Molecular epidemiology and population genetics of Schistosoma mansoni infecting school-aged children situated along the southern shoreline of Lake Malawi, Malawi.

BACKGROUND: In areas of low disease endemicity, highly sensitive diagnostic tools to identify, diagnose, and monitor intestinal schistosomiasis transmission are needed to reliably measure the burden and risk of infection. Here, we used highly sensitive molecular diagnostic methods to investigate Schistosoma mansoni prevalence and transmission along the southern shoreline of Lake Malawi, five years post-disease outbreak. METHODOLOGY AND PRINCIPAL FINDINGS: Faecal and urine samples were provided by school-aged children situated along the southern shoreline of Lake Malawi. Kato-Katz faecal-egg microscopy and point-of-care circulating cathodic antigen (POC-CCA) rapid diagnostic tests were then performed to diagnose infection with S. mansoni. Urine-egg microscopy was also used to diagnose infection with Schistosoma haematobium. In addition, Schistosoma miracidia were isolated from faecal material using a standard miracidium hatching technique. A two-step real-time PCR approach was then used to diagnose infection with S. mansoni using DNA isolated from faecal samples. Furthermore, isolated miracidia were genotyped to species level through PCR and Sanger sequencing. Phylogenetic analyses were then carried out to identify which previously defined S. mansoni cox1 lineage group S. mansoni miracidia were most closely related to. The measured prevalence of S. mansoni infection varied considerably depending on which diagnostic assay was used. When compared to real-time PCR, faecal-egg microscopy had a sensitivity of 9% and a specificity of 100%. When POC-CCA 'trace' results were considered positive, POC-CCA had a sensitivity of 73% and a specificity of 81% when compared to real-time PCR. However, when considered negative, POC-CCA sensitivity was reduced to 56%, whereas specificity was increased to 90%. In addition, a high degree of S. haematobium DNA was detected in DNA isolated from faecal samples and motile S. haematobium miracidia were recovered from faecal samples. Schistosoma mansoni miracidia were closely related to two independent cox1 lineage groups, suggesting multiple recent introduction and colonisation events originating from surrounding east African countries. CONCLUSIONS AND SIGNIFICANCE: Intestinal schistosomiasis is now highly prevalent along the southern shoreline of Lake Malawi just five years post-disease outbreak. In addition, a high prevalence of urogenital schistosomiasis persists. The revision of ongoing schistosomiasis control programmes in this area is therefore recommended. Our study also highlights the need for reliable diagnostic assays capable of distinguishing between Schistosoma species in multispecies co-endemic areas.

Revealing bovine schistosomiasis in Malawi: Connecting human and hybrid schistosomes within cattle.

In Malawi, the putative origin of a newly described Schistosoma haematobium-mattheei hybrid human schistosome was assessed upon a seminal molecular parasitological survey of cattle. Using miracidia hatch test (MHT) and carcass inspection at slaughter, mean prevalence of bovine schistosomiasis was 49.1% (95% CI: 43.7-54.6%) and 10.3% (95% CI: 6.0-16.2%) respectively, though significant spatial heterogeneity was noted. Approximately 2.0% of infected cattle, and only those from Mangochi District, shed S. haematobium-mattheei and/or S. haematobium in faeces. To quantify schistosome (re)infection dynamics, where a S. haematobium-mattheei hybrid was present, we undertook a novel pilot GPS-datalogging sub-study within a specific herd of cattle (n = 8) on the Lake Malawi shoreline, alongside a praziquantel (40 mg/kg) treatment efficacy spot check. At sub-study baseline, all GPS-tagged cattle had proven daily water contact with the lake. Each animal was patently infected upon MHT, with older animals shedding less miracidia. At one month review, whilst parasitological cure was 100.0%, from six weeks onwards, (re)infection was first noted in the youngest animal. By three-month review, all animals were patently (re)infected though only miracidia of S. mattheei were recovered, albeit in much lower numbers. To conclude, infection with S. mattheei is particularly common in cattle and demonstrates a previously cryptic burden of bovine schistosomiasis. Within Mangochi District, bovine transmission of both S. haematobium-mattheei hybrids and S. haematobium are now incriminated, with unequivocal evidence of contemporary zoonotic spill-over. Future control of urogenital schistosomiasis here in the southern region needs to develop, then successfully integrate, a One Health approach with appropriate mitigating strategies to reduce and/or contain bovine schistosomiasis transmission.

