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Abstract: Variances in global access to drugs and treatment practices make it challenging to understand the benefit of contemporary therapies in patients with relapsed and refractory (R/R) mature T-cell and natural killer–cell lymphomas (MTCL and MNKCL). We conducted an international retrospective cohort study of 925 patients with R/R MTCL and MNKCL. In peripheral T-cell lymphoma–not otherwise specified and anaplastic lymphoma kinase–negative anaplastic large cell lymphoma (ALK– ALCL), patients with relapsed lymphoma demonstrated a superior median overall survival (OS) relative to refractory from the time of second-line treatment. We identified several independent predictors of OS for R/R lymphoma including age >60 years, primary refractory disease, histological subtype other than angioimmunoblastic T-cell lymphoma (AITL), extranodal sites >1, Ki67 ≥40%, and absolute lymphocyte count less than the lower limit of normal. A multivariable model incorporating these formed the basis for a prognostic index for R/R TCL, in which patients are stratified into low-risk (0-1 risk factor), intermediate-risk (2-3 risk factors), or high-risk (≥4 risk factors) groups, which were associated with 3-year OS of 57.14%, 23.3%, and 7%, respectively. Patients received either a ''novel'' single agent (SA; 35%) or cytotoxic chemotherapy (CC; 60%) for their second-line treatment. Higher progression-free survival was observed with SA over CC for the entire cohort with a higher 3-year OS in AITL and ALK– ALCL. Among the SA, small-molecule inhibitors demonstrated OS advantage relative to CC in AITL. Our results highlight continued efficacy of novel drugs globally and the potential of a new prediction model in informing heterogeneous prognosis within the R/R population of MTCL and MNKCL.

Fuego, an active volcano in Guatemala, explodes regularly and generates powerful infrasound for which amplitude regularly exceeds 10 Pa at 10 km where rural communities are located. This study focuses on infrasound recorded at the Fuego Volcano Observatory, a ∼250 m3 building located ∼8 km from the vent. Records from infrasound sensors deployed on either side of a wall facing the volcano were used to measure differential dynamic pressures of more than 50 Pa imparted to the wall facing the volcano. We calculated the building’s infrasonic response as a function of frequency for situations where interior doors were both open and closed and found a remarkably well-defined ∼7.5 Hz tone induced by acoustic oscillations when the interior door was open. The transfer functions, from a week-long period of recording and 34 explosions, show that closing internal doors diminishes infrasonic resonance and could potentially reduce window damage.

Abstract Progressive supranuclear palsy (PSP), a rare Parkinsonian disorder, is characterized by problems with movement, balance, and cognition. PSP differs from Alzheimer’s disease (AD) and other diseases, displaying abnormal microtubule-associated protein tau by both neuronal and glial cell pathologies. Genetic contributors may mediate these differences; however, the genetics of PSP remain underexplored. Here we conduct the largest genome-wide association study (GWAS) of PSP which includes 2779 cases (2595 neuropathologically-confirmed) and 5584 controls and identify six independent PSP susceptibility loci with genome-wide significant (P

Abstract The biological aspects of infancy within late Upper Palaeolithic populations and the role of southern refugia at the end of the Last Glacial Maximum are not yet fully understood. This study presents a multidisciplinary, high temporal resolution investigation of an Upper Palaeolithic infant from Grotta delle Mura (Apulia, southern Italy) combining palaeogenomics, dental palaeohistology, spatially-resolved geochemical analyses, direct radiocarbon dating, and traditional anthropological studies. The skeletal remains of the infant – Le Mura 1 – were directly dated to 17,320-16,910 cal BP. The results portray a biological history of the infant’s development, early life, health and death (estimated at ~72 weeks). They identify, several phenotypic traits and a potential congenital disease in the infant, the mother’s low mobility during gestation, and a high level of endogamy. Furthermore, the genomic data indicates an early spread of the Villabruna-like components along the Italian peninsula, confirming a population turnover around the time of the Last Glacial Maximum, and highlighting a general reduction in genetic variability from northern to southern Italy. Overall, Le Mura 1 contributes to our better understanding of the early stages of life and the genetic puzzle in the Italian peninsula at the end of the Last Glacial Maximum.

IntroductionValidated models describing the biomechanics of tooth extraction are scarce. This study seeks to perform experimental and numerical characterization of vertical tooth extraction biomechanics in swine incisors with imposed vertical extraction loads. Imaging analysis related mechanical outcomes to tooth geometry and applied loading rate. Then, the predictive capabilities of the developed finite element analysis (FEA) models were demonstrated by testing different loading scenarios and validating the results against experimental equivalents.MethodsSimulated vertical extractions were performed on partial swine central incisors (n = 49) and studied for peak extraction force and dental complex stiffness. Post-extraction µCT images were obtained to measure root surface attachment area (RSAA) and observe patterns of periodontal ligament (PDL) rupture. Crosshead force-displacement data was used in an inverse finite element analysis (IFEA) to verify parameters for the PDL in an axisymmetric model of tooth extraction. New force-hold loading protocols were devised in silico and validated in a series of tests on swine incisors to demonstrate the predictive efficacy of the finite element model. Force-hold loading on an initially-damaged PDL was also simulated.ResultsReductions in loading rate and RSAA were found to significantly reduce peak extraction forces by 98N–120 N. Increases in instantaneous stiffness during loading were associated with increases in loading rate. Inverse finite element solutions demonstrated consistent PDL parameters across loading cases. Force-hold loading predicted extraction behaviour with large variance in extraction time. Damage imposed in the FEA model was able to predict experimental results from experiments on similarly-damaged dental complexes.ConclusionThis study presents a comprehensive experimental and numerical characterization of vertical tooth extraction biomechanics employing an ex vivo swine model. The results of these experiments suggest that the axisymmetric FEA model is a powerful tool for predicting a range of conditions and dental complex geometries. The predictive power of the FEA model demonstrated in this study encourages its use in pre-clinical testing and development of new vertical extraction loading schemes for improving clinical outcomes.

There are about two billion people suffered malnourished because of the failing global food system, historical emphasis on crop yield, notably lacking in Fe and Zn. Breeding biofortified staple crops is a sustainable strategy to tackle this issue, but it poses challenges, primarily due to limited genetic resources in modern breeding populations. Simultaneously, global climate change, marked by rising temperatures and increased atmospheric CO2, threatens the stability of micronutrient concentrations in harvest organs, such as gain, fruit, root, tubers etc. The rich biodiversity of crop wild relatives, including wild species, landraces, and natives, offers a promising genetic response to climate change. Advanced breeding technologies, like marker-assisted selection breeding, genomic selection, gene editing provide opportunities to enhance Fe and Zn concentrations in staple crops, such as rice, maize, wheat, cassava, etc. Genome-wide association studies and population genetics research will help found qualitative genes and major-effect homeostasis genes for Fe and Zn, which purpose is to uncover the molecular mechanisms governing Fe and Zn regulation in staple crops. Despite these strides, enhancing Fe and Zn bioavailability for human, requires considering absorption enhancers and inhibitors, rather than solely increasing concentrations. Absorption testing systems like the Caco-2 cell line, elucidating the meta-process of Fe and Zn absorption in the human body should be considered when breeding Fe and Zn biofortified crops through traditional and molecular breeding.

