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Abstract tRNA modifications affect ribosomal elongation speed and co-translational folding dynamics. The Elongator complex is responsible for introducing 5-carboxymethyl at wobble uridine bases (cm5U34) in eukaryotic tRNAs. However, the structure and function of human Elongator remain poorly understood. In this study, we present a series of cryo-EM structures of human ELP123 in complex with tRNA and cofactors at four different stages of the reaction. The structures at resolutions of up to 2.9 Å together with complementary functional analyses reveal the molecular mechanism of the modification reaction. Our results show that tRNA binding exposes a universally conserved uridine at position 33 (U33), which triggers acetyl-CoA hydrolysis. We identify a series of conserved residues that are crucial for the radical-based acetylation of U34 and profile the molecular effects of patient-derived mutations. Together, we provide the high-resolution view of human Elongator and reveal its detailed mechanism of action.

Mpox is a zoonotic disease caused by monkeypox virus (MPXV) and previously found primarily in forested areas of Central and West Africa (2,2). In May 2022, a multicountry outbreak of [...]

On 31 December 2019, the Municipal Health Commission of Wuhan, China, reported a cluster of atypical pneumonia cases. On 5 January 2020, the WHO publicly released a Disease Outbreak News (DON) report, providing information about the pneumonia cases, implemented response interventions, and WHO’s risk assessment and advice on public health and social measures. Following 9 additional DON reports and 209 daily situation reports, on 17 August 2020, WHO published the first edition of the COVID-19 Weekly Epidemiological Update (WEU). On 1 September 2023, the 158th edition of the WEU was published on WHO’s website, marking its final issue. Since then, the WEU has been replaced by comprehensive global epidemiological updates on COVID-19 released every 4 weeks. During the span of its publication, the webpage that hosts the WEU and the COVID-19 Operational Updates was accessed annually over 1.4 million times on average, with visits originating from more than 100 countries. This article provides an in-depth analysis of the WEU process, from data collection to publication, focusing on the scope, technical details, main features, underlying methods, impact and limitations. We also discuss WHO’s experience in disseminating epidemiological information on the COVID-19 pandemic at the global level and provide recommendations for enhancing collaboration and information sharing to support future health emergency responses.

The 2022–2023 mpox outbreak predominantly affected adult men; 1.3% of reported cases were in children and adolescents

Following the emergence of SARS-CoV-2 in late 2019, transmission expanded globally and on 30 January 2020, COVID-19 was declared as a public health emergency of international concern. (1) Analysis of [...]

Background Globally, since 1 January 2020 and as of 24 January 2023, there have been over 664 million cases of COVID-19 and over 6.7 million deaths reported to WHO. WHO developed an evidence-based alert system, assessing public health risk on a weekly basis in 237 countries, territories and areas from May 2021 to June 2022. This aimed to facilitate the early identification of situations where healthcare capacity may become overstretched.Methods The process involved a three-stage mixed methods approach. In the first stage, future deaths were predicted from the time series of reported cases and deaths to produce an initial alert level. In the second stage, this alert level was adjusted by incorporating a range of contextual indicators and accounting for the quality of information available using a Bayes classifier. In the third stage, countries with an alert level of ‘High’ or above were added to an operational watchlist and assistance was deployed as needed.Results Since June 2021, the system has supported the release of more than US$27 million from WHO emergency funding, over 450 000 rapid antigen diagnostic testing kits and over 6000 oxygen concentrators. Retrospective evaluation indicated that the first two stages were needed to maximise sensitivity, where 44% (IQR 29%–67%) of weekly watchlist alerts would not have been identified using only reported cases and deaths. The alerts were timely and valid in most cases; however, this could only be assessed on a non-representative sample of countries with hospitalisation data available.Conclusions The system provided a standardised approach to monitor the pandemic at the country level by incorporating all available data on epidemiological analytics and contextual assessments. While this system was developed for COVID-19, a similar system could be used for future outbreaks and emergencies, with necessary adjustments to parameters and indicators.

