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The COVID-19 pandemic has strained the resources of the world's healthcare systems. Most individuals with neurodevelopmental disabilities (NDDs) experience significant mental health issues and face substantial barriers in accessing appropriate supports which have been exacerbated during the pandemic. It is unknown the extent to which COVID-19 impacted the demand for and effectiveness of inpatient care for those with NDDs. The impact of COVID-19 on the number of admissions of youth with NDDs to pediatric inpatient psychiatry units, as well as their functioning and length of stay during the first two years of the pandemic was analyzed using Bayesian structural time series models. Admission data of youth with NDDs from four pediatric inpatient units in Alberta, Canada (n = 2144) was examined. Inpatient admissions of youth with NDDs significantly increased following the onset of the pandemic. Compared to the period prior to the pandemic, patients with NDDs had significantly worse overall functioning and received fewer days of treatment. These findings highlight the need for increased resources to support the mental health needs of this vulnerable population and are consistent with other studies in the general population examining the utilization of inpatient psychiatric units during the pandemic.

A floating unit with three pontoons made of epoxy-coated carbon textile reinforced, ultra-high durability concrete (ECF UHDC), mineral impregnated carbon fibre-reinforced UHDC (MCF UHDC) and, as references, steel-reinforced concretes has been designed and installed in the Northern Atlantic. While marine structures with steel reinforcement require large cover depths, which cause problems in size, cost, environmental friendliness and short service life, carbon textile reinforced concrete (TRC) cannot suffer from chloride-induced corrosion of a metal reinforcement. In the EU H2020 project “ReSHEALience” (rethinking coastal defence and green-energy service infrastructures through enhanced-durability highperformance cement-based materials), TRCs have been modified with functional admixtures from consortium partners. A mineral self-healing promoter and alumina nano-fibers have, among others, been implemented to boost high-performance concretes towards UHDCs. Resulting composite variants have been applied in a full-scale floating unit that has been launched in the harbor of Galway at the Irish West Coast in June 2020. Such a floating body is a representation of breakwaters installed to reduce wave impacts to the coast. Besides, TRC-based UHDC can be applied as strengthening and repair layer on concrete structures to enhance their service life in general.

BACKGROUND: Pegunigalsidase alfa is a PEGylated α-galactosidase A enzyme replacement therapy. BALANCE (NCT02795676) assessed non-inferiority of pegunigalsidase alfa versus agalsidase beta in adults with Fabry disease with an annualised estimated glomerular filtration rate (eGFR) slope more negative than -2 mL/min/1.73 m2/year who had received agalsidase beta for ≥1 year. METHODS: Patients were randomly assigned 2:1 to receive 1 mg/kg pegunigalsidase alfa or agalsidase beta every 2 weeks for 2 years. The primary efficacy analysis assessed non-inferiority based on median annualised eGFR slope differences between treatment arms. RESULTS: Seventy-seven patients received either pegunigalsidase alfa (n=52) or agalsidase beta (n=25). At baseline, mean (range) age was 44 (18-60) years, 47 (61%) patients were male, median eGFR was 74.5 mL/min/1.73 m2 and median (range) eGFR slope was -7.3 (-30.5, 6.3) mL/min/1.73 m2/year. At 2 years, the difference between median eGFR slopes was -0.36 mL/min/1.73 m2/year, meeting the prespecified non-inferiority margin. Minimal changes were observed in lyso-Gb3 concentrations in both treatment arms at 2 years. Proportions of patients experiencing treatment-related adverse events and mild or moderate infusion-related reactions were similar in both groups, yet exposure-adjusted rates were 3.6-fold and 7.8-fold higher, respectively, with agalsidase beta than pegunigalsidase alfa. At the end of the study, neutralising antibodies were detected in 7 out of 47 (15%) pegunigalsidase alfa-treated patients and 6 out of 23 (26%) agalsidase beta-treated patients. There were no deaths. CONCLUSIONS: Based on rate of eGFR decline over 2 years, pegunigalsidase alfa was non-inferior to agalsidase beta. Pegunigalsidase alfa had lower rates of treatment-emergent adverse events and mild or moderate infusion-related reactions. TRIAL REGISTRATION NUMBER: NCT02795676.