Phase I DAVIO Trial: EYP-1901 Bioerodible, Sustained-Delivery Vorolanib Insert in Patients With Wet Age-Related Macular Degeneration.

Purpose: To evaluate safety and tolerability of EYP-1901, an intravitreal insert containing vorolanib, a pan-VEGF receptor inhibitor packaged in a bioerodible delivery technology (Durasert E™) for sustained delivery, in patients with wet age-related macular degeneration (wAMD) previously treated with anti-VEGF therapy. Design: Phase I, multicenter, prospective, open-label, dose-escalation trial. Participants: Patients with wAMD and evidence of prior anti-VEGF therapy response. Methods: Patients received a single intravitreal injection of EYP-1901. Main Outcome Measures: The primary objective was to evaluate safety and tolerability of EYP-1901. Secondary objectives assessed biologic activity of EYP-1901 including best-corrected visual acuity (BCVA) and central subfield thickness (CST). Exploratory analyses included reduction in anti-VEGF treatment burden and supplemental injection-free rates. Results: Seventeen patients enrolled in the 440 µg (3 patients), 1030 µg (1 patient), 2060 µg (8 patients), and 3090 µg (5 patients) dose cohorts. No dose-limiting toxicity, ocular serious adverse events (AEs), or systemic AEs related to EYP-1901 were observed. There was no evidence of ocular or systemic toxicity related to vorolanib or the delivery technology. Moderate ocular treatment-emergent AEs (TEAEs) included reduced visual acuity (2/17) and retinal exudates (3/17). One patient with reduced BCVA had 3 separate reductions of 17, 18, and 16 letters, and another had a single drop of 25 letters. One severe TEAE, neovascular AMD (i.e., worsening/progressive disease activity), was reported in 1 of 17 study eyes but deemed unrelated to treatment. Mean change from baseline in BCVA was -1.8 letters and -5.4 letters at 6 and 12 months. Mean change from baseline in CST was +1.7 µm and +2.4 µm at 6 and 12 months. Reduction in treatment burden was 74% and 71% at 6 and 12 months. Of 16 study eyes, 13, 8, and 5 were injection-free up to 3, 6, and 12 months. Conclusion: In the DAVIO trial (ClinicalTrials.gov identifier, NCT04747197), EYP-1901 had a favorable safety profile and was well tolerated in previously treated eyes with wAMD. Measures of biologic activity remained relatively stable following a single EYP-1901 injection. These preliminary data support ongoing phase II and planned phase III trials to assess efficacy and safety. Financial Disclosures: The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Screen Failures in Clinical Trials in Retina.

PURPOSE: Disparities in clinical trials are a major problem because of significant underrepresentation of certain gender, racial, and ethnic groups. Several factors including stringent eligibility criteria and recruitment strategies hinder our understanding of retinal disease. Thus, we aimed to study the various reasons of screen failures and specific patient and study characteristics among screen failures. DESIGN: This is a cross-sectional retrospective study. METHODS: Screening data of 87 trials from 6 centers were analyzed. Study characteristics (disease studied, phase of trial, and route of drug administration) and patient demographics (age, gender, race, ethnicity, and employment status) were compared among different causes of screen failures. Screen failures were broadly classified into 6 categories: exclusion because of vision-based criteria, exclusion because of imaging findings, exclusion because of other factors, patient-related criteria, physician-related criteria, and miscellaneous. Descriptive statistics, Pearson chi-square test, and analysis of variance were used for statistical analysis. MAIN OUTCOME MEASURES: Prevalence of various reasons for screen failures in multiple trials and its trend among different study and patient characteristics. RESULTS: Among 87 trials and 962 patients, 465 (48.2%) patients were successfully randomized and 497 (51.8%) patients were classified as screen failures. The trials were conducted for various retinal diseases. Mean age was 76.50 ±10.45 years and 59.4% were females. Predominantly White patients (93.4%) and unemployed/retired patients (66.6%) were screened. Of the 497 screen failures, most were because of patients not meeting inclusion criteria of imaging findings (n = 221 [44.5%]) followed by inclusion of vision-based criteria (n = 73 [14.7%]), exclusion because of other factors (n = 75 [15.1%]), patient-related (n = 34 [6.8%]), physician-related (n = 28 [5.6%]), and miscellaneous reasons (n = 39 [7.8%]). Reason for screen failure was not available for 27 (5.4%) patients. A higher proportion of patients screened for surgical trials (15%) declined to participate in the study compared with noninvasive trials involving topical drugs and photobiomodulation (0%) (P = 0.02). CONCLUSIONS: Patients not meeting the imaging and vision-cased criteria were the most common reasons for screen failures. White patients and unemployed patients predominantly participated in clinical trials. Patients are more inclined to continue participation in noninvasive clinical trials compared with surgical trials. Better recruitment strategies and careful consideration of study criteria can aid in decreasing the rate of screen failures.

