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PURPOSE: To design and build a new disease registry to track the natural history and outcomes of approved gene therapy in patients with inherited retinal diseases. METHODS: A core committee of six members was convened to oversee the construction of the Fight Inherited Retinal Blindness! module. A further 11 experts formed a steering committee, which discussed disease classification and variables to form minimum datasets using a consensus approach. RESULTS: The web-based Fight Inherited Retinal Blindness! registry records baseline demographic, clinical, and genetic data together with follow-up data. The Human Phenotype Ontology and Monarch Disease Ontology nomenclature were incorporated within the Fight Inherited Retinal Blindness! architecture to standardize nomenclature. The registry software assigns individual diagnoses to one of seven broad phenotypic groups, with minimum datasets dependent on the broad phenotypic group. In addition, minimum datasets were agreed on for patients undergoing approved gene therapy with voretigene neparvovec (Luxturna). New patient entries can be completed in 5 minutes, and follow-up data can be entered in 2 minutes. CONCLUSION: Fight Inherited Retinal Blindness! is an organized, web-based system that uses observational study methods to collect uniform data from patients with inherited retinal disease to track natural history and (uniquely) treatment outcomes. It is free to users who have control over their data.

Nearly forty years ago, Stenhouse argued that the function of the curriculum was to stimulate teachers' everyday reflection about and learning from practice. This suggestion, alongside his support for teachers as researchers, aligns with the Welsh Government's commitment to build an evidence-informed profession as part of ongoing major education system-level reforms, including the implementation of the new Curriculum for Wales from September 2022. University initial teacher education (ITE) partnerships are playing an important role in building collaborative research capacity. This paper describes a case study of one such partnership which aims to promote research-informed, reflective practice among its postgraduate primary student teachers. We use one of Stenhouse's principles of empirical study to frame our discussion of how student teachers' reflective practice is supported through brief conversations with their teacher educators (mentors) during lessons. Using a mixed methods approach, the findings show that student teachers value in-the-moment feedback. The intervention also helps them to question aspects of teaching and learning, although such reflection is at a technical level. Our study is useful for teacher educators who are interested in supporting reflective practice through coaching and mentoring. It also cautions school leaders and policymakers implementing major curriculum reforms not to lose sight of Stenhouse's view that 'it is teachers who, in the end, will change the world of the school by understanding it'. The paper concludes by discussing the research implications in shaping emerging practice and policy in the context of ongoing system-level reform and curriculum implementation in Wales, with potential applicability and portability to other contexts and jurisdictions.

PURPOSE: To describe the clinical, electrophysiological and genetic spectrum of inherited retinal diseases associated with variants in the PRPH2 gene. METHODS: A total of 241 patients from 168 families across 15 sites in 9 countries with pathogenic or likely pathogenic variants in PRPH2 were included. Records were reviewed for age at symptom onset, visual acuity, full-field ERG, fundus colour photography, fundus autofluorescence (FAF), and SD-OCT. Images were graded into six phenotypes. Statistical analyses were performed to determine genotype-phenotype correlations. RESULTS: The median age at symptom onset was 40 years (range, 4-78 years). FAF phenotypes included normal (5%), butterfly pattern dystrophy, or vitelliform macular dystrophy (11%), central areolar choroidal dystrophy (28%), pseudo-Stargardt pattern dystrophy (41%), and retinitis pigmentosa (25%). Symptom onset was earlier in retinitis pigmentosa as compared with pseudo-Stargardt pattern dystrophy (34 vs 44 years; P = 0.004). The median visual acuity was 0.18 logMAR (interquartile range, 0-0.54 logMAR) and 0.18 logMAR (interquartile range 0-0.42 logMAR) in the right and left eyes, respectively. ERG showed a significantly reduced amplitude across all components (P < 0.001) and a peak time delay in the light-adapted 30-Hz flicker and single-flash b-wave (P < 0.001). Twenty-two variants were novel. The central areolar choroidal dystrophy phenotype was associated with 13 missense variants. The remaining variants showed marked phenotypic variability. CONCLUSIONS: We described six distinct FAF phenotypes associated with variants in the PRPH2 gene. One FAF phenotype may have multiple ERG phenotypes, demonstrating a discordance between structure and function. Given the vast spectrum of PRPH2 disease our findings are useful for future clinical trials.

