root GA lesion area from baseline to month 12. Secondary outcome measures included mean change from baseline in GA lesion area without the square root transformation, distance of GA lesion from the fovea, best-corrected visual acuity (BCVA), low-luminance BCVA, and low-luminance visual acuity deficit. The primary safety end point was the number and severity of treatment-emergent adverse events. RESULTS: In patients receiving pegcetacoplan monthly or EOM, the GA growth rate was reduced by 29% (95% confidence interval [CI], 9-49; P = 0.008) and 20% (95% CI, 0-40; P = 0.067) compared with the sham treatment group. Post hoc analysis showed that the effect was greater in the second 6 months of treatment, with observed reductions of 45% (P = 0.0004) and 33% (P = 0.009) for pegcetacoplan monthly and EOM, respectively. Two cases of culture-positive endophthalmitis and 1 case of culture-negative endophthalmitis occurred in the pegcetacoplan monthly group. New-onset investigator-determined exudative AMD was reported more frequently in pegcetacoplan-treated eyes (18/86 eyes [20.9%] and 7/79 eyes [8.9%] in monthly and EOM groups, respectively) than in sham-treated eyes (1/81 eyes [1.2%]). CONCLUSIONS: Local C3 inhibition with pegcetacoplan resulted in statistically significant reductions in the growth of GA compared with sham treatment. Phase 3 studies will define the efficacy and safety profile further.
Asunto(s)
Complemento C3/antagonistas & inhibidores , Inactivadores del Complemento/uso terapéutico , Atrofia Geográfica/tratamiento farmacológico , Degeneración Macular/complicaciones , Anciano , Anciano de 80 o más Años , Femenino , Angiografía con Fluoresceína , Atrofia Geográfica/diagnóstico , Atrofia Geográfica/etiología , Humanos , Inyecciones Intravítreas , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Tomografía de Coherencia Óptica , Agudeza Visual/fisiologíaRESUMEN
PURPOSE: To quantify retinal nonperfusion area and retinal vascular bed area (RVBA) in mm on ultra-widefield fluorescein angiography in eyes with diabetic macular edema (DME) and explore their relationship with the severity of DME. METHODS: Prospective, observational case series. Baseline ultra-widefield fluorescein angiography images of 40 eyes from 29 patients with treatment-naive DME who participated in the DAVE study (NCT01552408) were stereographically projected at Doheny Image Reading Center. The retinal vasculature was automatically extracted to calculate RVBA. Nonperfusion area was manually delineated by two masked certified graders. Retinal vascular bed area and nonperfusion area were computed in mm automatically by adjusting for peripheral distortion and then correlated with the severity of DME. RESULTS: The global RVBA for the entire retina in eyes with DME was increased compared with healthy controls (54.7 ± 16.6 mm vs. 37.2 ± 9.9 mm, P < 0.001) and correlated with the severity of DME (P < 0.05). Retinal ischemia (nonperfusion area) was nonuniformly distributed and not related to DME extent (P > 0.05). CONCLUSION: Eyes with DME have an increased RVBA compared with healthy controls. The severity of DME appears to be related to global RVBA, but not to retinal ischemia.