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"Hospital" can refer to a physical place or more figuratively to the people associated with it. Such place-for-institution metonyms are common in everyday language, but there remain several open questions in the literature regarding how they are processed. The goal of the current eyetracking experiments was to investigate how metonyms are interpreted when they appear as sentence subjects in structures that are temporarily syntactically ambiguous versus unambiguous (e.g., "The hospital [that was] requested by the doctor…"). If comprehenders have a bias to interpret metonyms in subject position as agents (Fishbein & Harris, 2014), they should initially access the figurative (institutional) sense of the metonym. This interpretation is rendered incorrect at the disambiguating by-phrase, which should lead to reanalysis (i.e., garden-path effects). In Experiment 1, larger garden-path effects were observed for metonyms compared to inanimate control nouns that did not have a figurative sense. In Experiment 2, garden-path effects were equivalent for metonyms and animate sentence subjects. In addition, there was some evidence that readers exhibited initial difficulty at the verb (e.g., "requested") when it immediately followed the metonym compared to the inanimate control nouns in Experiment 1. Overall, the results suggest that the subject-as-agent heuristic is a powerful cue during sentence processing, which can prompt the comprehender to access a figurative interpretation of a metonym.

Abstract Purpose The landiolol and organ failure in patients with septic shock (STRESS-L study) included a pre-planned sub-study to assess the effect of landiolol treatment on inflammatory and metabolomic markers. Methods Samples collected from 91 patients randomised to STRESS-L were profiled for immune and metabolomic markers. A panel of pro- and anti-inflammatory cytokines were measured through commercially acquired multiplex Luminex assays and statistically analysed by individual and cluster-level analysis (patient). Metabolite fingerprinting was carried out by flow infusion electrospray ionisation high-resolution mass spectrometry and metabolomic data were analysed using the R-based platform MetaboAnalyst. The metabolites were identified using DIMEdb (dimedb.ibers.aber.ac.uk) from their mass/charge ratios. These metabolomic data were also re-analysed using individual and cluster-level analysis. The individual-level models were adjusted for confounders, such as age, sex, noradrenaline dosage and patient (random effect). Results Analysis was undertaken at cluster- and individual-level. There were no significant differences in cytokine concentration level between trial arms nor survivors and non-survivors over the duration of the observations from day 1 to day 4. Metabolomic analysis showed some separation in the levels of ceramides and cardiolipins between those who survived and those who died. Following adjusted analysis for confounders, plasma metabolite concentrations remained statistically different between landiolol and standard care arms for succinic acid, l-tryptophan, l-alanine, 2,2,2-trichloroethanol, lactic acid and d-glucose. Conclusions In a study of ICU patients with established septic shock and a tachycardia, landiolol treatment used to reduce the heart rate from above 95 to a range between 80 and 94 beats per minute did not induce significant cytokine changes. d-Glucose, lactic acid, succinic acid, l-alanine, l-tryptophan and trichloroethanol were pathways that may merit further investigation. Trial Registration: EU Clinical Trials Register Eudra CT: 2017-001785-14 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-001785-14/GB ); ISRCTN registry Identifier: ISRCTN12600919 ( https://www.isrctn.com/ISRCTN12600919 ).

Objectives To evaluate whether osteopathic and related manual interventions improve adult mental health (depression, anxiety, stress) and psychophysiological measures (eg, heart rate variability, skin conductance).Design Systematic review and meta-analysis of randomised controlled trials (RCTs).Data sources PubMed, MEDLINE (Ovid), Scopus, Cochrane, and AMED, searched through September 2024.Eligibility criteria English-language RCTs with ≥30 participants investigating osteopathic or related manual therapies (eg, myofascial release, high-velocity low-amplitude thrusts) delivered by qualified practitioners, compared with no treatment or sham, and reporting immediate postintervention mental health or psychophysiological outcomes.Data extraction and synthesis Full-text screening, risk-of-bias assessment and data extraction were conducted independently by multiple reviewers using a standardised Joanna Briggs Institute (JBI) Extraction Form. Risk of bias was assessed using the JBI Critical Appraisal Checklist. For meta-analyses, Hedges’ g (with 95% CIs) was calculated from postintervention means and SD. Random-effects models accounted for heterogeneity, and prediction intervals were calculated to assess uncertainty in effect estimates.Results 20 RCTs were included. Osteopathic interventions reduced depression (Hedges’ g=−0.47, 95% CI: −0.86 to –0.09, p=0.02) and increased skin conductance (Hedges’ g=0.67, 95% CI: 0.00 to 1.34, p=0.05). Depression improvements were greater in pain populations (Hedges’ g=−0.61, 95% CI: –1.06 to –0.17, p=0.01). However, wide prediction intervals and moderate heterogeneity indicate uncertainty in true effect sizes, and limited studies and sample sizes restrict assessment of publication bias.Conclusions Osteopathic and related manual therapies may reduce depression and influence certain psychophysiological markers, particularly in pain populations, but uncertainty and heterogeneity limit confidence. More rigorous, larger, and longitudinal RCTs are needed.Trial registration number This meta-analysis was not formally registered, though the protocol and search strategy can be found at Open Science Framework, registration identification: https://osf.io/jrtpx/.