Abstract Background Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). Method In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. Results Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer’s disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10–3) in PSP. Conclusions Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

Abstract Algal biomass is a viable source of chemicals and metabolites for various energy, nutritional, medicinal and agricultural uses. While stresses have commonly been used to induce metabolite accumulation in microalgae in attempts to enhance high-value product yields, this is often very detrimental to growth. Therefore, understanding how to modify metabolism without deleterious consequences is highly beneficial. We demonstrate that low-doses (1–5 Gy) of ionizing radiation in the X-ray range induces a non-toxic, hormetic response in microalgae to promote metabolic activation. We identify specific radiation exposure parameters that give reproducible metabolic responses in Chlorella sorokiniana caused by transcriptional changes. This includes up-regulation of >30 lipid metabolism genes, such as genes encoding an acetyl-CoA carboxylase subunit, phosphatidic acid phosphatase, lysophosphatidic acid acyltransferase, and diacylglycerol acyltransferase. The outcome is an increased lipid yield in stationary phase cultures by 25% in just 24 hours, without any negative effects on cell viability or biomass.

Abstract The Aurignacian is the first European technocomplex assigned to Homo sapiens recognized across a wide geographic extent. Although archaeologists have identified marked chrono-cultural shifts within the Aurignacian mostly by examining the techno-typological variations of stone and osseous tools, unraveling the underlying processes driving these changes remains a significant scientific challenge. Scholars have, for instance, hypothesized that the Campanian Ignimbrite (CI) super-eruption and the climatic deterioration associated with the onset of Heinrich Event 4 had a substantial impact on European foraging groups. The technological shift from the Protoaurignacian to the Early Aurignacian is regarded as an archaeological manifestation of adaptation to changing environments. However, some of the most crucial regions and stratigraphic sequences for testing these scenarios have been overlooked. In this study, we delve into the high-resolution stratigraphic sequence of Grotta di Castelcivita in southern Italy. Here, the Uluzzian is followed by three Aurignacian layers, sealed by the eruptive units of the CI. Employing a comprehensive range of quantitative methods—encompassing attribute analysis, 3D model analysis, and geometric morphometrics—we demonstrate that the key technological feature commonly associated with the Early Aurignacian developed well before the deposition of the CI tephra. Our study provides thus the first direct evidence that the volcanic super-eruption played no role in this cultural process. Furthermore, we show that local paleo-environmental proxies do not correlate with the identified patterns of cultural continuity and discontinuity. Consequently, we propose alternative research paths to explore the role of demography and regional trajectories in the development of the Upper Paleolithic.