Abstract Supporting biodiversity conservation in an effective and sustainable way requires addressing biodiversity loss while satisfying the dependency of people on nature. Critical to this goal is to understand how the benefits and services delivered by ecosystems influence human values, and how these values can be leveraged to promote equitable economic, social and environmental outcomes. However, these values are challenging to capture in complex social‐ecological systems, particularly when the values are not consistent among different groups of stakeholders. We examined the values associated with Box Gum Grassy Woodland agro‐ecological systems in Australia, focusing on two key stakeholder groups that influence management decisions: farmers and ecological specialists. Using a state‐and‐transition model as a boundary object, we identified various dimensions of values—instrumental, intrinsic and relational—across four distinct states of the Box Gum Grassy Woodland: Grassy Woodland, Native Pastures, Crops and Sown/Fertilised Pastures and Revegetated Areas. We found that both groups of stakeholders identified multiple dimensions of values, although the intensity of values (i.e., the total number of values) associated with different states varied significantly—the values of ecological specialist respondents were concentrated in intact Grassy Woodlands, whereas the values of farmer respondents were concentrated in Native Pastures. These results demonstrate that ecological systems influence the values that are generated in human communities, and these values are likely to result in actions that may promote or diminish the presence of certain values. Characterising values and analysing their distribution between ecosystem states for different groups of stakeholders can offer valuable insights into the dynamics of human‐nature interactions and the values that influence human behaviour which can directly transform nature. Read the free Plain Language Summary for this article on the Journal blog.

Abstract The T-cell receptor (TCR)/CD3 complex plays an essential role in the immune response and is a key player in cancer immunotherapies. There are two classes of TCR/CD3 complexes, defined by their TCR chain usage (αβ or γδ). Recently reported structures have revealed the organization of the αβ TCR/CD3 complex, but similar studies regarding the γδ TCR/CD3 complex have lagged behind. Here, we report cryoelectron microscopy (cryoEM) structural analysis of two γδ TCRs, G115 (Vγ9 Vδ2) and 9C2 (Vγ5 Vδ1), in complex with CD3 subunits. Our results show that the overall subunit organization of the γδ TCR/CD3 complexes is similar to αβ TCRs. However, both γδ TCRs display highly mobile extracellular domains (ECDs), unlike αβ TCRs, which have TCR ECDs that are rigidly coupled to its transmembrane (TM) domains. We corroborate this finding in cells by demonstrating that a γδ T-cell specific antibody can bind a site that would be inaccessible in the more rigid αβ TCR/CD3 complex. Furthermore, we observed that the Vγ5 Vδ1 complex forms a TCR γ5 chain-mediated dimeric species whereby two TCR/CD3 complexes are assembled. Collectively, these data shed light on γδ TCR/CD3 complex formation and may aid the design of γδ TCR-based therapies.

Despite the growing numbers of dogs and cats cohabiting in US households, little research has focused on the influence of dogs on the human-animal bond of their feline roommates. The present study investigated whether cohabiting with a dog has an impact on the human-cat bond and the ways in which cats interact with humans. Based on existing knowledge of the differences between human-dog and human-cat interactions, we predicted that cats who have lived with a dog for at least 1 year will exhibit differences in the bond and interaction frequency with their owners. A 46-item survey was administered to 682 US cat owners via social media (SM) and Mechanical Turk (MTurk), Amazon’s crowdsourcing service, to collect data on demographics, interaction frequency, behavioral issues, and pet-owner bond. Although owners in cat-only households tended to report slightly higher bond scores with their cats ( μ SM = 30.34; μ Mturk = 28.32) than owners in mixed households ( μ SM = 29.33; μ Mturk = 27.42), the differences were small, and the association between household type and bond score was not significant (p SM = 0.973, p MTurk = 0.124). Owners who engaged in more frequent active interactions with their cats had higher bond scores. These results indicate that spending more time engaging in active interactions with one’s cat is associated with a stronger bond, and the frequency of these interactions may be more important than the presence of a cohabiting dog.

1 Leishmaniasis is a heterogeneous group of diseases caused by protozoan parasites of the genus Leishmania, transmitted by the bite of phlebotomine sand flies (1). The 3 typical clinical presentations [...]

Abstract Adoptive T-cell immunotherapy holds great promise for the treatment of viral complications in immunocompromised patients resistant to standard anti-viral strategies. We present a retrospective analysis of 78 patients from 19 hospitals across Australia and New Zealand, treated over the last 15 years with “off-the-shelf” allogeneic T cells directed to a combination of Epstein–Barr virus (EBV), cytomegalovirus (CMV), BK polyomavirus (BKV), John Cunningham virus (JCV) and/or adenovirus (AdV) under the Australian Therapeutic Goods Administration’s Special Access Scheme. Most patients had severe post-transplant viral complications, including drug-resistant end-organ CMV disease, BKV-associated haemorrhagic cystitis and EBV-driven post-transplant lymphoproliferative disorder. Adoptive immunotherapy is well tolerated with few adverse effects. Importantly, 46/71 (65%) patients show definitive clinical improvement including reduction in viral load, clinical symptoms and complete resolution of end-organ disease. In addition, seven high-risk patients remain disease free. Based on this long-term encouraging clinical experience, we propose that a dedicated nationally funded centre for anti-viral cellular therapies should be considered to provide T cell therapies for critically ill patients for compassionate use.