Abstract BackgroundResearchers have encountered challenges in recruiting unpaid caregivers of people living with Alzheimer disease and related dementias for intervention studies. However, little is known about the reasons for nonparticipation in in-home smart health interventions in community-based settings. ObjectiveThis study aimed to (1) assess recruitment rates in a smart health technology intervention for caregivers of people living with Alzheimer disease and related dementias and reasons for nonparticipation among them and (2) discuss lessons learned from recruitment challenges and strategies to improve recruitment. MethodsThe smart health intervention was a 4-month, single-arm trial designed to evaluate an in-home, technology-based intervention that monitors stressful moments for caregiving dyads through acoustic signals and to provide the caregivers with real-time stress management strategies. The recruitment involved two main methods: on-site engagement by a recruiter from a memory clinic and social media advertising. Caregivers were screened for eligibility by phone between January 2021 and September 2023. The recruitment rates, reasons for nonparticipation, and participant demographics were analyzed using descriptive statistics. ResultsOf 201 caregivers contacted, 11 were enrolled in this study. Eighty-two caregivers did not return the screening call, and others did not participate due to privacy concerns (n=30), lack of interest (n=29), and burdensome study procedures (n=26). Our recruitment strategies included addressing privacy concerns, visualizing collected data through a dashboard, boosting social media presence, increasing the recruitment budget, updating advertisements, and preparing and deploying additional study devices. ConclusionsThis study highlighted barriers to participation in the smart health intervention. Despite several recruitment strategies, enrollment rates remained below expectations. These findings underscore the need for future research to explore alternative methods for increasing the recruitment of informal dementia caregivers in technology-based intervention studies.

The discovery and localization of FRB 20240209A by the Canadian Hydrogen Intensity Mapping Fast Radio Burst (CHIME/FRB) experiment marks the first repeating FRB localized with the CHIME/FRB Outriggers and adds to the small sample of repeating FRBs with associated host galaxies. Here we present Keck and Gemini observations of the host that reveal a redshift z = 0.1384 ± 0.0004. We perform stellar population modeling to jointly fit the optical through mid-IR data of the host and infer a median stellar mass log( M _* / M _⊙ ) = 11.35 ± 0.01 and a mass-weighted stellar population age ~11 Gyr, corresponding to the most massive and oldest FRB host discovered to date. Coupled with a star formation rate

Background: The addition of computer navigation (CN) technology in direct anterior approach (DAA) total hip arthroplasty (THA) has the potential to improve restoration of hip offset and leg length. In this investigation, we examine the effect of one fluoroscopic-based CN system on biomechanical parameters in DAA THA with femur-first (FF) workflow. Methods: A retrospective review was performed on 235 primary DAA FF THA cases, with 100 CN cases and 135 in the conventional fluoroscopic overlay (FO) group. Radiographic examination was performed. Radiographic outcome measures included differences in hip center position, femoral offset, global offset, and leg length between the THA and native hips. Intraoperative and postoperative complications were also documented. Statistical analysis was performed using a t test for continuous data and a ꭓ2 test for categorical data. Results: While there were differences in individual components of femoral offset and the horizontal hip center, mean difference in global offset was not statistically different between the CN (mean: 2.15 mm) and FO (mean: 1.85 mm) groups (P = .898). The number of outliers was also statistically insignificant. The CN group demonstrated significant improvement in mean leg length discrepancy (mean: 1.52 mm) in comparison to the FO group (mean: 2.26 mm) (P = .001), with 1.09% and 8.89% of outliers, respectively (P = .013). Conclusions: The addition of CN technology to DAA FF THA improved the accuracy and precision of restoring leg length. CN did not significantly affect global offset. There was no significant difference in complications between the CN and FO groups.