Background Hospital ‘command centres’ use digital technologies to collect, analyse and present real-time information that may improve patient flow and patient safety. Bradford Royal Infirmary has trialled this approach and presents an opportunity to evaluate effectiveness to inform future adoption in the United Kingdom. Objective To evaluate the impact of the Bradford Command Centre on patient care and organisational processes. Design A comparative mixed-methods study. Operational data from a study and control site were collected and analysed. The intervention was observed, and staff at both sites were interviewed. Analysis was grounded in a literature review and the results were synthesised to form conclusions about the intervention. Setting The study site was Bradford Royal Infirmary, a large teaching hospital in the city of Bradford, United Kingdom. The control site was Huddersfield Royal Infirmary in the nearby city of Huddersfield. Participants Thirty-six staff members were interviewed and/or observed. Intervention The implementation of a digitally enabled hospital command centre. Main outcome measures Qualitative perspectives on hospital management. Quantitative metrics on patient flow, patient safety, data quality. Data sources Anonymised electronic health record data. Ethnographic observations including interviews with hospital staff. Cross-industry review including relevant literature and expert panel interviews. Results The Command Centre was implemented successfully and has improved staff confidence of better operational control. Unintended consequences included tensions between localised and centralised decision-making and variable confidence in the quality of data available. The Command Centre supported the hospital through the COVID-19 pandemic, but the direct impact of the Command Centre was difficult to measure as the pandemic forced all hospitals, including the study and control sites, to innovate rapidly. Late in the study we learnt that the control site had visited the study site and replicated some aspects of the command centre themselves; we were unable to explore this in detail. There was no significant difference between pre- and post-intervention periods for the quantitative outcome measures and no conclusive impact on patient flow and data quality. Staff and patients supported the command-centre approaches but patients expressed concern that individual needs might get lost to ‘the system’. Conclusions Qualitative evidence suggests the Command Centre implementation was successful, but it proved challenging to link quantitative evidence to specific technology interventions. Staff were positive about the benefits and emphasised that these came from the way they adapted to and used the new technology rather than the technology per se. Limitations The COVID-19 pandemic disrupted care patterns and forced rapid innovation which reduced our ability to compare study and control sites and data before, during and after the intervention. Future work We plan to follow developments at Bradford and in command centres in the National Health Service in order to share learning. Our mixed-methods approach should be of interest to future studies attempting similar evaluation of complex digitally enabled whole-system changes. Study registration The study is registered as IRAS No.: 285933. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: NIHR129483) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 41. See the NIHR Funding and Awards website for further award information. Plain language summary Safety-critical industries like airports often use ‘command centres’ to manage operations safely and efficiently. In contrast, most National Health Service hospitals have operational management that is fragmented across many departments and poorly co-ordinated. This may pose risks to the safety and care of patients and may partially explain excessive waiting times. Bradford Royal Infirmary is one of the first National Health Service hospitals to try out a command-centre approach using new digital technologies. Hospital staff at Bradford now work together in a purpose-built Command Centre room and monitor a ‘wall of analytics’ that displays real-time data from the hospital’s information systems. This study examines the implementation at Bradford in order to learn lessons that may help the National Health Service improve the way hospitals provide safe and efficient patient care. We reviewed what is known about the approach, analysed hospital data, observed teams working in the Command Centre, interviewed staff and ran workshops with patients. We also compared Bradford with a similar hospital that did not initially have a command centre. Our results showed the Bradford Command Centre does work. Staff told us the Command Centre helped them manage the hospital through the COVID-19 pandemic. Staff described how they used the new technology to improve efficiency and safety. We observed some challenges, including tension between the central team and local departments and concerns to make sure data were good quality. We could not measure the direct impact of the Command Centre on patient flow and safety using the hospital’s data because the pandemic disrupted normal operations so much. Patients expressed strong support for what they saw as modern methods but were concerned to ensure that the National Health Service tradition of personal care was preserved. Other National Health Service hospitals are interested in following a command-centre approach and our results should help them to learn from Bradford. Scientific summary Background A hospital command centre (CC) is a new approach to the management of hospital operations based on the colocation of decision-making staff and supported by digital technology to provide these staff with close to real-time information. Recent adoption of hospital CCs in the USA predominantly has demonstrated that the approach can be applied to manage hospital operations, despite their complexity. The supporting technology often includes decision-support algorithms that trigger digital notifications and alerts that identify potential safety or flow issues. These algorithms may be based on simple rules or more complex rules generated by machine learning from historic data, and the software technology has therefore been described as AI, meaning either artificial intelligence or, more accurately, augmented intelligence. In the UK, the implementation of a CC and associated technology by Bradford Teaching Hospitals NHS Trust represents a first of type for the UK NHS. To date, there has been limited evidence of the effectiveness of the CC approach and this study aims to address that evidence gap. Bradford Teaching Hospitals NHS Trust manages Bradford Royal Infirmary, an 800-bed NHS hospital located in Bradford in northern England. The Bradford Hospital Command Centre was implemented at Bradford Royal Infirmary through a phased approach in late 2019, was operational through the COVID-19 pandemic, and remains operational to date. It is designed to integrate and centralise operational decision-making to improve patient flow and patient safety across the whole hospital. The Comand Centre (CC) is implemented in a dedicated room in which up to 30 trained non-clinical management and support staff from different operational functions can sit together in teams facing a wall on which 8 large digital display screens are mounted. Each staff member answers telephone calls and performs their operational role using Information Technology (IT) systems on their desktop computer, information on the wall of display screens and communicating with team members and other teams within the room. A senior clinician or manager supports decision-making. The CC was implemented in November 2019, several months before the COVID-19 pandemic began to have a major impact on hospitals in the UK and globally. It was operational throughout the pandemic and, to date, it is firmly established as the centre for operational management of the hospital. The implementation of the CC at Bradford Royal Infirmary presents an opportunity to evaluate the potential strengths and weaknesses of the approach and to generate learning that can inform other hospitals considering adopting the approach. Objectives We aimed to evaluate the impact of the Bradford Command Centre on patient care and organisational processes. We hypothesised that the CC would improve patient flow, reduce bottlenecks and delays, enhance situational awareness to support operational decision-making, and facilitate identification and timely mitigation of threats to patient safety. This study had four research objectives: to evaluate the impact of the CC on patient safety, hospital operational efficiency and related organisational processes to understand the process of implementation of the CC and its integration into hospital management to contextualise the findings using cross-sector and cross-industry perspectives to synthesise the research findings to inform future investment and practice. Methods We conducted a comparative mixed-method case study at two sites: Study site – the CC at Bradford Royal Infirmary. Control site – Huddersfield Royal Infirmary, a hospital in the city of Huddersfield. The control site was selected as being geographically close (15 miles) and part of a similar-sized NHS hospital trust with similar challenges serving areas of high deprivation. At the start of this study, the control site had no plans to implement a CC but, during the study, they learnt from the study site and replicated some aspects of the Bradford Command Centre as part of their own pandemic response. The study combined ethnographic observation and interviews with data analytics of time-series operational data. We accessed and analysed data in the form of anonymised electronic health records from the study and control sites between January 2018 and August 2021 to cover the period before and after implementation of the Bradford Command Centre in November 2019. We conducted 72 hours of ethnographic observations of the CC operation over a period of 9 months after implementation. We conducted 15 interviews with hospital staff at the study site and 4 interviews with staff at the control site. To evaluate the impact of the CC (Objective 1), we described (qualitatively) and evaluated (statistically) the effect on hospital operations and outcomes. We used Interrupted Time Series Analysis to analyse variation in key output indicators in patient safety, patient flow and data quality. We qualitatively investigated situational awareness, operational decision-making, risk and co-ordination/communication across organisational units, from multiple stakeholder perspectives. To understand the process of implementation (Objective 2) our interviews explored staff recall of the implementation, including critical implementation factors and exploring unintended consequences. We used the interviews with staff at the control site to understand how a similar organisation adapted and changed over the same study period. To contextualise the findings (Objective 3), we reviewed the literature on command and control processes in non-healthcare safety-critical operations to extract key principles and contextual factors that may influence transferability of these models into a hospital setting. We also searched for evidence of other hospital CC implementations in the UK and worldwide. To synthesise the research findings (Objective 4), we developed a logic model to map system preconditions, processes, technology and outcomes. Results We were unable to evaluate the impact of the CC as fully as we had planned because the study was impacted by the COVID-19 pandemic. Hospital staff were extremely busy and access on site was challenging. The additional work negotiating access and the direct impact of the pandemic on our own team meant that we had fewer resources and were unable to complete all our objectives. We were able to observe how the CC helped support the hospital manage its operations through the pandemic and received strong positive evidence of its success. Complex pandemic challenges and rapid innovation to meet these challenges made it difficult to attribute outcomes to the specific intervention of the CC. Evaluation of the impact of the Command Centre (Objective 1) Our ethnographic observations and interviews with 15 study-site staff provided documentary evidence of successful use in a complex environment. The CC made a significant impact on the management of the hospital through the pandemic including through the introduction of a COVID-19 ‘tile’ which was used to managed COVID-19-specific processes. The CC and its staff worked with the new technology to change the way that the hospital operated. We identified unintended consequences that included front-line staff developing a sense of being monitored and a fear of interventions from the CC team that were perceived as unwelcome. Linked to this were challenges keeping electronic records up to date and acting on evidence of operational issues that were seen as being under local autonomy or ownership. Data quality was a constant concern for staff working in and around the CC and there were limitations in how up to date and accurate (or complete) records were, often necessitating triangulation and verification from multiple sources and systems and discrepancy between the data in the systems and what front-line staff reported. Compromise, goodwill and a shared sense of purpose were necessary to ensure the CC was effective. We were able to extract time-series data on patient safety, patient flow and data quality from operational systems by selecting representative indicators and plotting these over time. We were able to measure changes in these indicators over time and evaluate statistically the long-term impact of the CC on these indicators. We were not able to isolate improvements in these indicators that could directly be attributed to the introduction of the CC. Similarly, we were unable to isolate noticeable improvements in these indicators between study and control site. We found improvements in mortality and reduced rates of re-admission at the study site but caution against drawing conclusions from this at a time when the pandemic was raging. Some indicators, notably data quality, worsened rather than improved. We reason that the pandemic had such a profound impact on all aspects of operation that it is not possible to separate out and measure the impact of the CC. Similarly, the later adoption of a CC approach by the control site means we cannot use it to draw strong comparisons. Understanding the process of implementation of the Command Centre (Objective 2) Our project started after the CC had been implemented so our results rely on staff recall of the implementation. We identified five phases in the implementation: (1) pre-intervention, (2) a patient flow change programme, (3) Command Centre tile roll-in, (4) Command Centre go-live and (5) post-intervention engagement. Phase 2 was an organisational change, Phase 3 represents a soft-implementation period of training and familiarisation and Phase 4 represents the hard implementation of the new technology and new ways of working. Staff interviews suggest that the overall implementation approach was effective but that they found the implementation challenging and identified some need for more training and software improvements. The intention had been for a period of post-intervention engagement to support staff in getting used to new ways of working and to adapt procedures and technologies to optimise the new approach. This was disrupted by the pandemic, which started to impact on hospital operations only a few months after Phase 4 was complete. Staff recollections are therefore mixed between the pandemic response and the new technology but there is strong evidence that staff worked well together to find ways of working that were consistent with the CC approach while solving immediate challenges. Analysis of time-series data on patient safety, patient flow and data quality at different stages of implantation revealed patterns of change in response to the implementation, but these were confounded by the impact of the pandemic on the same outcome measures. When only the technology part of the Command Centre was assumed as the intervention, there was no significant difference between the pre- and post-intervention periods in the patient safety and patient flow indicators. The data quality had largely worsened in the post-implementation phase and we attribute this to the impact of the pandemic. Qualitative results show that the Command Centre has had a long bedding-in process and that this is expected to be a long process as the hospital and its staff adapt to new ways of working. Our qualitative results suggest that major improvements in patient flow, patient safety and data quality have yet to be achieved. Contextualising the findings using cross-sector and cross-industry perspectives (Objective 3) Results from the literature review found a strong body of research to support the adoption of a CC approach as part of a successful and resilient organisation. CCs are described as supporting situational awareness, decision-making, team structure and workload with the main aim of successfully delivering safety-critical operations reliably over time and in the face of dynamic risks and variations in the operating environment and system conditions. Digital technologies need to be tailored to the work done in the respective domain and should contribute to system resilience. Most articles attribute performance improvements to the physical and functional features of the centres themselves; this often includes the use of technology to generate and display real-time and/or predictive data in the centres. The implementation process usually affects process and policy changes in the organisation, including introducing new ways of working and workload distribution, adding new roles and altering the existing hierarchy of decision-making and responsibility. The literature advises caution in attributing improvements to the physical and functional aspects of the CCs versus the process and policy changes within the organisation that often arise out of the implementation process. There is emerging evidence that a CC approach can be adopted in acute health care. Effective implementations are characterised by a strong sense of shared situational awareness within a team with a shared focus on specific focal points for intelligence and intensification of this focus as threat level increases. System resilience is maintained in these implementations through simultaneous responsive and anticipatory strategies with variable resource allocation for both proactive planning for expected deviations and events with varying timescales. One paper advised caution in using the term ‘command and control’, as it may overly restrict the exploring of new ideas and new approaches seen as important to meeting the specific needs of health care, hospitals and staff given the strong culture of autonomy on the clinical front line. Synthesis of research findings to inform future investment and practice (Objective 4) We found evidence that the approach to implementation was broadly successful but that benefits take time and significant additional innovation to realise. We consolidate our learning as an intervention logic model that can be used by other hospitals planning an implementation of a digitally enabled hospital CC. Conclusions This study has presented a case study of a successful implementation of a CC in the UK NHS. The Bradford Command Centre demonstrates that systems are available but it also reveals challenges in the reliability, timeliness and quality of these data that reduce transparency and limit confidence. Management and staff have managed to overcome many of these challenges through determination, negotiation and gradual improvements while also dealing with the pandemic. There was a strong sense that the CC had been invaluable during the pandemic but we were not able to empirically validate this. Our case study was affected by the pandemic and does not provide sufficient evidence to demonstrate major benefits on its own. We therefore recommend: Command centres are a viable approach that should be considered. Reliable, modern hospital-wide information systems are an essential foundation for command-centre technology and poor data quality will undermine implementation if not addressed. Further work should follow the evolving use of the Bradford Command Centre and disseminate learning to other hospitals considering adoption. Further studies that use our time-series approach for performance metrics would allow comparison across more hospitals and support the evaluation of other implementations. Studies should consider mixed methods rather than relying solely on qualitative or quantitative approaches to draw conclusions. Study registration The study is registered as IRAS No.: 285933. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: NIHR129483) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 41. See the NIHR Funding and Awards website for further award information.

