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.

Shared Consensus Machine Learning Models for Predicting Blood Stage Malaria Inhibition.

The development of new antimalarial therapies is essential, and lowering the barrier of entry for the screening and discovery of new lead compound classes can spur drug development at organizations that may not have large compound screening libraries or resources to conduct high-throughput screens. Machine learning models have been long established to be more robust and have a larger domain of applicability with larger training sets. Screens over multiple data sets to find compounds with potential malaria blood stage inhibitory activity have been used to generate multiple Bayesian models. Here we describe a method by which Bayesian quantitative structure-activity relationship models, which contain information on thousands to millions of proprietary compounds, can be shared between collaborators at both for-profit and not-for-profit institutions. This model-sharing paradigm allows for the development of consensus models that have increased predictive power over any single model and yet does not reveal the identity of any compounds in the training sets.

(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium.

Drug discovery for malaria has been transformed in the last 5 years by the discovery of many new lead compounds identified by phenotypic screening. The process of developing these compounds as drug leads and studying the cellular responses they induce is revealing new targets that regulate key processes in the Plasmodium parasites that cause malaria. We disclose herein that the clinical candidate (+)-SJ733 acts upon one of these targets, ATP4. ATP4 is thought to be a cation-transporting ATPase responsible for maintaining low intracellular Na(+) levels in the parasite. Treatment of parasitized erythrocytes with (+)-SJ733 in vitro caused a rapid perturbation of Na(+) homeostasis in the parasite. This perturbation was followed by profound physical changes in the infected cells, including increased membrane rigidity and externalization of phosphatidylserine, consistent with eryptosis (erythrocyte suicide) or senescence. These changes are proposed to underpin the rapid (+)-SJ733-induced clearance of parasites seen in vivo. Plasmodium falciparum ATPase 4 (pfatp4) mutations that confer resistance to (+)-SJ733 carry a high fitness cost. The speed with which (+)-SJ733 kills parasites and the high fitness cost associated with resistance-conferring mutations appear to slow and suppress the selection of highly drug-resistant mutants in vivo. Together, our data suggest that inhibitors of PfATP4 have highly attractive features for fast-acting antimalarials to be used in the global eradication campaign.

Diversity-oriented natural product platform identifies plant constituents targeting Plasmodium falciparum.

BACKGROUND: A diverse library of pre-fractionated plant extracts, generated by an automated high-throughput system, was tested using an in vitro anti-malarial screening platform to identify known or new natural products for lead development. The platform identifies hits on the basis of in vitro growth inhibition of Plasmodium falciparum and counter-screens for cytotoxicity to human foreskin fibroblast or embryonic kidney cell lines. The physical library was supplemented by early-stage collection of analytical data for each fraction to aid rapid identification of the active components within each screening hit. RESULTS: A total of 16,177 fractions from 1300 plants were screened, identifying several P. falciparum inhibitory fractions from 35 plants. Although individual fractions were screened for bioactivity to ensure adequate signal in the analytical characterizations, fractions containing less than 2.0 mg of dry weight were combined to produce combined fractions (COMBIs). Fractions of active COMBIs had EC50 values of 0.21-50.28 and 0.08-20.04 µg/mL against chloroquine-sensitive and -resistant strains, respectively. In Berberis thunbergii, eight known alkaloids were dereplicated quickly from its COMBIs, but berberine was the most-active constituent against P. falciparum. The triterpenoids α-betulinic acid and ß-betulinic acid of Eugenia rigida were also isolated as hits. Validation of the anti-malarial discovery platform was confirmed by these scaled isolations from B. thunbergii and E. rigida. CONCLUSIONS: These results demonstrate the value of curating and exploring a library of natural products for small molecule drug discovery. Attention given to the diversity of plant species represented in the library, focus on practical analytical data collection, and the use of counter-screens all facilitate the identification of anti-malarial compounds for lead development or new tools for chemical biology.

Chemical genetics of Plasmodium falciparum.

Malaria caused by Plasmodium falciparum is a disease that is responsible for 880,000 deaths per year worldwide. Vaccine development has proved difficult and resistance has emerged for most antimalarial drugs. To discover new antimalarial chemotypes, we have used a phenotypic forward chemical genetic approach to assay 309,474 chemicals. Here we disclose structures and biological activity of the entire library-many of which showed potent in vitro activity against drug-resistant P. falciparum strains-and detailed profiling of 172 representative candidates. A reverse chemical genetic study identified 19 new inhibitors of 4 validated drug targets and 15 novel binders among 61 malarial proteins. Phylochemogenetic profiling in several organisms revealed similarities between Toxoplasma gondii and mammalian cell lines and dissimilarities between P. falciparum and related protozoans. One exemplar compound displayed efficacy in a murine model. Our findings provide the scientific community with new starting points for malaria drug discovery.