Conflict of interest: Yes, Full disclosures sent separately. Introduction and Objectives: Seladelpar reduces biochemical markers of cholestasis and pruritus in patients with primary biliary cholangitis. ASSURE (NCT03301506) is an ongoing, open-label, long-term Phase 3 trial of seladelpar in patients rolling over from Phase 3 RESPONSE (NCT04620733) or legacy studies (NCT03602560, NCT02955602, NCT03301506, and NCT04950764). We report interim 2-year efficacy and safety results. Patients / Materials and Methods: Patients with insufficient response/intolerance to ursodeoxycholic acid could enroll in ASSURE. Key endpoints were composite biochemical response (alkaline phosphatase [ALP]

Abstract We studied clinical AI-supported decision-making as an example of a high-stakes setting in which explainable AI (XAI) has been proposed as useful (by theoretically providing physicians with context for the AI suggestion and thereby helping them to reject unsafe AI recommendations). Here, we used objective neurobehavioural measures (eye-tracking) to see how physicians respond to XAI with N = 19 ICU physicians in a hospital’s clinical simulation suite. Prescription decisions were made both pre- and post-reveal of either a safe or unsafe AI recommendation and four different types of simultaneously presented XAI. We used overt visual attention as a marker for where physician mental attention was directed during the simulations. Unsafe AI recommendations attracted significantly greater attention than safe AI recommendations. However, there was no appreciably higher level of attention placed onto any of the four types of explanation during unsafe AI scenarios (i.e. XAI did not appear to ‘rescue’ decision-makers). Furthermore, self-reported usefulness of explanations by physicians did not correlate with the level of attention they devoted to the explanations reinforcing the notion that using self-reports alone to evaluate XAI tools misses key aspects of the interaction behaviour between human and machine.

Brain-computer interfaces (BCIs) enable direct communication between the brain and external computers, allowing processing of brain activity and the ability to control external devices. While often used for medical purposes, BCIs may also hold great promise for nonmedical purposes to unlock human neurocognitive potential. In this Essay, we discuss the prospects and challenges of using BCIs for cognitive enhancement, focusing specifically on invasive enhancement BCIs (eBCIs). We discuss the ethical, legal, and scientific implications of eBCIs, including issues related to privacy, autonomy, inequality, and the broader societal impact of cognitive enhancement technologies. We conclude that the development of eBCIs raises challenges far beyond practical pros and cons, prompting fundamental questions regarding the nature of conscious selfhood and about who-and what-we are, and ought, to be.

Objectives Understanding the burden of disease of sepsis is essential for monitoring the effectiveness of international strategies to improve sepsis care. Our objective was to describe the multinational trend of sepsis-related mortality for the period 1985–2019 from the WHO Mortality Database.Design Retrospective analysis of the WHO Mortality Database.Setting We included data from all countries defined by the WHO as having ‘high usability data’ and at least 10 years of total available data.Participants From the WHO list of 50 countries with high usability data, 14 (28%) were excluded due to excessive missingness. We included and analysed data separately for male and female.Primary and secondary outcome measures We analysed age-standardised mortality rates (ASMR) (weighted average of the age-specific mortality rates per 100 000 people, where the weights are the proportions of people in the corresponding age groups of the WHO standard population).Results We included 1104 country-years worth of data from 36 countries with high usability data, accounting for around 15% of the world’s population. The median ASMR for men decreased from 37.8 deaths/100 000 (IQR 28.4–46.7) in 1985–1987 to 25.8 deaths/100 000 (IQR 19.2–37) in 2017–2019, an approximately 12% absolute (31.8% relative) decrease. For women, the overall ASMR decreased from 22.9 deaths/100 000 (IQR 17.7–32.2) to 16.2 deaths/100 000 (IQR 12.6–21.6), an approximately 6.7% absolute decrease (29.3% relative decrease). The analysis of country-level data revealed wide variations in estimates and trends.Conclusions We observed a decrease in reported sepsis-related mortality across the majority of analysed nations between 1985 and 2019. However, significant variability remains between gender and health systems. System-level and population-level factors may contribute to these differences, and additional investigations are necessary to further explain these trends.

Abstract Background This study examined perceptions of coercion, pressures and procedural injustice and how such perceptions influenced psychological well-being in those who experienced a UK COVID-19 lockdown, with a view to preparing for the possibility of future lockdowns. Methods 40 individuals categorised as perceiving the lockdown(s) as either highly or lowly coercive took part in one of six asynchronous virtual focus groups (AVFGs). Results Using thematic analysis, the following key themes were identified in participants’ discussions: (1) Choice, control and freedom; (2) threats; (3) fairness; (4) circumstantial factors; and (5) psychological factors. Conclusions As the first qualitative study to investigate the psychological construct of perceived coercion in relation to COVID-19 lockdowns, its findings suggest that the extent to which individuals perceived pandemic-related lockdowns as coercive may have been linked to their acceptance of restrictions. Preparing for future pandemics should include consideration of perceptions of coercion and efforts to combat this, particularly in relation to differences in equity, in addition to clarity of public health messaging and public engagement.