Coarctation of the aorta (CoA) is one of the most common types of congenital heart disease. Unfortunately, there is a high prevalence of hypertension and late cardiovascular mortality in patients with CoA despite successful repair. The growing impact of acquired cardiovascular disease remains a significant concern as the adult congenital heart disease population continues to rapidly expand and age. This review aims to explore (1) the determinants of vascular health and atherosclerosis including endothelial dysfunction and vascular wall abnormalities, (2) the prevalence of atherosclerosis and associated sequelae in repaired CoA including coronary artery disease, coronary artery calcium, aortic calcium, stroke, and peripheral artery disease, and (3) the contributing factors specific to CoA. This review aims to guide optimization of long-term cardiovascular health to ultimately reduce mortality and morbidity in this young high-risk population.

BackgroundZoonotic P. knowlesi and P. cynomolgi symptomatic and asymptomatic infections occur across endemic areas of Southeast Asia. Most infections are low-parasitemia, with an unknown proportion below routine microscopy detection thresholds. Molecular surveillance tools optimizing the limit of detection (LOD) would allow more accurate estimates of zoonotic malaria prevalence.Methodology/principal findingsAn established ultra-sensitive Plasmodium genus quantitative-PCR (qPCR) assay targeting the 18S rRNA gene underwent LOD evaluation with and without reverse transcription (RT) for P. knowlesi, P. cynomolgi and P. vivax using total nucleic acid preserved (DNA/RNA Shield) isolates and archived dried blood spots (DBS). LODs for selected P. knowlesi-specific assays, and reference P. vivax- and P. cynomolgi-specific assays were determined with reverse transcription (RT). Assay specificities were assessed using clinical malaria samples and malaria-negative controls. The use of reverse transcription improved Plasmodium species detection by up to 10,000-fold (Plasmodium genus), 2759-fold (P. knowlesi) and 1000-fold (P. vivax and P. cynomolgi). The Kamau et al. Plasmodium genus RT-qPCR assay was highly sensitive for P. knowlesi detection with a median LOD of ≤0.0002 parasites/μL compared to 0.002 parasites/μL for P. cynomolgi and P. vivax. The LODs with RT for P. knowlesi-specific PCRs were enhanced for the Imwong et al. 18S rRNA (0.0007 parasites/μL) and Divis et al. real-time 18S rRNA (0.0002 parasites/μL) assays, but not for the Lubis et al. hemi-nested SICAvar (1.1 parasites/μL) and Lee et al. nested 18S rRNA (11 parasites/μL). The LOD for P. vivax- and P. cynomolgi-specific assays with RT were moderately improved at 0.02 and 0.002 parasites/μL, respectively (1000-fold change). For DBS P. knowlesi samples the use of RT also markedly improved the Plasmodium genus qPCR LOD from 19.89 to 0.08 parasites/μL (249-fold change); no LOD improvement was demonstrated in DBS archived beyond 6 years. The Plasmodium genus and P. knowlesi-assays were 100% specific for Plasmodium species and P. knowlesi detection, respectively, from 190 clinical infections and 48 healthy controls. Reference P. vivax-specific primers demonstrated known cross-reactivity with P. cynomolgi.Conclusions/significanceOur findings support the use of an 18S rRNA Plasmodium genus qPCR and species-specific nested PCR protocol with RT for highly-sensitive surveillance of zoonotic and human Plasmodium species infections.

Objective: Sexual and gender minority (SGM) populations experience health disparities compared to heterosexual and cisgender populations. The development of accurate, comprehensive sexual orientation and gender identity (SOGI) measures is fundamental to quantify and address SGM disparities, which first requires identifying SOGI-related research. As part of a larger project reviewing and synthesizing how SOGI has been assessed within the health literature, we provide an example of the application of automated tools for systematic reviews to the area of SOGI measurement. Methods: In collaboration with research librarians, a three-phase approach was used to prioritize screening for a set of 11,441 SOGI measurement studies published since 2012. In Phase 1, search results were stratified into two groups (title with vs. without measurement-related terms); titles with measurement-related terms were manually screened. In Phase 2, supervised clustering using DoCTER software was used to sort the remaining studies based on relevance. In Phase 3, supervised machine learning using DoCTER was used to further identify which studies deemed low relevance in Phase 2 should be prioritized for manual screening. Results: 1,607 studies were identified in Phase 1. Across Phases 2 and 3, the research team excluded 5,056 of the remaining 9,834 studies using DoCTER. In manual review, the percentage of relevant studies in results screened manually was low, ranging from 0.1 to 7.8 percent. Conclusions: Automated tools used in collaboration with research librarians have the potential to save hundreds of hours of human labor in large-scale systematic reviews of SGM health research.

