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Visual function benefit after treatment with pegcetacoplan: microperimetry analysis from the Phase 3 Oaks Trial Microperimetry: visual function benefit with pegcetacoplan
No full textPurpose To evaluate the impact of pegcetacoplan on its ability to slow the loss of visual function using microperimetry endpoints in eyes with geographic atrophy secondary to age-related macular degeneration (AMD). Design Post hoc analysis of phase 3 randomized controlled trial data. Methods Utilizing data from the OAKS study, which evaluated pegcetacoplan monthly (PM) or every other month (PEOM) versus sham for the treatment of GA secondary to AMD, microperimetry endpoints were assessed at baseline and every 6 months until 24 months, using a 10-2 grid composed of 68 points with a 4-2 threshold strategy. Main outcome measures included the time to development of absolute scotomas in the 4 and 16 central macular points. The number of absolute scotomatous points and mean retinal sensitivity (dB) within the junctional zone extending to 250 µm on either side of autofluorescence-determined GA border was analyzed for change from baseline. Results Among 605 patients with subfoveal or nonsubfoveal GA, treatment with pegcetacoplan delayed time to development of absolute scotomas of all 4 central macular points compared to sham at 24 months (PM: hazard ratio [HR]: 0.66 [34% risk reduction]; 95% confidence interval [CI]: 0.46, 0.96; p = 0.0282; PEOM: HR: 0.64 [36% risk reduction]; 95% CI: 0.44, 0.92; p = 0.0164). Similarly, PM and PEOM treatment delayed time to development of absolute scotomas of all 16 central points (PM: HR: 0.57 [43% risk reduction]; 95% CI: 0.33, 0.96; p = 0.0361; PEOM: HR: 0.52 [48% risk reduction]; 95% CI: 0.32, 0.85; p = 0.0084). Across the junctional zone of GA, pegcetacoplan-treated eyes developed fewer absolute scotomatous points (PM difference vs sham pooled: -0.68 points, p = 0.1444; PEOM difference vs sham pooled: -1.14 points, p = 0.0140) and experienced decreased loss of mean retinal sensitivity (PM difference vs sham pooled: 0.56 dB, p = 0.0650; PEOM difference vs sham pooled: 0.71 dB, p = 0.0202) compared with sham at 24 months. Conclusions Microperimetry demonstrates a reduced rate of visual function loss in the central macula and junctional zone with pegcetacoplan treatment in GA due to AMD
Genomic context analysis enables the discovery of an unusual NAD ‐dependent racemase in phosphonate catabolism
No full textPhosphonates are organic molecules containing a direct carbon–phosphorus (C–P) bond. They are chemically sturdy compounds that can, however, be degraded by environmental microorganisms. In the frame of bacterial phosphonate catabolism, we recently reported the discovery of (R)‐1‐hydroxy‐2‐aminoethylphosphonate ammonia‐lyase (PbfA), a lyase acting on the natural compound (R)‐2‐amino‐1‐hydroxyethylphosphonate (R‐HAEP). PbfA converts R‐HAEP into phosphonoacetaldehyde (PAA), which can be subsequently processed and cleaved by further enzymes. However, PbfA is not active toward S‐HAEP (the enantiomer of R‐HAEP), whose metabolic fate remained unknown. We now describe the identification of a racemase, discovered through genomic context analysis, which converts S‐HAEP into R‐HAEP, thereby enabling degradation of S‐HAEP. We propose for this enzyme the official name 2‐amino‐1‐hydroxyethylphosphonate racemase (shorthand PbfF). To our knowledge, PbfF is the first NAD‐dependent racemase ever described and is structurally unrelated to other known NAD‐dependent isomerases. The enzyme uses NAD+ as a cofactor, is inhibited by NADH, and shows catalytic parameters comparable to those of other racemases acting on similar substrates. The presence of a pathway for the breakdown of S‐HAEP in numerous bacteria suggests that this compound may be more common in the environment than currently appreciated. Notably, the route for S‐HAEP degradation appears to have developed through a mechanism of retrograde metabolic evolution
Contextual influences on adaptation in four types of hospital teams: An ethnographic study