Spatial scale, time and process in mega-events: The complexity of host community perspectives on neighbourhood change.

A focus on the 'mega' aspect of hallmark events can divert attention from the micro - those local communities who are most impacted by the event. Similarly, attention to the 'event' aspect underplays the long process of bidding and preparation before any putative legacy of urban transformation for local people. This paper uses qualitative data to unpack the complex and multi-layered views of local residents, living in a deprived neighbourhood beside the Glasgow 2014 Commonwealth Games site in Scotland. They reflect on five years of intensive urban regeneration, evaluate the experience of 'lockdown' at Games time, and consider their hopes and fears for the future of the community. Interviewing a mixture of lifelong, established, new and returning residents, we found considerable common ground across the different groups in terms of hopes for a new, mixed community in the area. However, findings also highlight concerns around urban governance practices and the limitations of a market-led approach to regeneration.

Treatment of murine cerebral malaria by artemisone in combination with conventional antimalarial drugs: antiplasmodial effects and immune responses.

The decreasing effectiveness of antimalarial therapy due to drug resistance necessitates constant efforts to develop new drugs. Artemisinin derivatives are the most recent drugs that have been introduced and are considered the first line of treatment, but there are already indications of Plasmodium falciparum resistance to artemisinins. Consequently, drug combinations are recommended for prevention of the induction of resistance. The research here demonstrates the effects of novel combinations of the new artemisinin derivative, artemisone, a recently described 10-alkylamino artemisinin derivative with improved antimalarial activity and reduced neurotoxicity. We here investigate its ability to kill P. falciparum in a high-throughput in vitro assay and to protect mice against lethal cerebral malaria caused by Plasmodium berghei ANKA when used alone or in combination with established antimalarial drugs. Artemisone effects against P. falciparum in vitro were synergistic with halofantrine and mefloquine, and additive with 25 other drugs, including chloroquine and doxycycline. The concentrations of artemisone combinations that were toxic against THP-1 cells in vitro were much higher than their effective antimalarial concentration. Artemisone, mefloquine, chloroquine, or piperaquine given individually mostly protected mice against cerebral malaria caused by P. berghei ANKA but did not prevent parasite recrudescence. Combinations of artemisone with any of the other three drugs did completely cure most mice of malaria. The combination of artemisone and chloroquine decreased the ratio of proinflammatory (gamma interferon, tumor necrosis factor) to anti-inflammatory (interleukin 10 [IL-10], IL-4) cytokines in the plasma of P. berghei-infected mice. Thus, artemisone in combinations with other antimalarial drugs might have a dual action, both killing parasites and limiting the potentially deleterious host inflammatory response.

Dihydroquinazolinone inhibitors of proliferation of blood and liver stage malaria parasites.

Drugs that target both the liver and blood stages of malaria will be needed to reduce the disease's substantial worldwide morbidity and mortality. Evaluation of a 259-member library of compounds that block proliferation of the blood stage of malaria revealed several scaffolds--dihydroquinazolinones, phenyldiazenylpyridines, piperazinyl methyl quinolones, and bis-benzimidazoles--with promising activity against the liver stage. Focused structure-activity studies on the dihydroquinazolinone scaffold revealed several molecules with excellent potency against both blood and liver stages. One promising early lead with dual activity is 2-(p-bromophenyl)-3-(2-(diethylamino)ethyl)-2,3-dihydroquinazolin-4(1H)-one with 50% effective concentrations (EC50s) of 0.46 µM and 0.34 µM against liver stage Plasmodium berghei ANKA and blood stage Plasmodium falciparum 3D7 parasites, respectively. Structure-activity relationships revealed that liver stage activity for this compound class requires a 3-dialkyl amino ethyl group and is abolished by substitution at the ortho-position of the phenyl moiety. These compounds have minimal toxicity to mammalian cells and are thus attractive compounds for further development.

Repositioning: the fast track to new anti-malarial medicines?