Abstract The defining feature of Parkinson disease (PD) and Lewy body dementia (LBD) is the accumulation of alpha-synuclein (Asyn) fibrils in Lewy bodies and Lewy neurites. Here we develop and validate a method to amplify Asyn fibrils extracted from LBD postmortem tissue samples and use solid state nuclear magnetic resonance (SSNMR) studies to determine atomic resolution structure. Amplified LBD Asyn fibrils comprise a mixture of single protofilament and two protofilament fibrils with very low twist. The protofilament fold is highly similar to the fold determined by a recent cryo-electron microscopy study for a minority population of twisted single protofilament fibrils extracted from LBD tissue. These results expand the structural characterization of LBD Asyn fibrils and approaches for studying disease mechanisms, imaging agents and therapeutics targeting Asyn.

BackgroundLow- and lower-middle-income countries account for a higher percentage of global epidemics and chronic diseases. In most low- and lower-middle-income countries, there is limited access to health care. The implementation of open-source electronic health records (EHRs) can be understood as a powerful enabler for low- and lower-middle-income countries because it can transform the way health care technology is delivered. Open-source EHRs can enhance health care delivery in low- and lower-middle-income countries by improving the collection, management, and analysis of health data needed to inform health care delivery, policy, and planning. While open-source EHR systems are cost-effective and adaptable, they have not proliferated rapidly in low- and lower-middle-income countries. Implementation barriers slow adoption, with existing research focusing predominantly on technical issues preventing successful implementation. ObjectiveThis interdisciplinary scoping review aims to provide an overview of contextual barriers affecting the adaptation and implementation of open-source EHR systems in low- and lower-middle-income countries and to identify areas for future research. MethodsWe conducted a scoping literature review following a systematic methodological framework. A total of 7 databases were selected from 3 disciplines: medicine and health sciences, computing, and social sciences. The findings were reported in accordance with the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) checklist. The Mixed Methods Appraisal Tool and the Critical Appraisal Skills Programme checklists were used to assess the quality of relevant studies. Data were collated and summarized, and results were reported qualitatively, adopting a narrative synthesis approach. ResultsThis review included 13 studies that examined open-source EHRs’ adaptation and implementation in low- and lower-middle-income countries from 3 interrelated perspectives: socioenvironmental, technological, and organizational barriers. The studies identified key issues such as limited funding, sustainability, organizational and management challenges, infrastructure, data privacy and protection, and ownership. Data protection, confidentiality, ownership, and ethics emerged as important issues, often overshadowed by technical processes. ConclusionsWhile open-source EHRs have the potential to enhance health care delivery in low- and lower-middle-income-country settings, implementation is fraught with difficulty. This scoping review shows that depending on the adopted perspective to implementation, different implementation barriers come into view. A dominant focus on technology distracts from socioenvironmental and organizational barriers impacting the proliferation of open-source EHRs. The role of local implementing organizations in addressing implementation barriers in low- and lower-middle-income countries remains unclear. A holistic understanding of implementers’ experiences of implementation processes is needed. This could help characterize and solve implementation problems, including those related to ethics and the management of data protection. Nevertheless, this scoping review provides a meaningful contribution to the global health informatics discipline.

Abstract Periodontal disease is a significant burden for oral health, causing progressive and irreversible damage to the support structure of the tooth. This complex structure, the periodontium, is composed of interconnected soft and mineralised tissues, posing a challenge for regenerative approaches. Materials combining silicon and lithium are widely studied in periodontal regeneration, as they stimulate bone repair via silicic acid release while providing regenerative stimuli through lithium activation of the Wnt/β-catenin pathway. Yet, existing materials for combined lithium and silicon release have limited control over ion release amounts and kinetics. Porous silicon can provide controlled silicic acid release, inducing osteogenesis to support bone regeneration. Prelithiation, a strategy developed for battery technology, can introduce large, controllable amounts of lithium within porous silicon, but yields a highly reactive material, unsuitable for biomedicine. This work debuts a strategy to lithiate porous silicon nanowires (LipSiNs) which generates a biocompatible and bioresorbable material. LipSiNs incorporate lithium to between 1% and 40% of silicon content, releasing lithium and silicic acid in a tailorable fashion from days to weeks. LipSiNs combine osteogenic, cementogenic and Wnt/β-catenin stimuli to regenerate bone, cementum and periodontal ligament fibres in a murine periodontal defect.

We consider an experiment with at least two stages or batches and O(N)O\left(N) subjects per batch. First, we propose a semiparametric treatment effect estimator that efficiently pools information across the batches, and we show that it asymptotically dominates alternatives that aggregate single batch estimates. Then, we consider the design problem of learning propensity scores for assigning treatment in the later batches of the experiment to maximize the asymptotic precision of this estimator. For two common causal estimands, we estimate this precision using observations from previous batches, and then solve a finite-dimensional concave maximization problem to adaptively learn flexible propensity scores that converge to suitably defined optima in each batch at rate Op(N−1⁄4){O}_{p}\left({N}^{-1/4}). By extending the framework of double machine learning, we show this rate suffices for our pooled estimator to attain the targeted precision after each batch, as long as nuisance function estimates converge at rate op(N−1⁄4){o}_{p}\left({N}^{-1/4}). These relatively weak rate requirements enable the investigator to avoid the common practice of discretizing the covariate space for design and estimation in batch adaptive experiments while maintaining the advantages of pooling. Our numerical study shows that such discretization often leads to substantial asymptotic and finite sample precision losses outweighing any gains from design.