As cost-effective next-generation genome sequencing rapidly develops, calls for greater inclusion of Black people in genomic research, policy, and practice are necessary for effective translation of genomic science into precision population health and medicine. Employing a community-based participatory mixed methods research design, we developed a semi-structured survey that was disseminated to three cancer advocacy organizations. Of the 81 survey respondents 49 (60%) self-identified as Black, and 26 (32%) indicated a prior breast cancer diagnosis. Black participants expressed concerns about genetic testing were evenly distributed between concerns that could be addressed through genetic counseling (24%) and concerns about subsequent use of their genetic data (27%). Patient advocates contributed to contextualization of respondent concerns in terms of community experiences. Although genetic counseling services and policies governing genomic data use are not always accessible to many Black communities, advocates on our research team provided a bridge to discussion of the intersection between respondent concerns and the roles advocates play in filling gaps in access to genetic counseling and data governance. Concerns expressed by Black patients underscore a shared need among all patients for access to education, inclusion in research, and assurances regarding the use and handling of genetic data. Black cancer patients have joined in patient-led efforts to overcome systemic inequities in cancer care to improve their health outcomes through representation. Often their efforts are overshadowed by a relentless burden of continued health disparities. Future research should support their hidden work as a means to reduce barriers and improve representation in genomic databases.

This translational scoping study investigates how ethics learning is assessed in engineering education worldwide and interprets concepts and practices for relevance to educational planners at the postsecondary level. It provides insights on how engineering education has achieved a level of standardization globally, a calibration process that has facilitated infusion of prioritized abilities across engineering graduates broadly. The engineering education system is designed and maintained through a series of multi-jurisdictional accords that seek to prepare engineering graduates for a global marketplace of engineered products, goods, and services. This paper synthesizes existing literature (research and policy) related to engineering ethics education (EEE), providing a useful introduction to planners regarding ethics, understood to incorporate global responsibility and sustainability. Conclusions provide a foundation for a further systematic investigation of EEE at a global level, highlighting implications of this scoping study for teaching, research, and planning.

Patrick B Deegan, Timothy M CoxDepartment of Medicine, University of Cambridge, Lysosomal Disorders Unit, Addenbrooke's NHS Foundation Hospitals Trust, Cambridge, UKAbstract: The scientific and therapeutic development of imiglucerase (Cerezyme®) by the Genzyme Corporation is a paradigm case for a critical examination of current trends in biotechnology. In this article the authors argue that contemporary interest in treatments for rare diseases by major pharmaceutical companies stems in large part from an exception among rarities: the astonishing commercial success of Cerezyme. The fortunes of the Genzyme Corporation, latterly acquired by global giant Sanofi SA, were founded on the evolution of a blockbuster therapy for a single but, as it turns out, propitious ultra-orphan disorder: Gaucher disease.Keywords: enzyme therapy, ultra-orphan, macrophage targeting, lysosomal disease, mannose lectin, biopharmaceutical

Here the Human Pangenome Reference Consortium presents a first draft of the human pangenome reference. The pangenome contains 47 phased, diploid assemblies from a cohort of genetically diverse individuals1. These assemblies cover more than 99% of the expected sequence in each genome and are more than 99% accurate at the structural and base pair levels. Based on alignments of the assemblies, we generate a draft pangenome that captures known variants and haplotypes and reveals new alleles at structurally complex loci. We also add 119 million base pairs of euchromatic polymorphic sequences and 1,115 gene duplications relative to the existing reference GRCh38. Roughly 90 million of the additional base pairs are derived from structural variation. Using our draft pangenome to analyse short-read data reduced small variant discovery errors by 34% and increased the number of structural variants detected per haplotype by 104% compared with GRCh38-based workflows, which enabled the typing of the vast majority of structural variant alleles per sample.