Vision Loss Reduction with Avacincaptad Pegol for Geographic Atrophy: A 12-Month Post Hoc Analysis of the GATHER1 and GATHER2 Trials.

PURPOSE: To evaluate the impact of reduction in geographic atrophy (GA) lesion growth on visual acuity in the GATHER trials using categorical outcome measures. DESIGN: Randomized, double-masked, sham-controlled phase 3 trials. PARTICIPANTS: Aged ≥50 years with noncenter point-involving GA and best-corrected visual acuity (BCVA) of 25 to 80 ETDRS letters in the study eye. METHODS: GATHER1 consisted of 2 parts. In part 1, 77 patients were randomized 1:1:1 to avacincaptad pegol (ACP) 1 mg, ACP 2 mg, and sham. In part 2, 209 patients were randomized 1:2:2 to ACP 2 mg, ACP 4 mg, and sham. In GATHER2, patients were randomized 1:1 to ACP 2 mg (n = 225) and sham (n = 223). A post hoc analysis of 12-month data for pooled ACP 2 mg and sham groups is reported. MAIN OUTCOME MEASURES: Proportion of study eyes that experienced ≥10-, ≥15-, or ≥20-BCVA ETDRS letter loss from baseline to month 12; time-to-event analysis of persistent vision loss of ≥10, ≥15, or≥ 20 BCVA letters from baseline at ≥2 consecutive visits over 12 months; proportion of study eyes with BCVA loss to a level below driving eligibility threshold at month 12 among those eligible to drive at baseline. RESULTS: Lower proportions of study eyes experienced ≥10-, ≥15-, or ≥20-BCVA letter loss from baseline over 12 months with ACP 2 mg (11.6%, 4.0%, and 1.6%, respectively) versus sham (14.1%, 7.6%, and 4.5%, respectively). There was a reduction in the risk of persistent loss of ≥15 BCVA ETDRS letters with ACP 2 mg (3.4%) versus sham (7.8%) through 12 months. A lower proportion of study eyes treated with ACP 2 mg reached the threshold for driving ineligibility versus sham by 12 months. CONCLUSIONS: Treatment with ACP 2 mg delayed the risk of progression to persistent vision loss (i.e., ≥10-, ≥15-, and ≥20-BCVA letter loss or BCVA loss to a level below driving eligibility threshold) versus sham over 12 months. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Development, validation, and pilot application of a high throughput molecular xenomonitoring assay to detect Schistosoma mansoni and other trematode species within Biomphalaria freshwater snail hosts.

Schistosomiasis is a neglected tropical disease (NTD) caused by infection with parasitic trematodes of the genus Schistosoma that can lead to debilitating morbidity and mortality. The World Health Organization recommend molecular xenomonitoring of Biomphalaria spp. freshwater snail intermediate hosts of Schistosoma mansoni to identify highly focal intestinal schistosomiasis transmission sites and monitor disease transmission, particularly in low-endemicity areas. A standardised protocol to do this, however, is needed. Here, two previously published primer sets were selected to develop and validate a multiplex molecular xenomonitoring end-point PCR assay capable of detecting S. mansoni infections within individual Biomphalaria spp. missed by cercarial shedding. The assay proved highly sensitive and highly specific in detecting and amplifying S. mansoni DNA and also proved highly sensitive in detecting and amplifying non-S. mansoni trematode DNA. The optimised assay was then used to screen Biomphalaria spp. collected from a S. mansoni-endemic area for infection and successfully detected S. mansoni infections missed by cercarial shedding as well as infections with non-S. mansoni trematodes. The continued development and use of molecular xenomonitoring assays such as this will aid in improving disease control efforts, significantly reducing disease-related morbidities experienced by those in schistosomiasis-endemic areas.