BACKGROUND: Repositioning of existing drugs has been suggested as a fast track for developing new anti-malarial agents. The compound libraries of GlaxoSmithKline (GSK), Pfizer and AstraZeneca (AZ) comprising drugs that have undergone clinical studies in other therapeutic areas, but not achieved approval, and a set of US Food and Drug Administration (FDA)-approved drugs and other bio-actives were tested against Plasmodium falciparum blood stages. METHODS: Molecules were tested initially against erythrocytic co-cultures of P. falciparum to measure proliferation inhibition using one of the following methods: SYBR®I dye DNA staining assay (3D7, K1 or NF54 strains); [(3)H] hypoxanthine radioisotope incorporation assay (3D7 and 3D7A strain); or 4',6-diamidino-2-phenylindole (DAPI) DNA imaging assay (3D7 and Dd2 strains). After review of the available clinical pharmacokinetic and safety data, selected compounds with low µM activity and a suitable clinical profile were tested in vivo either in a Plasmodium berghei four-day test or in the P. falciparum Pf3D7(0087/N9) huSCID 'humanized' mouse model. RESULTS: Of the compounds included in the GSK and Pfizer sets, 3.8% (9/238) had relevant in vitro anti-malarial activity while 6/100 compounds from the AZ candidate drug library were active. In comparison, around 0.6% (24/3,800) of the FDA-approved drugs and other bio-actives were active. After evaluation of available clinical data, four investigational drugs, active in vitro were tested in the P. falciparum humanized mouse model: UK-112,214 (PAF-H1 inhibitor), CEP-701 (protein kinase inhibitor), CEP-1347 (protein kinase inhibitor), and PSC-833 (p-glycoprotein inhibitor). Only UK-112,214 showed significant efficacy against P. falciparum in vivo, although at high doses (ED90 131.3 mg/kg [95% CI 112.3, 156.7]), and parasitaemia was still present 96 hours after treatment commencement. Of the six actives from the AZ library, two compounds (AZ-1 and AZ-3) were marginally efficacious in vivo in a P. berghei model. CONCLUSIONS: Repositioning of existing therapeutics in malaria is an attractive proposal. Compounds active in vitro at µM concentrations were identified. However, therapeutic concentrations may not be effectively achieved in mice or humans because of poor bio-availability and/or safety concerns. Stringent safety requirements for anti-malarial drugs, given their widespread use in children, make this a challenging area in which to reposition therapy.

Antimalarial activity of abietane ferruginol analogues possessing a phthalimide group.

The abietane-type diterpenoid (+)-ferruginol, a bioactive compound isolated from New Zealand's Miro tree (Podocarpus ferruginea), displays relevant pharmacological properties, including antimicrobial, cardioprotective, anti-oxidative, anti-plasmodial, leishmanicidal, anti-ulcerogenic, anti-inflammatory and anticancer. Herein, we demonstrate that ferruginol (1) and some phthalimide containing analogues 2-12 have potential antimalarial activity. The compounds were evaluated against malaria strains 3D7 and K1, and cytotoxicity was measured against a mammalian cell line panel. A promising lead, compound 3, showed potent activity with an EC50 = 86 nM (3D7 strain), 201 nM (K1 strain) and low cytotoxicity in mammalian cells (SI>290). Some structure-activity relationships have been identified for the antimalarial activity in these abietane analogues.

Antimalarial evaluation of the chemical constituents of hairy root culture of Bixa orellana L.

Over 216 million malaria cases are reported annually worldwide and about a third of these cases, primarily children under the age of five years old, will not survive the infection. Despite this significant world health impact, only a limited number of therapeutic agents are currently available. The lack of scaffold diversity poses a threat in the event that multi-drug-resistant strains emerge. Terrestrial natural products have provided a major source of chemical diversity for starting materials in many FDA approved drugs over the past century. Bixa orellana L. is a popular plant used in South America for the treatment of malaria. In search of new potential therapeutic agents, the chemical constituents of a selected hairy root culture line of Bixa orellana L. were characterized utilizing NMR and mass spectrometry methods, followed by its biological evaluation against malaria strains 3D7 and K1. The crude extract and its isolated compounds demonstrated EC50 values in the micromolar range. Herein, we report our findings on the chemical constituents of Bixa orellana L. from hairy roots responsible for the observed antimalarial activity.

Acute adrenal necrosis in a young female cat.