There has been tremendous progress in phased genome assembly production by combining long-read data with parental information or linked-read data. Nevertheless, a typical phased genome assembly generated by trio-hifiasm still generates more than 140 gaps. We perform a detailed analysis of gaps, assembly breaks, and misorientations from 182 haploid assemblies obtained from a diversity panel of 77 unique human samples. Although trio-based approaches using HiFi are the current gold standard, chromosome-wide phasing accuracy is comparable when using Strand-seq instead of parental data. Importantly, the majority of assembly gaps cluster near the largest and most identical repeats (including segmental duplications [35.4%], satellite DNA [22.3%], or regions enriched in GA/AT-rich DNA [27.4%]). Consequently, 1513 protein-coding genes overlap assembly gaps in at least one haplotype, and 231 are recurrently disrupted or missing from five or more haplotypes. Furthermore, we estimate that 6-7 Mbp of DNA are misorientated per haplotype irrespective of whether trio-free or trio-based approaches are used. Of these misorientations, 81% correspond to bona fide large inversion polymorphisms in the human species, most of which are flanked by large segmental duplications. We also identify large-scale alignment discontinuities consistent with 11.9 Mbp of deletions and 161.4 Mbp of insertions per haploid genome. Although 99% of this variation corresponds to satellite DNA, we identify 230 regions of euchromatic DNA with frequent expansions and contractions, nearly half of which overlap with 197 protein-coding genes. Such variable and incompletely assembled regions are important targets for future algorithmic development and pangenome representation.

The human reference genome is the most widely used resource in human genetics and is due for a major update. Its current structure is a linear composite of merged haplotypes from more than 20 people, with a single individual comprising most of the sequence. It contains biases and errors within a framework that does not represent global human genomic variation. A high-quality reference with global representation of common variants, including single-nucleotide variants, structural variants and functional elements, is needed. The Human Pangenome Reference Consortium aims to create a more sophisticated and complete human reference genome with a graph-based, telomere-to-telomere representation of global genomic diversity. Here we leverage innovations in technology, study design and global partnerships with the goal of constructing the highest-possible quality human pangenome reference. Our goal is to improve data representation and streamline analyses to enable routine assembly of complete diploid genomes. With attention to ethical frameworks, the human pangenome reference will contain a more accurate and diverse representation of global genomic variation, improve gene-disease association studies across populations, expand the scope of genomics research to the most repetitive and polymorphic regions of the genome, and serve as the ultimate genetic resource for future biomedical research and precision medicine.

The Earth BioGenome Project (EBP) is an audacious endeavor to obtain whole-genome sequences of representatives from all eukaryotic species on Earth. In addition to the project's technical and organizational challenges, it also faces complicated ethical, legal, and social issues. This paper, from members of the EBP's Ethical, Legal, and Social Issues (ELSI) Committee, catalogs these ELSI concerns arising from EBP. These include legal issues, such as sample collection and permitting; the applicability of international treaties, such as the Convention on Biological Diversity and the Nagoya Protocol; intellectual property; sample accessioning; and biosecurity and ethical issues, such as sampling from the territories of Indigenous peoples and local communities, the protection of endangered species, and cross-border collections, among several others. We also comment on the intersection of digital sequence information and data rights. More broadly, this list of ethical, legal, and social issues for large-scale genomic sequencing projects may be useful in the consideration of ethical frameworks for future projects. While we do not-and cannot-provide simple, overarching solutions for all the issues raised here, we conclude our perspective by beginning to chart a path forward for EBP's work.

The Global Alliance for Genomics and Health (GA4GH) aims to accelerate biomedical advances by enabling the responsible sharing of clinical and genomic data through both harmonized data aggregation and federated approaches. The decreasing cost of genomic sequencing (along with other genome-wide molecular assays) and increasing evidence of its clinical utility will soon drive the generation of sequence data from tens of millions of humans, with increasing levels of diversity. In this perspective, we present the GA4GH strategies for addressing the major challenges of this data revolution. We describe the GA4GH organization, which is fueled by the development efforts of eight Work Streams and informed by the needs of 24 Driver Projects and other key stakeholders. We present the GA4GH suite of secure, interoperable technical standards and policy frameworks and review the current status of standards, their relevance to key domains of research and clinical care, and future plans of GA4GH. Broad international participation in building, adopting, and deploying GA4GH standards and frameworks will catalyze an unprecedented effort in data sharing that will be critical to advancing genomic medicine and ensuring that all populations can access its benefits.