Background: Contribution of dominance effects to cancer heritability is unknown. We leveraged existing genome-wide association data for seven cancers to estimate the contribution of dominance effects to the heritability of individual cancer types. Methods: We estimated the proportion of phenotypic variation caused by dominance genetic effects using genome-wide association data for seven cancers (breast, colorectal, lung, melanoma, nonmelanoma skin, ovarian, and prostate) in a total of 166,772 cases and 284,824 controls. Results: We observed no evidence of a meaningful contribution of dominance effects to cancer heritability. By contrast, additive effects ranged between 0.11 and 0.34. Conclusions: In line with studies of other human traits, the dominance effects of common genetic variants play a minimal role in cancer etiology. [ABSTRACT FROM AUTHOR]

Singe‐turnover active chlorophyll a fluorometry (STAF) can be used to assess phytoplankton photosynthetic rates in terms of the photosystem II photochemical flux (JVPII, μmol e− m−3 s−1) instantaneously, autonomously, and at high resolution. While JVPII provides an upper limit to rates of phytoplankton primary productivity in units of carbon fixation, the conversion between these two rates is variable, limiting our ability to utilize high‐resolution JVPII data to monitor phytoplankton primary productivity. Simultaneous measurements of JVPII and 14C‐fixation help in understanding the factors controlling the variable ratio between the two rates. However, to date, methodological inconsistencies, including differences in incubation lengths and light quality, have greatly inhibited practical assessment of such electron to carbon ratios (Φe,C, mol e− mol C−1). We here present data from a range of dual‐incubation experiments in northeast Atlantic waters during which JVPII and 14C‐fixation were measured simultaneously on the same sample. Time‐course experiments show how Φe,C increases with incubation length, likely reflecting the transition from gross to net 14C‐fixation. Dual‐incubation experiments conducted under different light levels show a tendency for increased Φe,C under (super‐)saturating light. Finally, data from a diurnal experiment demonstrate how Φe,C increases over the course of a day, due to downregulation of 14C‐fixation. We provide a detailed description of our methodological approach, including a critical discussion of improvements to the calculation of JVPII implemented in the LabSTAF instrument used for active fluorescence measurements and the limitations of the well‐established 14C‐fixation approach. [ABSTRACT FROM AUTHOR]

This study examined the mental fitness skills (MFS) of First Generation College Students (FGCS) and its relationship to psychological resilience and academic achievement with data from 286 students from a large regional university. Cluster analysis revealed four emergent MFS profile groups: (1) strong skills; (2) weak skills; (3) go with the flow; and (4) emotionally fragile clusters. FGCS in the strong skill profile group reported higher scores for a variety of indicators of psychological resilience than their peers in the other profile groups. We discuss the implications of our findings for theory, research and practice.

Abstract Background Risk assessment is essential to informed decision making in surgery. Preoperative use of the Surgical Risk Preoperative Assessment System (SURPAS) providing individualized risk assessment, may enhance informed consent. We assessed patient and provider perceptions of SURPAS as a risk assessment tool. Methods A convergent mixed-methods study assessed SURPAS’s trial implementation, concurrently collecting quantitative and qualitative data, separately analyzing it, and integrating the results. Patients and providers were surveyed and interviewed on their opinion of how SURPAS impacted the preoperative encounter. Relationships between patient risk and patient and provider assessment of SURPAS were examined. Results A total of 197 patients were provided their SURPAS postoperative risk estimates in nine surgeon’s clinics. Of the total patients, 98.8% reported they understood their surgical risks very or quite well after exposure to SURPAS; 92.7% reported SURPAS was very helpful or helpful. Providers shared that 83.4% of the time they reported SURPAS was very or somewhat helpful; 44.7% of the time the providers reported it changed their interaction with the patient and this change was beneficial 94.3% of the time. As patient risk increased, providers reported that SURPAS was increasingly helpful (p

Mediolateral patella displacement is of interest for diagnostics and clinically relevant research questions. Apart from manual testing, no standardized method is currently available. Proper quantification of patella mobility is necessary to better understand pathologies at the patellofemoral joint. Patella mobility was assessed in 25 healthy individuals using a Patellostabilometer, a new prototype instrument for quantification of the mediolateral patella displacement. The participants underwent measurements of the mediolateral displacement three times using the Patellostabilometer. A maximal force of 10 N was applied for patella movement. Additionally, leg length and circumference of the knee, upper- and lower-leg were measured. Lateral patella displacement of 18.27 ± 3.76 mm (range 15.85–20.64 mm, interquartile range (IQR) of 4.79) was measured. The medial patella displacement showed 24.47 ± 6.59 mm (range 19.29–29.76 mm, IQR of 10.47). The test–retest measurement error was 2.32 ± 1.76 mm (IQR of 2.38 mm), with five outliers. There was greater test–retest variability between the measurements of the medial displacement compared to the lateral one. The test–retest variability reached 7% of the patella displacement. Other parameters provided no significant correlations. Based on the natural patellofemoral mobility, a precise and clinically relevant quantification of patella mobility is allowed.