No full textHealthcare quality and safety efforts increasingly focus on understanding how complex systems adapt to maintain operations during disruptions. This paper explores team adaptation within hospitals, examining how different types of teams respond to misalignments between demand and capacity. To explore whether different types of teams experience different types of demand capacity misalignments, and whether and how teams differ in how they adapt. The overall goal was to identify whether and how different types of teams might have different requirements to support their adaptive capacity and system resilience. This study used ethnographic observations to collect data from five wards in a large London hospital: two surgical wards, an older adult ward, a critical care unit, and the Acute Assessment Unit (AAU) specifically designed to expedite patient flow from the Emergency Department. A typology of hospital teams and the CARE Model 2.0 framework were used to analyse misalignments and adaptations. All team types experienced misalignments, but their adaptations in response to misalignments varied. Team design, structure, and membership influenced adaptation strategies. Structural and satellite teams, with stable membership, had fewer misalignments and coordinated adaptations effectively. Hybrid teams, with both stable and unstable members, were more vulnerable due to their fragmented interactions. Coordinating teams, integrating representatives from multiple areas, faced challenges due to conflicting priorities and information changes. Different hospital teams adapt in different ways to misalignments. Team features influence adaptation strategies. Designing and supporting adaptive teams is crucial for improving healthcare quality and safety. Future research should focus on adaptive teamwork and explore interventions to enhance team adaptive capacity
Bioactivity evaluation of peptide QUB-2511 from the skin secretion of the Fukien gold-striped pond frog,<i> Pelophylax plancyi fukienensis</i>
No full textThe radio flare and multiwavelength afterglow of the short GRB 231117A: energy injection from a violent shell collision
No full textWe present the early radio detection and multiwavelength modeling of the short gamma-ray burst (GRB) 231117A at redshift z = 0.257. The Australia Telescope Compact Array automatically triggered a 9 hr observation of GRB 231117A at 5.5 and 9 GHz following its detection by the Neil Gehrels Swift Observatory just 1.3 hr post-burst. Splitting this observation into 1 hr time bins, the early radio afterglow exhibited flaring, scintillating and plateau phases. The scintillation allowed us to place the earliest upper limit ( 35 to Γ > 5 between ∼0.1 and 1 day. These results demonstrate the importance of rapid and sensitive radio follow-up of GRBs for exploring their central engines and outflow behaviour
Correlation between P53 immunohistochemical staining and TP53 molecular testing in endometrial carcinomas: a detailed assessment of discrepant cases with implications for patient management
No full textAimsThe 2013 Cancer Genome Atlas (TCGA) study identified four molecular types of endometrial carcinoma (EC) that are prognostic and predictive of therapy response. The p53 abnormal (p53abn) group of tumours is associated with aggressive clinical behaviour, chemoresponsiveness and generally high-grade histology. p53abn tumours may be identified by p53 immunohistochemical staining (a surrogate marker) or molecular testing. In this study, we evaluated the concordance between p53 immunohistochemistry and TP53 molecular testing in a consecutive cohort of ECs from a population-based setting. Our aim was to investigate the rate of concordance and reasons for discordance between the immunohistochemistry and molecular testing and to provide recommendations for pathologists and clinicians dealing with these discordant cases.Methods and resultsA total of 386 ECs were included where all biopsy specimens underwent molecular testing using a next-generation sequencing (NGS) panel (including POLE and TP53 genes and MSI testing) and immunohistochemistry for oestrogen receptor (ER), p53 and mismatch repair (MMR) proteins. Concordance between p53 immunohistochemistry and TP53 NGS was initially 88.6% (discordance of 11.4%) following review of the pathology and molecular reports; most of the discordant cases comprised carcinomas with wild-type p53 immunohistochemistry but TP53 mutations identified on NGS. The discordance reduced to 6.5% after review of the p53 stained slides, which revealed subclonal mutation-type staining in some tumours, and to 5% after excluding POLE mutated and mismatch repair deficient carcinomas. However, there remained a small cohort of 19 POLE wild-type/MMR proficient carcinomas (8 low-grade endometrioid, 9 high-grade endometrioid, 2 carcinosarcomas), with wild-type p53 staining but with TP53 mutations on NGS. Altogether, there were 12 POLE wild-type/MMR proficient low-grade endometrioid carcinomas with TP53 mutations on NGS; all were stage I (11 IA, 1 IB).ConclusionsOur study demonstrated a good overall concordance between p53 immunohistochemical staining and TP53 molecular results. The concordance can be increased by reviewing the p53 stained slides in discrepant cases but there remains a small cohort of cases, mostly low-grade endometrioid carcinomas (POLE wild-type/MMR proficient), where TP53 mutations are present on NGS but p53 immunohistochemistry is wild-type. Such cases present a dilemma for the pathologist (which TCGA group should they be placed into) and the clinician (should adjuvant therapy be instigated based on the presence of a TP53 mutation alone with no other adverse features). For now, we advise classifying such cases as p53abn but not to administer adjuvant therapy based on the presence of a TP53 mutation alone without other adverse pathological factors. The significance of TP53 mutations in such cases should be determined by larger studies with long-term follow-up