Climate change is altering naturally fluctuating environmental conditions in coastal and estuarine ecosystems across the globe. Departures from long-term averages and ranges of environmental variables are increasingly being observed as directional changes [e.g., rising sea levels, sea surface temperatures (SST)] and less predictable periodic cycles (e.g., Atlantic or Pacific decadal oscillations) and extremes (e.g., coastal flooding, marine heatwaves). Quantifying the short- and long-term impacts of climate change on tidal marsh seascape structure and function for nekton is a critical step toward fisheries conservation and management. The multiple stressor framework provides a promising approach for advancing integrative, cross-disciplinary research on tidal marshes and food web dynamics. It can be used to quantify climate change effects on and interactions between coastal oceans (e.g., SST, ocean currents, waves) and watersheds (e.g., precipitation, river flows), tidal marsh geomorphology (e.g., vegetation structure, elevation capital, sedimentation), and estuarine and coastal nekton (e.g., species distributions, life history adaptations, predator-prey dynamics). However, disentangling the cumulative impacts of multiple interacting stressors on tidal marshes, whether the effects are additive, synergistic, or antagonistic, and the time scales at which they occur, poses a significant research challenge. This perspective highlights the key physical and ecological processes affecting tidal marshes, with an emphasis on the trophic linkages between marsh production and estuarine and coastal nekton, recommended for consideration in future climate change studies. Such studies are urgently needed to understand climate change effects on tidal marshes now and into the future.

Coastal salt marshes are distributed widely across the globe and are considered essential habitat for many fish and crustacean species. Yet, the literature on fishery support by salt marshes has largely been based on a few geographically distinct model systems, and as a result, inadequately captures the hierarchical nature of salt marsh pattern, process, and variation across space and time. A better understanding of geographic variation and drivers of commonalities and differences across salt marsh systems is essential to informing future management practices. Here, we address the key drivers of geographic variation in salt marshes: hydroperiod, seascape configuration, geomorphology, climatic region, sediment supply and riverine input, salinity, vegetation composition, and human activities. Future efforts to manage, conserve, and restore these habitats will require consideration of how environmental drivers within marshes affect the overall structure and subsequent function for fisheries species. We propose a future research agenda that provides both the consistent collection and reporting of sources of variation in small-scale studies and collaborative networks running parallel studies across large scales and geographically distinct locations to provide analogous information for data poor locations. These comparisons are needed to identify and prioritize restoration or conservation efforts, identify sources of variation among regions, and best manage fisheries and food resources across the globe.

Millions of people today have access to their personal genomic information. Direct-to-consumer services and integration with other “big data” increasingly commoditize what was rightly celebrated as a singular achievement in February 2001 when the first draft human genomes were published. But such remarkable technical and scientific progress has not been without its share of missteps and growing pains. Science invited the experts below to help explore how we got here and where we should (or ought not) be going.

In September 2020, a detailed report on Heritable Human Genome Editing was published. The report offers a translational pathway for the limited approval of germline editing under limited circumstances and assuming various criteria have been met. In this perspective, some three dozen experts from the fields of genome editing, medicine, bioethics, law, and related fields offer their candid reactions to the National Academies/Royal Society report, highlighting areas of support, omissions, disagreements, and priorities moving forward.

Approximately one third of cancer patients die due to complexities related to cachexia. However, the mechanisms of cachexia and the potential therapeutic interventions remain poorly studied. We observed a significant positive correlation between SIRT1 expression and muscle fiber cross-sectional area in pancreatic cancer patients. Rescuing Sirt1 expression by exogenous expression or pharmacological agents reverted cancer cell-induced myotube wasting in culture conditions and mouse models. RNA-seq and follow-up analyses showed cancer cell-mediated SIRT1 loss induced NF-κB signaling in cachectic muscles that enhanced the expression of FOXO transcription factors and NADPH oxidase 4 (Nox4), a key regulator of reactive oxygen species production. Additionally, we observed a negative correlation between NOX4 expression and skeletal muscle fiber cross-sectional area in pancreatic cancer patients. Knocking out Nox4 in skeletal muscles or pharmacological blockade of Nox4 activity abrogated tumor-induced cachexia in mice. Thus, we conclude that targeting the Sirt1-Nox4 axis in muscles is an effective therapeutic intervention for mitigating pancreatic cancer-induced cachexia.