Mutations in the PINK1 and PRKN genes are the most frequent genetic cause of early-onset Parkinson disease. The pathogenic p.R275W substitution in PRKN is the most frequent substitution observed in patients, and thus far has been characterized mostly through overexpression models that suggest a possible gain of toxic misfunction. However, its effects under endogenous conditions are largely unknown. We used patient fibroblasts, isogenic neurons, and post-mortem human brain samples from carriers with and without PRKN p.R275W to assess functional impact. Immunoblot analysis and immunofluorescence were used to study mitophagy activation, and mitophagy execution was analyzed by flow cytometry of the reporter mitoKeima. The functional analysis was accompanied by structural investigation of PRKN p.R275W. We observed lower PRKN protein in fibroblasts with compound heterozygous p.R275W mutations. Isogenic neurons showed an allele-dose dependent decrease in PRKN protein. Lower PRKN protein levels were accompanied by diminished phosphorylated ubiquitin and decreased MFN2 modification. Mitochondrial degradation was also allele-dose dependently impaired. Consistently, PRKN protein levels were drastically reduced in human brain samples from p.R275W carriers. Finally, structural simulations showed significant changes in the closed form of PRKN p.R275W. Our data suggest that under endogenous conditions the p.R275W mutation results in a loss-of-function by destabilizing PRKN.

Soil CO2 concentration and flux measurements are important in diverse fields, including geoscience, climate science, soil ecology, and agriculture. However, practitioners in these fields face difficulties with existing soil CO2 gas probes, which have had problems with high costs and frequent failures when deployed. Confronted with a recent research project’s need for long-term in-soil CO2 monitoring at a large number of sites in harsh environmental conditions, we developed our own CO2 logging system to reduce expense and avoid the expected failures of commercial instruments. Our newly developed soil probes overcome the central challenge of soil gas probes—surviving continuous exposure to soil moisture while remaining open to soil gases—via three approaches: a 3D printed housing (economical for small-scale production) following design principles that correct the usual water permeability flaw of 3D printed materials; passive moisture protection via a hydrophobic, CO2-permeable PTFE membrane; and active moisture protection via a low-power micro-dehumidifier. Our CO2 instrumentation performed well and yielded a high-quality dataset that includes signals related to a prescribed fire as well as seasonal and diel cycles. We expect our technology to support underground CO2 monitoring in fields where it is already practiced and stimulate its expansion into diverse new fields.

Abstract Background Stroke survivors rate longer-term (> 2 years) psychological recovery as their top priority, but data on how frequently psychological consequences occur is lacking. Prevalence of cognitive impairment, depression/anxiety, fatigue, apathy and related psychological outcomes, and whether rates are stable in long-term stroke, is unknown. Methods N = 105 long-term stroke survivors (M [SD] age = 72.92 [13.01]; M [SD] acute NIH Stroke Severity Score = 7.39 [6.25]; 59.0% Male; M [SD] years post-stroke = 4.57 [2.12]) were recruited (potential N = 208). Participants completed 3 remote assessments, including a comprehensive set of standardized cognitive neuropsychological tests comprising domains of memory, attention, language, and executive function, and questionnaires on emotional distress, fatigue, apathy and other psychological outcomes. Ninety participants were re-assessed one year later. Stability of outcomes was assessed by Cohen’s d effect size estimates and percent Minimal Clinically Important Difference changes between time points. Results On the Montreal Cognitive Assessment 65.3% scored 2 years post-event exhibited psychological difficulties including domains of cognition, mood, and fatigue, which impact long-term quality of life. Stroke is a chronic condition with highly prevalent psychological needs, which require monitoring and intervention development.

Mechanically-assisted crevice corrosion (MACC) is a synergistic combination of wear and crevice corrosion. The major differences between tribocorrosion, fretting corrosion and MACC relate to the relative scale of motion and contact area, are clarified in this work. Experimental testing methods for MACC and design of simulation apparatuses are compared and discussed. MACC associated with biomedical alloys used as orthopedic implants, screws, and dental implants has been the subject of most recent research regarding this corrosion mechanism. However, there are also many engineering structures where the pre-requisite conditions for MACC are met but have to date received less scientific scrutiny. Examples are tubes and supportive bars/plates constructions, bolt-type structures and rail track foot covered by fastening systems. Reasonable selection of fretting-resistant materials, proper mounting methods and development of lubricating coating and oil/grease would be effective for mitigating MACC, and it is proposed that surface modification regarding contact geometries and surface compliances may have future promise.

Abstract Frontotemporal lobar degeneration (FTLD) is a group of disorders characterized by degeneration of the frontal and temporal lobes, leading to progressive decline in language, behavior, and motor function. FTLD can be further subdivided into three main subtypes, FTLD-tau, FTLD-TDP and FTLD-FUS based which of the three major proteins – tau, TDP-43 or FUS – forms pathological inclusions in neurons and glia. In this report, we describe an 87-year-old woman with a 7-year history of cognitive decline, hand tremor and gait problems, who was thought to have Alzheimer’s disease. At autopsy, histopathological analysis revealed severe neuronal loss, gliosis and spongiosis in the medial temporal lobe, orbitofrontal cortex, cingulate gyrus, amygdala, basal forebrain, nucleus accumbens, caudate nucleus and anteromedial thalamus. Tau immunohistochemistry showed numerous argyrophilic grains, pretangles, thorn-shaped astrocytes, and ballooned neurons in the amygdala, hippocampus, parahippocampal gyrus, anteromedial thalamus, insular cortex, superior temporal gyrus and cingulate gyrus, consistent with diffuse argyrophilic grain disease (AGD). TDP-43 pathology in the form of small, dense, rounded neuronal cytoplasmic inclusion with few short dystrophic neurites was observed in the limbic regions, superior temporal gyrus, striatum and midbrain. No neuronal intranuclear inclusion was observed. Additionally, FUS-positive inclusions were observed in the dentate gyrus. Compact, eosinophilic intranuclear inclusions, so-called “cherry spots,” that were visible on histologic stains were immunopositive for α-internexin. Taken together, the patient had a mixed neurodegenerative disease with features of diffuse AGD, TDP-43 proteinopathy and neuronal intermediate filament inclusion disease. She met criteria for three subtypes of FTLD: FTLD-tau, FTLD-TDP and FTLD-FUS. Her amnestic symptoms that were suggestive of Alzheimer’s type dementia are best explained by diffuse AGD and medial temporal TDP-43 proteinopathy, and her motor symptoms were likely explained by neuronal loss and gliosis due to tau pathology in the substantia nigra. This case underscores the importance of considering multiple proteinopathies in the diagnosis of neurodegenerative diseases.

Abstract Background Archaea of the order Thermoplasmatales are widely distributed in natural acidic areas and are amongst the most acidophilic prokaryotic organisms known so far. These organisms are difficult to culture, with currently only six genera validly published since the discovery of Thermoplasma acidophilum in 1970. Moreover, known great diversity of uncultured Thermoplasmatales represents microbial dark matter and underlines the necessity of efforts in cultivation and study of these archaea. Organisms from the order Thermoplasmatales affiliated with the so-called “alphabet-plasmas”, and collectively dubbed “E-plasma”, were the focus of this study. These archaea were found predominantly in the hyperacidic site PM4 of Parys Mountain, Wales, UK, making up to 58% of total metagenomic reads. However, these archaea escaped all cultivation attempts. Results Their genome-based metabolism revealed its peptidolytic potential, in line with the physiology of the previously studied Thermoplasmatales isolates. Analyses of the genome and evolutionary history reconstruction have shown both the gain and loss of genes, that may have contributed to the success of the “E-plasma” in hyperacidic environment compared to their community neighbours. Notable genes among them are involved in the following molecular processes: signal transduction, stress response and glyoxylate shunt, as well as multiple copies of genes associated with various cellular functions; from energy production and conversion, replication, recombination, and repair, to cell wall/membrane/envelope biogenesis and archaella production. History events reconstruction shows that these genes, acquired by putative common ancestors, may determine the evolutionary and functional divergences of “E-plasma”, which is much more developed than other representatives of the order Thermoplasmatales. In addition, the ancestral hereditary reconstruction strongly indicates the placement of Thermogymnomonas acidicola close to the root of the Thermoplasmatales. Conclusions This study has analysed the metagenome-assembled genome of “E-plasma”, which denotes the basis of their predominance in Parys Mountain environmental microbiome, their global ubiquity, and points into the right direction of further cultivation attempts. The results suggest distinct evolutionary trajectories of organisms comprising the order Thermoplasmatales, which is important for the understanding of their evolution and lifestyle.