CENTRAL RETINAL VEIN OCCLUSION ASSOCIATED WITH USE OF AMYL NITRITE "POPPERS".

PURPOSE: To report a case of central retinal vein occlusion in a young patient after the use of amyl nitrate "poppers." METHODS: Description of the patient's clinical history, ophthalmic examination, retinal imaging, and treatment. RESULTS: A 38-year-old man presented with a central retinal vein occlusion in his right eye after inhaling amyl nitrite "poppers." There appeared to be a definitive temporal association between poppers use and both the onset of the vein occlusion and the patient's visual scotomata, which recurred immediately after drug use multiple times. Optical coherence tomography displayed cystic macular edema, which was treated with intravitreal bevacizumab. The patient's hypercoagulable laboratory workup was negative. CONCLUSION: This is the first report of a central retinal vein occlusion associated with poppers inhalation. A high index of suspicion for poppers use should be maintained in young patients who present with retinal vein occlusion, particularly in homosexual patients with a normal laboratory workup that fails to reveal a hypercoagulable etiology.

Pegcetacoplan for the treatment of geographic atrophy secondary to age-related macular degeneration (OAKS and DERBY): two multicentre, randomised, double-masked, sham-controlled, phase 3 trials.

BACKGROUND: Geographic atrophy is a leading cause of progressive, irreversible vision loss. The objectives of OAKS and DERBY were to assess the efficacy and safety of pegcetacoplan compared with sham treatment in patients with geographic atrophy. METHODS: OAKS and DERBY were two 24-month, multicentre, randomised, double-masked, sham-controlled, phase 3 studies, in which patients aged 60 years and older with geographic atrophy secondary to age-related macular degeneration were enrolled at 110 clinical sites and 122 clinical sites worldwide, respectively. Patients were randomly assigned (2:2:1:1) by central web-based randomisation system to intravitreal 15 mg per 0·1 mL pegcetacoplan monthly or every other month, or sham monthly or every other month using stratified permuted block randomisation (stratified by geographic atrophy lesion area at screening, history or presence of active choroidal neovascularisation in the eye not under assessment, and block size of six). Study site staff, patients, reading centre personnel, evaluating physicians, and the funder were masked to group assignment. Sham groups were pooled for the analyses. The primary endpoint was the change from baseline to month 12 in the total area of geographic atrophy lesions in the study eye based on fundus autofluorescence imaging, in the modified intention-to-treat population (ie, all patients who received one or more injections of pegcetacoplan or sham and had a baseline and at least one post-baseline value of lesion area). Key secondary endpoints (measured at 24 months) were change in monocular maximum reading speed of the study eye, change from baseline in mean functional reading independence index score, change from baseline in normal luminance best-corrected visual acuity score, and change from baseline in the mean threshold sensitivity of all points in the study eye by mesopic microperimetry (OAKS only). Safety analyses included patients who were randomly assigned and received at least one injection of pegcetacoplan or sham. The now completed studies are registered with ClinicalTrials.gov, NCT03525613 (OAKS) and NCT03525600 (DERBY). FINDINGS: Between Aug 30, 2018, and July 3, 2020, 1258 patients were enrolled in OAKS and DERBY. The modified intention-to-treat populations comprised 614 (96%) of 637 patients in OAKS (202 receiving pegcetacoplan monthly, 205 pegcetacoplan every other month, and 207 sham) and 597 (96%) of 621 patients in DERBY (201 receiving pegcetacoplan monthly, 201 pegcetacoplan every other month, and 195 sham). In OAKS, pegcetacoplan monthly and pegcetacoplan every other month significantly slowed geographic atrophy lesion growth by 21% (absolute difference in least-squares mean -0·41 mm2, 95% CI -0·64 to -0·18; p=0·0004) and 16% (-0·32 mm2, -0·54 to -0·09; p=0·0055), respectively, compared with sham at 12 months. In DERBY, pegcetacoplan monthly and pegcetacoplan every other month slowed geographic atrophy lesion growth, although it did not reach significance, by 12% (-0·23 mm2, -0·47 to 0·01; p=0·062) and 11% (-0·21 mm2, -0·44 to 0·03; p=0·085), respectively, compared with sham at 12 months. At 24 months, pegcetacoplan monthly and pegcetacoplan every other month slowed geographic atrophy lesion growth by 22% (-0·90 mm2, -1·30 to -0·50; p<0·0001) and 18% (-0·74 mm2, -1·13 to -0·36; p=0·0002) in OAKS, and by 19% (-0·75 mm2, -1·15 to -0·34; p=0·0004) and 16% (-0·63 mm2, -1·05 to -0·22; p=0·0030) in DERBY, respectively, compared with sham. There were no differences in key secondary visual function endpoints at 24 months. Serious ocular treatment-emergent adverse events were reported in five (2%) of 213, four (2%) of 212, and one (<1%) of 211 patients in OAKS, and in four (2%) of 206, two (1%) of 208, and two (1%) of 206 patients in DERBY receiving pegcetacoplan monthly, pegcetacoplan every other month, and sham, respectively, at 24 months. New-onset exudative age-related macular degeneration was reported in 24 (11%), 16 (8%), and four (2%) patients in OAKS, and in 27 (13%), 12 (6%), and nine (4%) patients in DERBY receiving pegcetacoplan monthly, pegcetacoplan every other month, and sham, respectively, at 24 months. INTERPRETATION: Pegcetacoplan, the first treatment approved by the US Food and Drug Administration for geographic atrophy, slowed geographic atrophy lesion growth with an acceptable safety profile. FUNDING: Apellis Pharmaceuticals.