Specialized computational chemistry packages have permanently reshaped the landscape of chemical and materials science by providing tools to support and guide experimental efforts and for the prediction of atomistic and electronic properties. In this regard, electronic structure packages have played a special role by using first-principle-driven methodologies to model complex chemical and materials processes. Over the past few decades, the rapid development of computing technologies and the tremendous increase in computational power have offered a unique chance to study complex transformations using sophisticated and predictive many-body techniques that describe correlated behavior of electrons in molecular and condensed phase systems at different levels of theory. In enabling these simulations, novel parallel algorithms have been able to take advantage of computational resources to address the polynomial scaling of electronic structure methods. In this paper, we briefly review the NWChem computational chemistry suite, including its history, design principles, parallel tools, current capabilities, outreach, and outlook.

The long atmospheric residence time of CO2 creates an urgent need to add atmospheric carbon drawdown to CO2 regulatory strategies. Synthetic and systems biology (SSB), which enables manipulation of cellular phenotypes, offers a powerful approach to amplifying and adding new possibilities to current land management practices aimed at reducing atmospheric carbon. The participants (in attendance: Christina Agapakis, George Annas, Adam Arkin, George Church, Robert Cook-Deegan, Charles DeLisi, Dan Drell, Sheldon Glashow, Steve Hamburg, Henry Jacoby, Henry Kelly, Mark Kon, Todd Kuiken, Mary Lidstrom, Mike MacCracken, June Medford, Jerry Melillo, Ron Milo, Pilar Ossorio, Ari Patrinos, Keith Paustian, Kristala Jones Prather, Kent Redford, David Resnik, John Reilly, Richard J. Roberts, Daniel Segre, Susan Solomon, Elizabeth Strychalski, Chris Voigt, Dominic Woolf, Stan Wullschleger, and Xiaohan Yang) identified a range of possibilities by which SSB might help reduce greenhouse gas concentrations and which might also contribute to environmental sustainability and adaptation. These include, among other possibilities, engineering plants to convert CO2 produced by respiration into a stable carbonate, designing plants with an increased root-to-shoot ratio, and creating plants with the ability to self-fertilize. A number of serious ecological and societal challenges must, however, be confronted and resolved before any such application can be fully assessed, realized, and deployed.

Abstract Introduction Paediatric patients (individuals below 18 years of age) requiring cranial‐spinal irradiation (CSI) at our institution are commonly planned and treated using a three isocentre (3‐ISO) volumetric modulated arc therapy (VMAT) technique. A modified two isocentre (2‐ISO) VMAT technique was investigated with the aim to improve workflow and reduce planning and treatment time. Methods Five CSI paediatric patients previously treated with a 3‐ISO VMAT technique were retrospectively replanned using a 2‐ISO VMAT technique. The 2‐ISO VMAT plans were reviewed and approved by a radiation oncologist (RO) before undergoing patient‐specific quality assurance (QA) procedures, performed by a radiation oncology medical physicist (ROMP). Planning target volume (PTV) coverage, organ‐at‐risk (OAR) dose as well as planning and treatment durations of the first five patients utilising 2‐ISO technique were compared with 3‐ISO technique. Results The average percentage difference in PTV coverage by 95% reference dose between the 2‐ISO and 3‐ISO is 0.14%, and the average difference in OAR median dose is 0.68 Gy. Conformity and homogeneity indices have the same averages at 1.18 and 0.4 respectively. Patient‐specific physics QA results were all comparable with the 3‐ISO averages at 98.84% and the 2‐ISO at 98.71%. Planning duration for the 2‐ISO was reduced by up to 75%, and daily treatment duration was reduced by up to 50%. Of all the previously treated CSI patients using a 3‐ISO technique, 45% were suitable for the 2‐ISO technique. Conclusion The 2‐ISO VMAT technique provided comparable dose distribution based on PTV coverage, OAR dose and plan metric indices. Reduced planning and treatment duration with the 2‐ISO technique facilitated improved workflow with decreased sedation time for paediatric patients requiring a general anaesthesia.