Abstract Magnetic transition metal chalcogenides form an emerging platform for exploring spin-orbit driven Berry phase phenomena owing to the nontrivial interplay between topology and magnetism. Here we show that the anomalous Hall effect in pristine Cr2Te3 thin films manifests a unique temperature-dependent sign reversal at nonzero magnetization, resulting from the momentum-space Berry curvature as established by first-principles simulations. The sign change is strain tunable, enabled by the sharp and well-defined substrate/film interface in the quasi-two-dimensional Cr2Te3 epitaxial films, revealed by scanning transmission electron microscopy and depth-sensitive polarized neutron reflectometry. This Berry phase effect further introduces hump-shaped Hall peaks in pristine Cr2Te3 near the coercive field during the magnetization switching process, owing to the presence of strain-modulated magnetic layers/domains. The versatile interface tunability of Berry curvature in Cr2Te3 thin films offers new opportunities for topological electronics.

Abstract Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are distinct clinicopathological subtypes of frontotemporal lobar degeneration. They both have atypical parkinsonism, and they usually have distinct clinical features. The most common clinical presentation of PSP is Richardson syndrome, and the most common presentation of CBD is corticobasal syndrome. In this report, we describe a patient with a five-year history of Richardson syndrome and a family history of PSP in her mother and sister. A tau PET scan (18F-APN-1607) revealed low-to-moderate uptake in the substantia nigra, globus pallidus, thalamus and posterior cortical areas, including temporal, parietal and occipital cortices. Neuropathological evaluation revealed widespread neuronal and glial tau pathology in cortical and subcortical structures, including tufted astrocytes in the motor cortex, striatum and midbrain tegmentum. The subthalamic nucleus had mild-to-moderate neuronal loss with globose neurofibrillary tangles, consistent with PSP. On the other hand, there were also astrocytic plaques, a pathological hallmark of CBD, in the neocortex and striatum. To further characterize the mixed pathology, we applied two machine learning-based diagnostic pipelines. These models suggested diagnoses of PSP and CBD depending on the brain region – PSP in the motor cortex and superior frontal gyrus and CBD in caudate nucleus. Western blots of insoluble tau from motor cortex showed a banding pattern consistent with mixed features of PSP and CBD, whereas tau from the superior frontal gyrus showed a pattern consistent with CBD. Real-time quaking-induced conversion (RT-QuIC) using brain homogenates from the motor cortex and superior frontal gyrus showed ThT maxima consistent with PSP, while reaction kinetics were consistent with CBD. There were no pathogenic variants in MAPT with whole genome sequencing. We conclude that this patient had an unclassified tauopathy and features of both PSP and CBD. The different pathologies in specific brain regions suggests caution in diagnosis of tauopathies with limited sampling.

Understanding the growth patterns and developmental trajectories of teeth during early life stages provides valuable insights into the ontogeny of individuals, particularly in archaeological populations where such information is scarce. This study focuses on first deciduous molars, specifically investigating crown formation times and daily secretion rates, through histological analysis. A total of 34 teeth from the Early Medieval necropolises of Casalmoro and Guidizzolo (Mantua, Lombardy, northern Italy) were analysed assessing growth parameters and identifying possible differences between sites and between sexes, which are determined through proteomic analysis. Furthermore, a robust linear regression model relating prism length and secretion time was built to estimate growth rates also in teeth in which the finest incremental markings are not visible. The daily secretion rates (DSR) in inner enamel showed a high homogeneity between dental arches, sexes and the two sites. Values fall within the known range reported in the literature for the same tooth class in archaeological populations. However, a difference in DSR was observed when compared with modern sample published values. Crown formation times and age at crown completion differ between dental arches, with maxillary first molars initiating their matrix apposition earlier than mandibular molars as formerly reported. However, no significant differences were highlighted in association with sex. This study expands our understanding of the growth and development of the first deciduous molars in a medieval population, providing valuable insights into growth trajectories specific to the dental arch. These findings highlight the need for extensive investigations using similar methodologies to attain more accurate and comprehensive information about the developmental patterns of first deciduous molars. Additionally, proteomic analysis improves the capability to conduct sex-specific histological assessments of immature individuals, thanks to this method's application in determining their sex.

We describe a 66-year-old woman with Parkinson’s disease, carrying a known pathogenic missense variant in the Valosin-containing-protein (VCP) gene. She responded excellently to L-dopa, had no cognitive or motoneuronal dysfunction. Laboratory analyses and MRI were unremarkable. Genetic testing revealed a heterozygous variant in VCP(NM_007126.5), chr9 (GRCh3 7):g.35060820C > T, c.1460G > A p.Arg487His (p.R487H).

Abstract Both PD1/PD-L1 and CD47 blockades have demonstrated limited activity in most subtypes of NHL save NK/T-cell lymphoma. The hemotoxicity with anti-CD47 agents in the clinic has been speculated to account for their limitations. Herein we describe a first-in-class and rationally designed bispecific antibody (BsAb), HX009, targeting PD1 and CD47 but with weakened CD47 binding, which selectively hones the BsAb for tumor microenvironment through PD1 interaction, potentially reducing toxicity. In vitro characterization confirmed: (1) Both receptor binding/ligand blockade, with lowered CD47 affinity; (2) functional PD1/CD47 blockades by reporter assays; (3) T-cell activation in Staphylococcal-enterotoxin-B-pretreated PBMC and mixed-lymphocyte-reaction. In vivo modeling demonstrated antitumor activity in Raji-B and Karpass-229-T xenograft lymphomas. In the humanized mouse syngeneic A20 B-lymphoma (huCD47-A20) HuGEMM model, which has quadruple knocked-in hPD1xhPD-L1xhCD47xhSIRPα genes and an intact autologous immune-system, a contribution of effect is demonstrated for each targeted biologic (HX008 targeting PD1 and SIRPα-Fc targeting CD47), which is clearly augmented by the dual targeting with HX009. Lastly, the expression of the immune-checkpoints PD-L1/L2 and CD47 seemed co-regulated among a panel of lymphoma-derived-xenografts, where HX009 maybe more effective in those with upregulated CD47. Our data warrants HX009’s further clinical development for treating NHLs.

Let K be a field and σ an automorphism of K of order n. Employing a nonassociative algebra, we study the eigenspace of a bounded skew polynomial f ∈ K[t; σ]. We mainly treat the case that K/F is a cyclic field extension of degree n with Galois group generated by σ.We obtain lower bounds on the dimension of the eigenspace, and compute it in special cases as a quotient algebra. Conditions under which a monic polynomial f ∈ F [t] ⊂ K[t; σ] is reducible are obtained in special cases.