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.

Avacincaptad pegol for geographic atrophy secondary to age-related macular degeneration: 18-month findings from the GATHER1 trial.

BACKGROUND/OBJECTIVES: To assess the safety and efficacy of avacincaptad pegol (ACP), a C5 inhibitor, for geographic atrophy (GA) secondary to age-related macular degeneration (AMD) over an 18-month treatment course. SUBJECTS/METHODS: This study was an international, prospective, randomized, double-masked, sham-controlled, phase 2/3 clinical trial that consisted of 2 parts. In part 1, 77 participants were randomized 1:1:1 to receive monthly intravitreal injections of ACP 1 mg, ACP 2 mg, or sham. In part 2, 209 participants were randomized 1:2:2 to receive monthly ACP 2 mg, ACP 4 mg, or sham. The mean rate of change of GA over 18 months was measured by fundus autofluorescence. RESULTS: Compared with their respective sham cohorts, monthly ACP treatment reduced the mean GA growth (square root transformation) over 18 months by 28.1% (0.168 mm, 95% CI [0.066, 0.271]) for the 2 mg cohort and 30.0% (0.167 mm, 95% CI [0.062, 0.273]) for the 4 mg cohort. ACP treatment was generally well tolerated over 18 months, with most ocular adverse events (AEs) related to the injection procedure. Macular neovascularization (MNV) was more frequent in both 2 mg (11.9%) and 4 mg (15.7%) cohorts than their respective sham control groups (2.7% and 2.4%). CONCLUSIONS: Over this 18-month study, ACP 2 mg and 4 mg showed continued reductions in the progression of GA growth compared to sham and continued to be generally well tolerated. A pivotal phase 3 GATHER2 trial is currently underway to support the efficacy and safety of ACP as a potential treatment for GA.

HIGH-RESOLUTION SPECTRAL-DOMAIN OPTICAL COHERENCE TOMOGRAPHY OF MULTIPLE EVANESCENT WHITE DOT SYNDROME.