Abstract Background A pro-oxidant enzyme, NADPH oxidase 4 (Nox4) has been reported to be a critical downstream effector of TGFβ-induced myofibroblast transformation during fibrosis. While there are a small number of studies suggesting an oncogenic role of Nox4 derived from activated fibroblasts, direct evidence linking this pro-oxidant to the tumor-supporting CAF phenotype and the mechanisms involved are lacking, particularly in breast cancer. Methods We targeted Nox4 in breast patient-derived CAFs via siRNA-mediated knockdown or administration of a pharmaceutical inhibitor (GKT137831). We also determine primary tumor growth and metastasis of implanted tumor cells using a stable Nox4-/- syngeneic mouse model. Autophagic flux of CAFs was assessed using a tandem fluorescent-tagged ptfl-LC3 plasmid via confocal microscopy analysis and determination of the expression level of autophagy markers (beclin-1 and LC3B). Nox4 overexpressing CAFs depend on the Nrf2 (nuclear factor-erythroid factor 2-related factor 2) pathway for survival. We then determined the dependency of Nox4-overexpressing CAFs on the Nrf2-mediated adaptive stress response pathway for survival. Furthermore, we investigated the involvement of Birc5 on CAF phenotype (viability and collagen contraction activity) as well as the expression level of CAF markers, FAP and αSMA. Conclusions We found that deletion of stroma Nox4 and pharmaceutically targeting its activity with GKT137831 significantly inhibited orthotopic tumor growth and metastasis of implanted E0771 and 4T1 murine mammary carcinoma cell lines in mice. More importantly, we found a significant upregulation of Nox4 expression in CAFs isolated from human breast tumors versus normal mammary fibroblasts (RMFs). Our in situ RNA hybridization analysis for Nox4 transcription on a human breast tumor microarray further support a role of this pro-oxidant in the stroma of breast carcinomas. In addition, we found that Nox4 promotes autophagy in CAFs. Moreover, we found that Nox4 promoted survival of CAFs via activation of Nrf2, a master regulator of oxidative stress response. We have further shown Birc5 is involved as a downstream modulator of Nrf2-mediated pro-survival phenotype. Together these studies indicate a role of redox signaling via the Nox4-Nrf2 pathway in tumorigenesis and metastasis of breast cancer cells by promoting autophagy and survival of CAFs.

The 2021 eruption in the Reykjanes Peninsula of Iceland was the first in 800 years and was supplied by melts from diverse mantle source domains with near-identical oxygen isotope ratios, providing a unique insight into the Icelandic mantle plume.

The BRCA Challenge is a long-term data-sharing project initiated within the Global Alliance for Genomics and Health (GA4GH) to aggregate BRCA1 and BRCA2 data to support highly collaborative research activities. Its goal is to generate an informed and current understanding of the impact of genetic variation on cancer risk across the iconic cancer predisposition genes, BRCA1 and BRCA2. Initially, reported variants in BRCA1 and BRCA2 available from public databases were integrated into a single, newly created site, www.brcaexchange.org. The purpose of the BRCA Exchange is to provide the community with a reliable and easily accessible record of variants interpreted for a high-penetrance phenotype. More than 20,000 variants have been aggregated, three times the number found in the next-largest public database at the project's outset, of which approximately 7,250 have expert classifications. The data set is based on shared information from existing clinical databases-Breast Cancer Information Core (BIC), ClinVar, and the Leiden Open Variation Database (LOVD)-as well as population databases, all linked to a single point of access. The BRCA Challenge has brought together the existing international Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium expert panel, along with expert clinicians, diagnosticians, researchers, and database providers, all with a common goal of advancing our understanding of BRCA1 and BRCA2 variation. Ongoing work includes direct contact with national centers with access to BRCA1 and BRCA2 diagnostic data to encourage data sharing, development of methods suitable for extraction of genetic variation at the level of individual laboratory reports, and engagement with participant communities to enable a more comprehensive understanding of the clinical significance of genetic variation in BRCA1 and BRCA2.