ABSTRACT N-terminal protein acetylation is a ubiquitous post-translational modification that impacts diverse cellular processes in higher organisms. Bacterial proteins are also N-terminally acetylated, but the mechanisms and consequences of this modification in bacteria are poorly understood. The major virulence factor EsxA (ESAT-6, early secreted antigen, 6 kDa) was one of the first N-terminally acetylated proteins identified in bacteria. EsxA is conserved in mycobacterial pathogens, including Mycobacterium tuberculosis and Mycobacterium marinum, a non-tubercular mycobacterial species that causes tuberculosis-like disease in ectotherms. However, the enzyme responsible for EsxA N-terminal acetylation has been elusive. Here, we used genetics, molecular biology, and mass-spectroscopy-based proteomics to demonstrate that MMAR_1839 (renamed Emp1, ESX-1 modifying protein, 1) is the putative N-acetyltransferase (NAT) solely responsible for EsxA acetylation in M. marinum. We demonstrated that ERD_3144, the orthologous gene in M. tuberculosis Erdman, is functionally equivalent to Emp1. We previously quantified widespread N-terminal protein acetylation in pathogenic mycobacteria (C. R. Thompson, M. M. Champion, and P. A. Champion, J Proteome Res 17:3246–3258, 2018, https:// doi: 10.1021/acs.jproteome.8b00373). We identified at least 22 additional proteins that require Emp1 for acetylation, demonstrating that this putative NAT is not dedicated to EsxA. Finally, we showed that loss of emp1 did not prevent phagosomal escape but resulted in a significant reduction in macrophage cytolysis by and cell-to-cell spread of M. marinum during infection. Collectively, this study identified a NAT required for N-terminal acetylation and pathogenesis in Mycobacterium. IMPORTANCE N-terminal acetylation is a protein modification that broadly impacts basic cellular function and disease in higher organisms. Although bacterial proteins are N-terminally acetylated, little is understood how N-terminal acetylation impacts bacterial physiology and pathogenesis. Mycobacterial pathogens cause acute and chronic disease in humans and in animals. Approximately 15% of mycobacterial proteins are N-terminally acetylated, but the responsible enzymes are largely unknown. We identified a conserved mycobacterial protein required for the N-terminal acetylation of 23 mycobacterial proteins including the EsxA virulence factor. Loss of this enzyme from M. marinum reduced macrophage killing and spread of M. marinum to new host cells. Defining the acetyltransferases responsible for the N-terminal protein acetylation of essential virulence factors could lead to new targets for therapeutics against mycobacteria.

Multiple system atrophy (MSA) is a rare and progressive neurodegenerative disorder characterized by motor and autonomic dysfunction. Accurate and early diagnosis of MSA is challenging due to its clinical similarity with other neurodegenerative disorders, such as Parkinson’s disease and atypical parkinsonian disorders. Currently, MSA diagnosis is based on clinical criteria drawing from the patient’s symptoms, lack of response to levodopa therapy, neuroimaging studies, and exclusion of other diseases. However, these methods have limitations in sensitivity and specificity. Recent advances in molecular biomarker research, such as α-synuclein protein amplification assays (RT-QuIC) and other biomarkers in cerebrospinal fluid and blood, have shown promise in improving the diagnosis of MSA. Additionally, these biomarkers could also serve as targets for developing disease-modifying therapies and monitoring treatment response. In this review, we provide an overview of the clinical syndrome of MSA and discuss the current diagnostic criteria, limitations of current diagnostic methods, and emerging molecular biomarkers that offer hope for improving the accuracy and early detection of MSA.

The American university has been guided by classical liberalism in its defense of the freedom of speech and academic freedom. The idea is that a university is a place where all ideas and perspectives can be debated. However, this idea is increasingly being challenged by those who want the secular university to be a place that advances a social philosophy that promises to transform society by dismantling structural racism and providing for greater equity. In this article, I will argue that both of these models have been shaped by democratic legal ideals and both share a common skeptical assumption about the basic questions of meaning that each person must answer. The legal structures developed by Westphalian modernity attempt neutrality on questions about meaning. This can be seen even in recent Supreme Court decisions affirming the individual’s right to determine meaning for themselves. This skeptical root has produced the conflict between classical liberals and the social transformation that we are witnessing at our universities. I argue for a third option that I find in the Declaration of Independence, which affirms that we can and should know the answers to basic questions which then provide the foundation for education and law.

Abstract By suppressing gene transcription through the recruitment of corepressor proteins, B-cell lymphoma 6 (BCL6) protein controls a transcriptional network required for the formation and maintenance of B-cell germinal centres. As BCL6 deregulation is implicated in the development of Diffuse Large B-Cell Lymphoma, we sought to discover novel small molecule inhibitors that disrupt the BCL6-corepressor protein–protein interaction (PPI). Here we report our hit finding and compound optimisation strategies, which provide insight into the multi-faceted orthogonal approaches that are needed to tackle this challenging PPI with small molecule inhibitors. Using a 1536-well plate fluorescence polarisation high throughput screen we identified multiple hit series, which were followed up by hit confirmation using a thermal shift assay, surface plasmon resonance and ligand-observed NMR. We determined X-ray structures of BCL6 bound to compounds from nine different series, enabling a structure-based drug design approach to improve their weak biochemical potency. We developed a time-resolved fluorescence energy transfer biochemical assay and a nano bioluminescence resonance energy transfer cellular assay to monitor cellular activity during compound optimisation. This workflow led to the discovery of novel inhibitors with respective biochemical and cellular potencies (IC50s) in the sub-micromolar and low micromolar range.

Background: Identification of predictors of antibiotic use can inform targeted antimicrobial stewardship initiatives and can account for sources of bias in before-and-after interventional stewardship studies. To date, no study has identified clinical predictors of antimicrobial use within intensive care units (ICUs), where antimicrobial resistance is most prevalent and problematic. Methods: As part of an ongoing prospective, single-arm, pilot feasibility trial of an ICU diagnostic stewardship intervention, we performed a nested retrospective cohort study to explore associations between patient clinical variables and ICUs antimicrobial use and resistance rates (AURs). We included all patients hospitalized in 3 ICUs (surgical, medical, and cardiac) from 2017 to 2021 at Michigan Medicine, a large, tertiary-care, academic medical center. Data were extracted from the electronic medical record using a structured query. Admission-level data were captured, including patient demographics, medical comorbidities, International Classification of Disease, Tenth Revision (ICD-10) admission diagnoses, as well as calendar day-level data including vital signs, clinical and microbiologic laboratory data, measures of acute severity of illness, ventilator–supplemental oxygen metrics, and procedural interventions using current procedural terminology (CPT) codes. ICU AURs were defined as total antibiotic days of therapy per patient per 100 ICU days. Associations between clinical variables and ICU AURs were calculated as rate ratios (RRs). Multiple imputation using fully conditional specification was performed to create 25 imputation data sets. Negative binomial regression models were constructed for each data set using backward selection. Variables retained in >50% of models were included in a final multivariate model. Results: In total, 15,177 ICU patient admissions were captured. Age, sex assigned at birth, and race did not independently associate with ICU AURs. Comorbidities, medical interventions, admission diagnoses, and laboratory data that independently associated with ICU-AURs are shown in Table 1. The clinical variables most strongly associated with increased ICU-AURs were pneumonia (RR, 1.55; 95% CI, 1.451.64), bacteremia (RR, 1.35; 95% CI, 1.25– 1.46), intraabdominal infection (RR, 1.35; 95% CI, 1.18–1.55), SOFA score (RR, 1.27; 95% CI, 1.14–1.42), abnormal WBC (RR, 1.26; 95% CI, 1.20–1.32), and immunocompromised status (RR, 1.20; 95% CI, 1.10–1.31). Clinical variables most strongly associated with decreased ICU-AURs were cardiac ICU (RR, 0.56; 95% CI, 0.52–0.60), COVID-19 (RR, 0.62; 95% CI, 0.56–0.70), and receipt of an invasive nonsurgical procedure (RR, 0.90; 95% CI, 0.82–0.98). Conclusions: In this single-center retrospective cohort study, several clinical variables were independently associated with ICU-AURs. These results may be used to identify patient subgroups for potentially high-yield ICU-based stewardship interventions and to account for sources of bias in before-and-after studies of ICU-based stewardship interventions.