National identification and trust in institutions: understanding lower COVID-19 vaccination uptake among ethnic minorities in Europe
No full textCOVID-19 vaccine hesitancy among ethnic minority groups presents a public health challenge. However, there is limited understanding as to why ethnic minorities often exhibit lower levels of vaccine uptake. This study investigates the role of national identification and institutional trust in explaining differences in COVID-19 vaccine uptake between majority and minority ethnic groups. Using a large, cross-national dataset of 20 European countries (N = 31 240), we conducted multilevel structural equation modelling to assess the impact of ethnic identification on COVID-19 vaccine uptake, mediated by national identification and trust in institutions. Our findings revealed significant group differences, with minority group members reporting lower levels of national identification, trust in institutions and COVID-19 vaccine uptake compared to majority group members. We also found that ethnic identification indirectly influences COVID-19 vaccine uptake through national identification and trust in institutions. Specifically, people from minority ethnic groups tend to report lower levels of national identification, which makes them less likely to trust institutions. This lower level of trust, in turn, reduces their likelihood of COVID-19 vaccine uptake. Our findings underscore the importance of fostering inclusive national identities and building institutional trust to reduce COVID-19 vaccine hesitancy among ethnic minorities. Public health strategies that address these social dynamics are essential for increasing vaccination rates and ensuring equitable health outcomes across diverse populations
The Xinhai Revolution in the Irish press: the birth of the Republic of China as a medium of the Easter Rising debate
No full textIreland played an important role to end the British Empire. At the Paris Peace Conference in 1919, the discussions were bringing to the forefront the malaise of many subjugated people, the racial discrimination was still rampant and the unequal treatment among winners was evident even though the peace talking process was going to establish one of the most modern and still very actual institution, the League of Nations. The paper compares the Xinhai Revolution to the Easter Rising scrutinizing the Irish newspapers to assess the Irish reaction to the Chinese revolutionary cause, and so it focuses on: nationalism vs. imperialism, the reformist and the revolutionary reaction, the revolutionaries, the use of violence as a legitimated political tool, the revolutions, the republic and the war, the politicization of the masses, World War One and the Paris Peace Conference, and the economic interests at stake
Microstructure, porosity, and bending fatigue behaviour of PBF-LB/M SS316L for biomedical applications
No full textBending fatigue significantly affects the mechanical stability and lifespan of biomedical implants, such as bone plates and orthopaedic fixation devices, which undergo cyclic loading in the human body. This study examines the microstructure, porosity, and bending fatigue properties of PBF-LB/M SS316L. Samples were analysed across three faces (top, front, and side) using optical microscopy (OM) and scanning electron microscopy (SEM) to observe microstructural features and porosity. Elemental composition was measured by energy-dispersive X-ray spectroscopy (EDX). Phase structures and grain orientations were characterised via X-ray diffraction (XRD) and electron backscatter diffraction (EBSD). Four-point bending fatigue tests, conducted under two loading conditions, below and slightly above the yield point, demonstrated that defects inherent to the PBF-LB/M process, particularly micropores and unmelted powder particles, strongly influence fatigue crack initiation. Real-time monitoring of crack initiation and propagation on the external sample surface was performed using a high-speed digital microscope. These findings indicate the influence of microstructural defects on fatigue performance in PBF-LB/M SS316L, supporting the design and development of more reliable patient-specific biomedical implants