Abstract Catastrophic lava dome collapse is considered an unpredictable volcanic hazard because the physical properties, stress conditions, and internal structure of lava domes are not well understood and can change rapidly through time. To explain the locations of dome instabilities at Merapi volcano, Indonesia, we combined geochemical and mineralogical analyses, rock physical property measurements, drone-based photogrammetry, and geoinformatics. We show that a horseshoe-shaped alteration zone that formed in 2014 was subsequently buried by renewed lava extrusion in 2018. Drone data, as well as geomechanical, mineralogical, and oxygen isotope data suggest that this zone is characterized by high-porosity hydrothermally altered materials that are mechanically weak. We additionally show that the new lava dome is currently collapsing along this now-hidden weak alteration zone, highlighting that a detailed understanding of dome architecture, made possible using the monitoring techniques employed here, is essential for assessing hazards associated with dome and edifice failure at volcanoes worldwide.

Abstract Background Disease-specific patient-reported outcome measures (PROMs) are fundamental to understanding the impact on, and expectations of, patients with genetic disorders, and can facilitate constructive and educated conversations about treatments and outcomes. However, generic PROMs may fail to capture disease-specific concerns. Here we report the development and validation of a Gaucher disease (GD)-specific PROM for patients with type 1 Gaucher disease (GD1) a lysosomal storage disorder characterized by hepatosplenomegaly, thrombocytopenia, anemia, bruising, bone disease, and fatigue. Results and discussion The questionnaire was initially developed with input from 85 patients or parents of patients with GD1 or GD3 in Israel. Owing to few participating patients with GD3, content validity was assessed for patients with GD1 only. Content validity of the revised questionnaire was assessed in 33 patients in the US, France, and Israel according to US Food and Drug Administration standards, with input from a panel of six GD experts and one patient advocate representative. Concept elicitation interviews explored patient experience of symptoms and treatments, and a cognitive debriefing exercise explored patients’ understanding and relevance of instructions, items, response scales, and recall period. Two versions of the questionnaire were subsequently developed: a 24-item version for routine monitoring in clinical practice (rmGD1-PROM), and a 17-item version for use in clinical trials (ctGD1-PROM). Psychometric validation of the ctGD1-PROM was assessed in 46 adult patients with GD1 and re-administered two weeks later to examine test–retest reliability. Findings from the psychometric validation study revealed excellent internal consistency and strong evidence of convergent validity of the ctGD1-PROM based on correlations with the 36-item Short Form Health Survey. Most items were found to show moderate, good, or excellent test–retest reliability. Conclusions Development of the ctGD1-PROM represents an important step forward for researchers measuring the impact of GD and its respective treatment.

BackgroundBrain metastases are a common complication of renal cell carcinoma (RCC). Our group previously published the Renal Graded Prognostic Assessment (GPA) tool. In our prior RCC study (n = 286, 1985-2005), we found marked heterogeneity and variation in outcomes. In our recent update in a larger, more contemporary cohort, we identified additional significant prognostic factors. The purpose of this study is to update the original Renal-GPA based on the newly identified prognostic factors.MethodsA multi-institutional retrospective institutional review board-approved database of 711 RCC patients with new brain metastases diagnosed from January 1, 2006 to December 31, 2015 was created. Clinical parameters and treatment were correlated with survival. A revised Renal GPA index was designed by weighting the most significant factors in proportion to their hazard ratios and assigning scores such that the patients with the best and worst prognoses would have a GPA of 4.0 and 0.0, respectively.ResultsThe 4 most significant factors were Karnofsky performance status, number of brain metastases, extracranial metastases, and hemoglobin. The overall median survival was 12 months. Median survival for GPA groups 0-1.0, 1.5-2.0, 2.5-3, and 3.5-4.0 (% n = 25, 27, 30 and 17) was 4, 12, 17, and 35 months, respectively.ConclusionThe updated Renal GPA is a user-friendly tool that will help clinicians and patients better understand prognosis, individualize clinical decision making and treatment selection, provide a means to compare retrospective literature, and provide more robust stratification of future clinical trials in this heterogeneous population. To simplify use of this tool in daily practice, a free online application is available at brainmetgpa.com.