We evaluated immune cell subsets in patients with chronic lymphocytic leukemia (CLL) who received first-line therapy with 3 cycles of ibrutinib then 13 cycles of ibrutinib plus venetoclax in the minimal residual disease (MRD) cohort of the CAPTIVATE study (NCT02910583). Patients with Confirmed undetectable MRD (uMRD) were randomly assigned to placebo or ibrutinib groups; patients without Confirmed uMRD were randomly assigned to ibrutinib or ibrutinib plus venetoclax groups. We compared immune cell subsets in samples collected at 7 time points with age-matched healthy donors. CLL cells decreased within 3 cycles after venetoclax initiation; from cycle 16 onward, levels were similar to healthy donor levels (HDL; ≤0.8 cells per μL) in patients with Confirmed uMRD and slightly above HDL in patients without Confirmed uMRD. By 4 months after cycle 16, normal B cells had recovered to HDL in patients randomly assigned to placebo. Regardless of randomized treatment, abnormal counts of T cells, classical monocytes, and conventional dendritic cells recovered to HDL within 6 months (median change from baseline -49%, +101%, and +91%, respectively); plasmacytoid dendritic cells recovered by cycle 20 (+598%). Infections generally decreased over time regardless of randomized treatment and were numerically lowest in patients randomly assigned to placebo within 12 months after cycle 16. Sustained elimination of CLL cells and recovery of normal B cells were confirmed in samples from patients treated with fixed-duration ibrutinib plus venetoclax in the GLOW study (NCT03462719). These results demonstrate promising evidence of restoration of normal blood immune composition with ibrutinib plus venetoclax.

Multiple sclerosis (MS) is a complex disease of the CNS thought to require an environmental trigger. Gut dysbiosis is common in MS, but specific causative species are unknown. To address this knowledge gap, we used sensitive and quantitative PCR detection to show that people with MS were more likely to harbor and show a greater abundance of epsilon toxin-producing (ETX-producing) strains of C. perfringens within their gut microbiomes compared with individuals who are healthy controls (HCs). Isolates derived from patients with MS produced functional ETX and had a genetic architecture typical of highly conjugative plasmids. In the active immunization model of experimental autoimmune encephalomyelitis (EAE), where pertussis toxin (PTX) is used to overcome CNS immune privilege, ETX can substitute for PTX. In contrast to PTX-induced EAE, where inflammatory demyelination is largely restricted to the spinal cord, ETX-induced EAE caused demyelination in the corpus callosum, thalamus, cerebellum, brainstem, and spinal cord, more akin to the neuroanatomical lesion distribution seen in MS. CNS endothelial cell transcriptional profiles revealed ETX-induced genes that are known to play a role in overcoming CNS immune privilege. Together, these findings suggest that ETX-producing C. perfringens strains are biologically plausible pathogens in MS that trigger inflammatory demyelination in the context of circulating myelin autoreactive lymphocytes.

Purpose: To describe the clinical and imaging characteristics of the acute progressive phase of a recently proposed clinical entity, Multizonal Outer Retinopathy and Retinal Pigment Epitheliopathy (MORR), a variant of Acute Zonal Occult Outer Retinopathy (AZOOR) Methods: Single observational case report. Results: We present the case of a 49-year-old myopic female with progressive outer retinopathy most consistent with a diagnosis of MORR. Through multimodal imaging and longitudinal follow-up, we delineate the clinical course and imaging findings of asymmetrical episodic progressive centrifugal extension of retinal pigment epithelial disturbance in both eyes, highlighting the features of an acute progressive episode not previously described. Conclusions: Clinicians should be aware of the active clinical and multimodal imaging features of MORR and its distinction from other outer retinopathies due to its sight-threatening distinct clinical course, bilateral involvement with peripapillary lesions, and episodic progression into the macula. Additionally, we describe a “grass-fire” and “spot-fire” progression pattern during acute exacerbation, highlighting the need for vigilant monitoring and early intervention in MORR.