CASE DESCRIPTION: An 18-month-old spayed female domestic short haired cat was presented for poor appetite, lethargy, exaggerated swallowing, and regurgitation 2 weeks after endoscopic retrieval of gastric foreign material. CLINICAL FINDINGS: The cat was quiet with tacky mucous membranes on physical examination. Point-of-care blood testing identified mild azotemia, moderate hypercalcemia, and a sodium-to-potassium ratio of 26. An ultrasound examination the next day identified moderate to marked bilateral adrenomegaly. Cytology of a fine needle aspirate of the adrenal glands was consistent with necrosis and associated inflammation. Hypoadrenocorticism was diagnosed by a confirmatory adrenocorticotropic hormone stimulation test. TREATMENT AND OUTCOME: The cat normalized both clinically and biochemically after treatment with prednisolone and desoxycorticosterone pivalate. CLINICAL RELEVANCE: Acute adrenal necrosis has been well documented in human medicine after anesthetic events. To our knowledge, hypoadrenocorticism caused by cytologically confirmed acute adrenal necrosis has not been previously reported in dogs and cats.

Characterization of clinical presentation, histological features, ultrasonographic findings, and survival in 29 dogs with granulomatous hepatitis.

BACKGROUND: Granulomatous hepatitis (GH) is a form of chronic hepatitis (CH) in dogs for which limited information is published. HYPOTHESIS: Describe the clinical presentation, clinical pathology, ultrasound, and hepatic histopathology findings and to report survival times in dogs with GH. ANIMALS: Twenty-nine client-owned dogs with GH. METHODS: Retrospective observational study. Pathology records were searched. Inclusion criteria included a histopathologic diagnosis of GH, absence of an identified etiology or evidence of extrahepatic granulomatous disease, and a medical record available for review. Clinical presentation, clinical pathologic findings, treatment protocols, and survival times were recorded. Available hepatic biopsy material was graded and scored, and ultrasound evaluations reviewed. RESULTS: The median age was 7 years (range, 0.66-12 years). Nineteen breeds were represented. Decreased appetite (19/29), lethargy (16/29), and fever (13/29) were seen most commonly. All dogs had increased serum transaminase activities, whereas 21/29 and 12/24 had hyperbilirubinemia and neutrophilia, respectively. Ultrasonographic findings included hepatomegaly (12/22), nodular parenchymal lesions (9/22), and hyperechoic parenchymal bands (8/22). Histopathologic necroinflammatory scores were moderate to severe in 16/19 dogs, and fibrosis scores were mild in 14/19 dogs. Treatments varied and included antibiotics, immunosuppressive drugs, and hepatoprotectants. Overall median survival was 635 days (range, 1-2482 days). CONCLUSION AND CLINICAL IMPORTANCE: Granulomatous hepatitis in dogs is associated with high histopathologic grade, fever, neutrophilia, and a high incidence of hepatomegaly and focal parenchymal lesions on ultrasound examination. Despite disease severity on presentation, dogs with GH can have a good outcome with prolonged survival.

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.

Correlation Between Blue Fundus Autofluorescence and SD-OCT Measurements of Geographic Atrophy in Dry Age-Related Macular Degeneration.

PURPOSE: To compare fundus autofluorescence (FAF) and spectral domain optical coherence tomography (OCT) measurements of geographic atrophy (GA) area and to analyze lesion area changes measured by spectral domain OCT in GATHER1. DESIGN: An assessment reliability analysis using prospective, randomized, double-masked phase 2/3 clinical trial data. METHODS: GATHER1 examined the efficacy and safety of avacincaptad pegol (ACP) for GA treatment. A post hoc analysis was performed to identify correlations between FAF- and OCT-based measurements of GA. GA area was measured on blue-light FAF images using semiautomatic segmentation software with support from OCT and near-infrared imaging. Machine-learning enhanced, multilayer segmentation of OCT scans were reviewed by human readers, and segmentation errors were corrected as needed. GA area was defined as total RPE loss on cross-sectional B scans. Time points included Months 0, 6, 12, and 18. Additionally, OCT-based GA-area changes between ACP and sham were analyzed. RESULTS: There was a strong correlation (r = 0.93) between FAF and OCT GA area measurements that persisted through 18 months. Mean (SD) differences between OCT and FAF GA measurements were negligible: 0.11 mm2 (1.42) at Month 0, 0.03 mm2 (1.62) at Month 6, -0.17 mm2 (1.81) at Month 12, and -0.07 mm2 (1.78) at Month 18. OCT assessments of GA growth revealed a 30% and 27% reduction at Months 12 and 18, respectively, between ACP and sham, replicating FAF measurements from GATHER1. CONCLUSIONS: The strong correlation between blue FAF and OCT measurements of GA area supports OCT as a reliable method to measure GA lesion area in clinical trials.

Discovery of novel antimalarial compounds enabled by QSAR-based virtual screening.