PURPOSE: To evaluate a patient with multiple evanescent white dot syndrome with multimodal imaging including high-resolution spectral-domain optical coherence tomography. METHODS: The patient was evaluated with wide-field color and autofluorescence imaging, microperimetry, and near-infrared imaging. Spectral-domain optical coherence tomography was performed using an instrument capable of 3- µ m axial resolution, the high-resolution Heidelberg Spectralis. RESULTS: A 28-year-old woman developed photopsias and a scotoma in the field of vision of her left eye. She had multiple whitish spots with granularity in her fovea, consistent with the diagnosis of multiple evanescent white dot syndrome. She had supportive fluorescein angiographic and autofluorescence findings. Because of the high resolution and good layer contrast, it was possible to create en face slab images of the external limiting membrane, ellipsoid zone, interdigitation zone, and retinal pigment epithelium. The external limiting membrane showed no abnormalities. There were multiple regions of decreased reflectance in the ellipsoid zone slab but even more prominent changes in the interdigitation zone. The retinal pigment epithelium showed nearly no variation in layer reflectivity. With resolution of symptoms, the color and autofluorescence images returned to normal, the defects in the ellipsoid zone almost completely resolved, and the interdigitation zone continued to show abnormalities. CONCLUSION: Although past studies concluded that the ellipsoid zone was the main region of involvement in multiple evanescent white dot syndrome, high-resolution spectral-domain optical coherence tomography suggests the interdigitation zone was more prominently affected in this case.

Hygiene in early childhood development centres in low-income areas of Blantyre, Malawi.

Diarrhoeal disease remains a leading cause of death in children in sub-Saharan Africa, attributed to environmental health factors such as inadequate water, sanitation and hygiene (WASH) and food hygiene. This formative study in low-income areas of Blantyre focussed on the practices in Early Childhood Development Centre (ECDCs) environments where children spend a significant amount of time. A mixed-methods approach was applied to identify key hygiene behaviours in ECDCs through; checklist and structured observations (n = 849 children; n = 33 caregivers), focus group discussions (n = 25) and microbiological sampling (n = 261) of drinking water, food handler's hands, and eating utensils. ECDCs had inadequate WASH infrastructure; coupled with poor hygiene practices and unhygienic environments increased the risk of faecal-oral disease transmission. Presence of E. coli in drinking water confirmed observed poor water handling habits by staff and children. Addressing undesired hygiene practices in ECDCs has the potential to improve the health outcomes of children in low-income settings.

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.

Subretinal Fluid Resolution and Visual Acuity in Patients with Neovascular Age-Related Macular Degeneration: A HARBOR Post Hoc Analysis.

OBJECTIVE: To determine the effect of subretinal fluid (SRF) resolution on visual acuity in patients with neovascular age-related macular degeneration (nAMD) from the HARBOR trial. DESIGN: Post hoc analysis of the HARBOR trial (a phase 3, double-masked, randomized, active treatment-controlled trial of ranibizumab conducted between July 2009 and August 2012 [NCT00891735]) was carried out from January 2020 to July 2021. PARTICIPANTS: Treatment-naive patients with nAMD and active subfoveal choroidal neovascularization (N = 1097). Multiple intervention arms were pooled for this analysis if SRF was present at baseline and intraretinal fluid/SRF resolved during the study, based on spectral-domain OCT (n = 349). INTERVENTION: Three monthly loading doses followed by intravitreal injections of 0.5-mg or 2.0-mg ranibizumab were administered monthly or pro re nata over 24 months. MAIN OUTCOME MEASURES: Mean change in ETDRS best-corrected visual acuity (BCVA) between the month before SRF resolution and the month of SRF resolution detection. Visual outcomes at months 12 and 24 were analyzed in eyes without SRF recurrence after SRF resolution. The proportion of patients who lost ≤ 4 letters were considered as vision gainers/maintainers and those who lost ≥ 5 were considered as vision losers. RESULTS: Of 349 patients, 32 patients (9%) lost ≥ 5 ETDRS letters (mean [95% confidence interval (CI)], -9.9 letters [-12.0, -7.9]) and 317 (91%) of the eyes gained/maintained BCVA (mean, 6.1 letters [95% CI, 5.3, 6.8]) between the month before SRF resolution and the month of SRF resolution. There were no differences in baseline ocular characteristics between patient groups. Among eyes without SRF recurrence after SRF resolution (64%; 224/349), eyes that lost ≥ 5 ETDRS letters compared with those that gained/maintained letters at the time of SRF resolution had reduced visual outcome gains from baseline to month 12 (1.4 vs. 12.9 letters) and month 24 (0.0 vs. 12.6 letters). CONCLUSIONS: A greater proportion of ranibizumab-treated eyes with nAMD gained/maintained visual acuity at SRF resolution. Approximately 9% of eyes lost vision during SRF resolution; these eyes had reduced final visual acuity gains at 12 and 24 months. Further analyses are warranted to investigate potential underlying factors and discuss the treatment implications if confirmed.