Background Command centres have been piloted in some hospitals across the developed world in the last few years. Their impact on patient safety, however, has not been systematically studied. Hence, we aimed to investigate this.Methods This is a retrospective population-based cohort study. Participants were patients who visited Bradford Royal Infirmary Hospital and Calderdale & Huddersfield hospitals between 1 January 2018 and 31 August 2021. A five-phase, interrupted time series, linear regression analysis was used.Results After introduction of a Command Centre, while mortality and readmissions marginally improved, there was no statistically significant impact on postoperative sepsis. In the intervention hospital, when compared with the preintervention period, mortality decreased by 1.4% (95% CI 0.8% to 1.9%), 1.5% (95% CI 0.9% to 2.1%), 1.3% (95% CI 0.7% to 1.8%) and 2.5% (95% CI 1.7% to 3.4%) during successive phases of the command centre programme, including roll-in and activation of the technology and preparatory quality improvement work. However, in the control site, compared with the baseline, the weekly mortality also decreased by 2.0% (95% CI 0.9 to 3.1), 2.3% (95% CI 1.1 to 3.5), 1.3% (95% CI 0.2 to 2.4), 3.1% (95% CI 1.4 to 4.8) for the respective intervention phases. No impact on any of the indicators was observed when only the software technology part of the Command Centre was considered.Conclusion Implementation of a hospital Command Centre may have a marginal positive impact on patient safety when implemented as part of a broader hospital-wide improvement programme including colocation of operations and clinical leads in a central location. However, improvement in patient safety indicators was also observed for a comparable period in the control site. Further evaluative research into the impact of hospital command centres on a broader range of patient safety and other outcomes is warranted.

Abstract Dementia with Lewy bodies (DLB) is clinically diagnosed when patients develop dementia less than a year after parkinsonism onset. Age is the primary risk factor for DLB and mitochondrial health influences ageing through effective oxidative phosphorylation (OXPHOS). Patterns of stable polymorphisms in the mitochondrial genome (mtDNA) alter OXPHOS efficiency and define individuals to specific mtDNA haplogroups. This study investigates if mtDNA haplogroup background affects clinical DLB risk and neuropathological disease severity. 360 clinical DLB cases, 446 neuropathologically confirmed Lewy body disease (LBD) cases with a high likelihood of having DLB (LBD-hDLB), and 910 neurologically normal controls had European mtDNA haplogroups defined using Agena Biosciences MassARRAY iPlex technology. 39 unique mtDNA variants were genotyped and mtDNA haplogroups were assigned to mitochondrial phylogeny. Striatal dopaminergic degeneration, neuronal loss, and Lewy body counts were also assessed in different brain regions in LBD-hDLB cases. Logistic regression models adjusted for age and sex were used to assess associations between mtDNA haplogroups and risk of DLB or LBD-hDLB versus controls in a case-control analysis. Additional appropriate regression models, adjusted for age at death and sex, assessed associations of haplogroups with each different neuropathological outcome measure. No mtDNA haplogroups were significantly associated with DLB or LBD-hDLB risk after Bonferroni correction.Haplogroup H suggests a nominally significant reduced risk of DLB (OR=0.61, P=0.006) but no association of LBD-hDLB (OR=0.87, P=0.34). The haplogroup H observation in DLB was consistent after additionally adjusting for the number of APOE ε4 alleles (OR=0.59, P=0.004). Haplogroup H also showed a suggestive association with reduced ventrolateral substantia nigra neuronal loss (OR=0.44, P=0.033). Mitochondrial haplogroup H may be protective against DLB risk and neuronal loss in substantia nigra regions in LBD-hDLB cases but further validation is warranted.

Sample return capsules (SRCs) entering Earth’s atmosphere at hypervelocity from interplanetary space are a valuable resource for studying meteor phenomena. The 2023 September 24 arrival of the Origins, Spectral Interpretation, Resource Identification, and Security-Regolith Explorer SRC provided an unprecedented chance for geophysical observations of a well-characterized source with known parameters, including timing and trajectory. A collaborative effort involving researchers from 16 institutions executed a carefully planned geophysical observational campaign at strategically chosen locations, deploying over 400 ground-based sensors encompassing infrasound, seismic, distributed acoustic sensing, and Global Positioning System technologies. Additionally, balloons equipped with infrasound sensors were launched to capture signals at higher altitudes. This campaign (the largest of its kind so far) yielded a wealth of invaluable data anticipated to fuel scientific inquiry for years to come. The success of the observational campaign is evidenced by the near-universal detection of signals across instruments, both proximal and distal. This paper presents a comprehensive overview of the collective scientific effort, field deployment, and preliminary findings. The early findings have the potential to inform future space missions and terrestrial campaigns, contributing to our understanding of meteoroid interactions with planetary atmospheres. Furthermore, the data set collected during this campaign will improve entry and propagation models and augment the study of atmospheric dynamics and shock phenomena generated by meteoroids and similar sources.

International commitments to preserve global biodiversity target the protection of 30% of marine habitats by 2030. The lack of even basic knowledge of many marine areas (e.g., deep oceans) combined with short timelines require integrative knowledge and multidisciplinary techniques to be used to efficiently identify areas worthy of protection. Here we outline a case study of the discovery of the Makkovik Hanging Gardens found in a deep-water trough in coastal Labrador, Canada. The area is of ecological significance because it supports high densities of vulnerable marine ecosystem indicator taxa, including the gorgonian coral Primnoa resedaeformis on portions of its vertical submarine walls. This study illustrates the exploratory process initiated by Nunatsiavut, which integrated local knowledge, scientific models, and a variety of technologies (such as remotely operated vehicles and multibeam sonar) to discover deep-water hidden biodiversity toward the advancement of both local Indigenous and global conservation goals.

Compositional traits in potato [Solanum tuberosum L.] are economically important but genetically complex, often controlled by many loci of small effect; new methods need to be developed to accelerate analysis and improvement of such traits, like chip quality. In this study, we used network analysis to organize hundreds of metabolic features detected by mass spectrometry into groups, as a precursor to genetic analysis. 981 features were condensed into 44 modules; module eigenvalues were used for genetic mapping and correlation analysis with phenotype data collected by the Solanaceae Coordinated Agricultural Project. Half of the modules were associated with at least one SNP according to GWAS; 11 of those modules were also significantly correlated with chip color. Within those modules features associated with chipping provide potential targets for selection in addition to selection for reduced glucose. Loci associated with module eigenvalues were not evenly distributed throughout the genome but were instead clustered on chromosomes 3, 7, and 8. Comparison of GWAS on single features and modules of clustered features often identified the same SNPs. However, features with related chemistries (for example, glycoalkaloids with precursor/product relationships) were not found to be near neighbors in the network analysis and did not share common SNPs from GWAS. Instead, the features within modules were often structurally disparate, suggesting that linkage disequilibrium complicates network analyses in potato. This result is consistent with recent genomic studies of potato showing that chromosomal rearrangements that create barriers to recombination are common in cultivated germplasm.