Abstract Background The Surgical Risk Preoperative Assessment System (SURPAS) is a parsimonious set of models providing accurate preoperative prediction of common adverse outcomes for individual patients. However, focus groups with surgeons and patients have developed a list of questions about and recommendations for how to further improve SURPAS’s usability and usefulness. Eight issues were systematically evaluated to improve SURPAS. Methods The eight issues were divided into three groups: concerns to be addressed through further analysis of the database; addition of features to the SURPAS tool; and the collection of additional outcomes. Standard multiple logistic regression analysis was performed using the 2005–2015 American College of Surgeons National Surgical Quality Improvement Participant Use File (ACS NSQIP PUF) to refine models: substitution of the preoperative sepsis variable with a procedure-related risk variable; testing of an indicator variable for multiple concurrent procedure codes in complex operations; and addition of outcomes to increase clinical applicability. Automated risk documentation in the electronic health record and a patient handout and supporting documentation were developed. Long term functional outcomes were considered. Results Model discrimination and calibration improved when preoperative sepsis was replaced with a procedure-related risk variable. Addition of an indicator variable for multiple concurrent procedures did not significantly improve the models. Models were developed for a revised set of eleven adverse postoperative outcomes that separated bleeding/transfusion from the cardiac outcomes, UTI from the other infection outcomes, and added a predictive model for unplanned readmission. Automated documentation of risk assessment in the electronic health record, visual displays of risk for providers and patients and an “About” section describing the development of the tool were developed and implemented. Long term functional outcomes were considered to be beyond the scope of the current SURPAS tool. Conclusion Refinements to SURPAS were successful in improving the accuracy of the models, while reducing manual entry to five of the eight variables. Adding a predictor variable to indicate a complex operation with multiple current procedure codes did not improve the accuracy of the models. We developed graphical displays of risk for providers and patients, including a take-home handout and automated documentation of risk in the electronic health record. These improvements should facilitate easier implementation of SURPAS.

Abstract Background Risk assessment in surgery is essential to guide treatment decisions but is highly variable in practice. Providing formal preoperative risk assessment to surgical teams and patients may optimize understanding of risk. Implementation of the Surgical Risk Preoperative Assessment System (SURPAS), an innovative real time, universal, preoperative tool providing individualized risk assessment, may enhance informed consent and reduce adverse outcomes. To ensure optimal development and implementation of SURPAS we performed an in-depth pre-implementation evaluation of SURPAS at an academic tertiary referral center in Colorado. Methods Four focus groups with 24 patients, three focus groups with 29 surgical providers and clinic administrators, and five individual interviews with administrative officials were conducted to elicit their perspectives about the development and implementation of SURPAS. Qualitative data collection and analyses, utilizing a Matrix Analysis approach were used to explore insights regarding SURPAS. Results Participants were positive about SURPAS and provided suggestions to improve and address concerns regarding it. For healthcare personnel three major themes emerged: 1) The SURPAS tool - Important work especially for high risk patients, yet not a substitute for clinical judgment; 2) Benefits of SURPAS to the risk assessment process - Improves the processes, enhances patients’ participation in shared decision-making process, and creates a permanent record; and 3) Facilitators and barriers of implementation of SURPAS - Easy to incorporate into clinical practice in spite of surgical providers’ resistance to adoption of new technology. For patients three major themes emerged: 1) Past experience of preoperative risk assessment discussions – Patients were not made aware of possible complications that occurred; 2) The SURPAS tool - All patients liked SURPAS and believed having printed material would be useful to guide discussions and facilitate remembering conversations with the providers; and 3) Potential concerns with having risk assessment information – Patients were mixed in deciding to have an operation with high risks. Conclusions Systematically capturing data from the beginning of the implementation process from key stakeholders (patients, surgical providers, clinical staff, and administrators) that includes adaptations to the tool and implementation process will help to inform pragmatic approaches for implementing the SURPAS tool in various settings, scaling-up, and sustaining it.