Evaluation of a self-imaging SD-OCT system designed for remote home monitoring.

PURPOSE: To compare identification rates of retinal fluid of the Notal Vision Home Optical Coherence Tomography (OCT) device (NVHO) when used by people with age-related macular degeneration (AMD) to those captured by a commercial OCT. METHODS: Prospective, cross-sectional study where patients underwent commercial OCT imaging followed by self-imaging with either the NVHO 2.5 or the NVHO 3 in clinic setting. Outcomes included patients' ability to acquire analyzable OCT images with the NVHO and to compare those with commercial images. RESULTS: Successful images were acquired with the NVHO 2.5 in 469/531 eyes (88%) in 264/290 subjects (91%) with the mean (SD) age of 78.8 (8.8); 153 (58%) were female with median visual acuity (VA) of 20/40. In the NVHO 3 cohort, 69 eyes of 45 subjects (93%) completed the self-imaging. Higher rates of successful imaging were found in eyes with VA ≥ 20/320. Positive percent agreement/negative percent agreement for detecting the presence of subretinal and/or intraretinal fluid when reviewing for fluid in three repeated volume scans were 97%/95%, respectively for the NVHO v3. CONCLUSION: Self-testing with the NVHO can produce high quality images suitable for fluid identification by human graders, suggesting the device may be able to complement standard-of-care clinical assessments and treatments.

PRPH2-Associated Macular Dystrophy in 4 Family Members with a Novel Mutation.

Peripherin-2 (PRPH2) gene variants are a well-established cause of multiple inherited maculopathies including central areolar choroidal dystrophy (CACD) and pattern dystrophy. In this familial case study, we present a 63-year-old proband who presented with visual acuity of 20/63 right eye and 20/100 left eye with a complaint of lowered visual acuity in the left eye for unknown duration. Fundus examination presented with unifocal atrophic lesions bilaterally. Multi-modal imaging was obtained and genetic testing (My Retina Tracker; Blueprint Genetics) was performed. The proband was monoallelic for a novel missense mutation within the PRPH2 gene (Arg203Pro) not previously found in the literature or large databases (gnomAD, ClinVar, and HGMD). Subsequent examination of the proband's mother, older sister (65 years old), younger sister (53), and daughter (35) found the novel mutation to segregate with maculopathy ranging from speckled fundus autofluorescence with EZ disruption and RPE attenuation on spectral domain optical coherence tomography to large unifocal atrophic lesions throughout the macula bilaterally. The purpose of this case report is to add to the literature of PRPH2-associated disease by providing a comprehensive fundus examination of a family with autosomal dominant PRPH2-associated maculopathy diagnosed as central areolar choroidal dystrophy and pattern dystrophy.

Early Experience With Brolucizumab Treatment of Neovascular Age-Related Macular Degeneration.