Quantitative structure-activity relationship (QSAR) models have been developed for a data set of 3133 compounds defined as either active or inactive against P. falciparum. Because the data set was strongly biased toward inactive compounds, different sampling approaches were employed to balance the ratio of actives versus inactives, and models were rigorously validated using both internal and external validation approaches. The balanced accuracy for assessing the antimalarial activities of 70 external compounds was between 87% and 100% depending on the approach used to balance the data set. Virtual screening of the ChemBridge database using QSAR models identified 176 putative antimalarial compounds that were submitted for experimental validation, along with 42 putative inactives as negative controls. Twenty five (14.2%) computational hits were found to have antimalarial activities with minimal cytotoxicity to mammalian cells, while all 42 putative inactives were confirmed experimentally. Structural inspection of confirmed active hits revealed novel chemical scaffolds, which could be employed as starting points to discover novel antimalarial agents.

Antimalarial activity of 10-alkyl/aryl esters and -aminoethylethers of artemisinin.

A series of n-alkyl/aryl esters were synthesized and their in vitro antiplasmodial activity was measured alongside that of previously synthesized aminoethylethers of artemisinin ozonides against various strains of Plasmodium falciparum. The cytotoxicity against human cell lines was also assessed. The esters were synthesized in a one-step reaction by derivatization on carbon C-10 of dihydroartemisinin. Both classes were active against both the 3D7 and K1 strains of P. falciparum, with all compounds being significantly more potent than artemether against both strains. The majority of compounds possessed potency either comparable or more than artesunate with a high degree of selectivity towards the parasitic cells. The 10α-n-propyl 11 and 10α-benzyl 18 esters were the most potent of all synthesized ozonides, possessing a moderate (~3-fold) and significant (22- and 12-fold, respectively) potency increases against the 3D7 and K1 strains, respectively, in comparison with artesunate.

Addressing career barriers for high risk adolescent girls: the PATHS curriculum intervention.

The study evaluated a gender-specific comprehensive career development curriculum designed to target career barriers faced by high risk adolescent girls - those with disabilities and at risk for school failure. The goal of the curriculum was to promote social cognitive career and self determination outcomes associated with adaptive career development and adjustment. A pre-post control group design was used to evaluate the curriculum. Findings suggest that participation in the curriculum resulted in significant and large gains in autonomy and in disability and gender-related knowledge. Meaningful gains were noted in perceptions of social support and relevance of school. Participants in a high fidelity sample made significant and large gains in vocational skills self-efficacy and disability and gender-related knowledge. Meaningful improvements were noted in self-advocacy, autonomy, and vocational outcome expectations. The findings suggest that the curriculum can improve important indicators of positive career development and adjustment in high risk adolescent girls.

Neptune versus canister-based surgical waste management in Europe: results of the GREEN study.

Background: Ineffective surgical fluid waste management in operating rooms (OR) creates a significant environmental burden, reduces OR efficiency, and adds physical challenges for surgical staff. There is a need for waste management systems that improve OR efficiency, safety, and sustainability. The GREEN study (Greening operating Rooms in EuropE comparing Neptune vs. canisters) was conducted to compare the impact of two fluid waste management systems. Materials and methods: This 2-arm, nonrandomized, prospective service evaluation of fluid waste extraction was conducted using observational time series and surveys. Fluid waste-related data were collected from routine urologic and orthopedic surgeries across three European hospital sites. The primary endpoint of waste disposal impact was the volume of treated waste after surgery (kilograms) using Stryker's Neptune device (n=43) or canisters (n=41). The authors hypothesized that the surgical waste volume related to Neptune is less than the waste volume related to canisters. Secondary endpoints included time efficiency, user satisfaction, and staff ergonomics. Results: The total weight of device-related treated waste products was reduced by 98.5% when using Neptune (0.2±0.7 kg) compared with traditional canisters (13.2±16.6 kg; P<0.001). Decreased waste weight also translated to enhanced ergonomic safety for surgical staff, as Neptune reduced surgical fluid weight handled by staff by an average of 34 kg per procedure, a 96% reduction compared to canisters. Furthermore, the use of the Neptune system improved OR efficiency by reducing the number of staff required to manage the fluid suction device (P<0.001) and the time spent disposing of fluid waste (P<0.001). Conclusion: Stryker's Neptune waste management system significantly reduces the volume of treated waste per surgery and improves OR efficiency, staff safety, and user satisfaction over the traditional canister system. This is a more eco-responsible approach to OR fluid waste management and could be considered in any healthcare establishment that generates fluid waste.