IMPORTANCE: Outcome data are limited regarding early experience with brolucizumab, the most recently approved anti-vascular endothelial growth factor (VEGF) agent for the treatment of neovascular age-related macular degeneration (nAMD). OBJECTIVE: To report clinical outcomes after intravitreous injection (IVI) of brolucizumab, 6 mg, for nAMD. DESIGN, SETTING, AND PARTICIPANTS: This retrospective case series conducted at 15 private or academic ophthalmological centers in the United States included all consecutive patients with eyes treated with brolucizumab by 6 retina specialists between October 17, 2019, and April 1, 2020. EXPOSURES: Treatment with brolucizumab IVI, 6 mg. MAIN OUTCOMES AND MEASURES: Change in mean visual acuity (VA) and optical coherence tomography parameters, including mean central subfield thickness and presence or absence of subretinal and/or intraretinal fluid. Secondary outcomes included ocular and systemic safety. RESULTS: A total of 172 eyes from 152 patients (87 women [57.2%]; mean [SD] age, 80.0 [8.0] years) were included. Most eyes (166 [96.5%]) were not treatment naive, and 65.7% of these eyes (109 of 166) were switched from the prior anti-VEGF agent because of persistent fluid detected on optical coherence tomography scans. Study eyes received a mean (SD) of 1.46 (0.62) brolucizumab IVIs. The mean (SD) VA prior to starting brolucizumab was a 64.1 (15.9) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score (Snellen equivalent, 20/50) and was a 63.3 (17.2) ETDRS letter score (Snellen equivalent, 20/63) at the last study evaluation (mean difference, 0.8; 95% CI, -2.7 to 4.3; P = .65). When analyzed by number of brolucizumab IVIs, the presence or absence of fluid prior to starting brolucizumab, or the presence or absence of intraocular inflammation after receiving brolucizumab, there was no difference in mean VA prior to starting brolucizumab compared with after brolucizumab IVIs or at the final study evaluation. The mean (SD) central subfield thickness in all eyes prior to starting brolucizumab was 296.7 (88.0) µm and was 269.8 (66.5) µm at the last study examination (mean difference, 26.9 µm; 95% CI, 9.0-44.7 µm; P = .003). Intraocular inflammation was reported in 14 eyes (8.1%) and was self-limited and resolved without treatment in almost half those eyes (n = 6). One previously reported eye (0.6%) had occlusive retinal vasculitis and severe loss of vision. CONCLUSIONS AND RELEVANCE: In this analysis of brolucizumab IVI for nAMD, VA remained stable, with a reduction in central subfield thickness. Intraocular inflammation events ranged from mild with spontaneous resolution to severe occlusive retinal vasculitis in 1 eye.

An outbreak of intestinal schistosomiasis, alongside increasing urogenital schistosomiasis prevalence, in primary school children on the shoreline of Lake Malawi, Mangochi District, Malawi.

BACKGROUND: Intestinal schistosomiasis was not considered endemic in Lake Malawi until November 2017 when populations of Biomphalaria pfeifferi were first reported; in May 2018, emergence of intestinal schistosomiasis was confirmed. This emergence was in spite of ongoing control of urogenital schistosomiasis by preventive chemotherapy. Our current study sought to ascertain whether intestinal schistosomiasis is transitioning from emergence to outbreak, to judge if stepped-up control interventions are needed. METHODS: During late-May 2019, three cross-sectional surveys of primary school children for schistosomiasis were conducted using a combination of rapid diagnostic tests, parasitological examinations and applied morbidity-markers; 1) schistosomiasis dynamics were assessed at Samama (n = 80) and Mchoka (n = 80) schools, where Schistosoma mansoni was first reported, 2) occurrence of S. mansoni was investigated at two non-sampled schools, Mangochi Orphan Education and Training (MOET) (n = 60) and Koche (n = 60) schools, where B. pfeifferi was nearby, and 3) rapid mapping of schistosomiasis, and B. pfeifferi, conducted across a further 8 shoreline schools (n = 240). After data collection, univariate analyses and Chi-square testing were performed, followed by binary logistic regression using generalized linear models, to investigate epidemiological associations. RESULTS: In total, 520 children from 12 lakeshore primary schools were examined, mean prevalence of S. mansoni by 'positive' urine circulating cathodic antigen (CCA)-dipsticks was 31.5% (95% confidence interval [CI]: 27.5-35.5). Upon comparisons of infection prevalence in May 2018, significant increases at Samama (relative risk [RR] = 1.7, 95% CI: 1.4-2.2) and Mchoka (RR = 2.7, 95% CI: 1.7-4.3) schools were observed. Intestinal schistosomiasis was confirmed at MOET (18.3%) and Koche (35.0%) schools, and in all rapid mapping schools, ranging from 10.0 to 56.7%. Several populations of B. pfeifferi were confirmed, with two new eastern shoreline locations noted. Mean prevalence of urogenital schistosomiasis was 24.0% (95% CI: 20.3-27.7). CONCLUSIONS: We notify that intestinal schistosomiasis, once considered non-endemic in Lake Malawi, is now transitioning from emergence to outbreak. Once control interventions can resume after coronavirus disease 2019 (COVID-19) suspensions, we recommend stepped-up preventive chemotherapy, with increased community-access to treatments, alongside renewed efforts in appropriate environmental control.