Background/Objectives: Two fibre optic probes were custom designed to perform Raman and near-infrared spectroscopic measurements. Our long-term objective is to develop a non-destructive tool able to collect data in hard-to-access locations for real-time analysis or diagnostic purposes. This study evaluated the quantitative performances of Probe A and Probe B using model pharmaceutical tablets. Methods: Measurements were performed using pharmaceutical tablets containing hydroxyl propylcellulose, titanium dioxide (anatase), lactose monohydrate, and indomethacin (γ form). Material content and thickness of bilayer samples (samples consisting of a top layer and a bottom layer of differing materials) were also assessed using Probe A to evaluate its capabilities to collect sub-surface information. Principal component analysis and partial least squares regression models were using individual and fused data to evaluate the performances of the different probe configurations. Results: Hydroxymethyl cellulose (RP2=0.98, RMSEP = 2.27% w/w) and lactose monohydrate (RP2=0.97, RMSEP = 2.96% w/w) content were most effectively estimated by near-infrared spectroscopy data collected using Probe A. Titanium dioxide (RP2=0.99, RMSEP = 0.21% w/w) content was most effectively estimated using a combination of 785 nm Raman spectroscopy and near-infrared spectroscopy using Probe B. Indomethacin (RP2=0.97, RMSEP = 1.01% w/w) was best estimated using a low-level fused dataset collected using 0 mm, 2.5 mm, and 5.0 mm lateral offsets of 785 nm spatially offset Raman spectroscopy using Probe A. Conclusions: The different probe configurations were able to reliably collect data and demonstrated robust quantitative performances. These results highlight the advantage of using multiple techniques for analysing different structures.

Background & Aims: Patients with nonalcoholic fatty liver disease (NAFLD)/metabolic dysfunction-associated steatotic liver disease (MASLD) face a multifaceted disease burden which includes impaired health-related quality of life (HRQL) and potential stigmatization. We aimed to assess the burden of liver disease in patients with NAFLD and the relationship between experience of stigma and HRQL. Methods: Members of the Global NASH Council created a survey about disease burden in NAFLD. Participants completed a 35-item questionnaire to assess liver disease burden (LDB) (seven domains), the 36-item CLDQ-NASH (six domains) survey to assess HRQL and reported their experience with stigmatization and discrimination. Results: A total of 2,117 patients with NAFLD from 24 countries completed the LDB survey (48% Middle East and North Africa, 18% Europe, 16% USA, 18% Asia) and 778 competed CLDQ-NASH. Of the study group, 9% reported stigma due to NAFLD and 26% due to obesity. Participants who reported stigmatization due to NAFLD had substantially lower CLDQ-NASH scores (all p

Abstract The influence of AI recommendations on physician behaviour remains poorly characterised. We assess how clinicians’ decisions may be influenced by additional information more broadly, and how this influence can be modified by either the source of the information (human peers or AI) and the presence or absence of an AI explanation (XAI, here using simple feature importance). We used a modified between-subjects design where intensive care doctors (N = 86) were presented on a computer for each of 16 trials with a patient case and prompted to prescribe continuous values for two drugs. We used a multi-factorial experimental design with four arms, where each clinician experienced all four arms on different subsets of our 24 patients. The four arms were (i) baseline (control), (ii) peer human clinician scenario showing what doses had been prescribed by other doctors, (iii) AI suggestion and (iv) XAI suggestion. We found that additional information (peer, AI or XAI) had a strong influence on prescriptions (significantly for AI, not so for peers) but simple XAI did not have higher influence than AI alone. There was no correlation between attitudes to AI or clinical experience on the AI-supported decisions and nor was there correlation between what doctors self-reported about how useful they found the XAI and whether the XAI actually influenced their prescriptions. Our findings suggest that the marginal impact of simple XAI was low in this setting and we also cast doubt on the utility of self-reports as a valid metric for assessing XAI in clinical experts.

Large randomized trials in sepsis have generally failed to find effective novel treatments. This is increasingly attributed to patient heterogeneity, including heterogeneous cardiovascular changes in septic shock. We discuss the potential for machine learning systems to personalize cardiovascular resuscitation in sepsis. While the literature is replete with proofs of concept, the technological readiness of current systems is low, with a paucity of clinical trials and proven patient benefit. Systems may be vulnerable to confounding and poor generalization to new patient populations or contemporary patterns of care. Typical electronic health records do not capture rich enough data, at sufficient temporal resolution, to produce systems that make actionable treatment suggestions. To resolve these issues, we recommend a simultaneous focus on technical challenges and removing barriers to translation. This will involve improving data quality, adopting causally grounded models, prioritizing safety assessment and integration into healthcare workflows, conducting randomized clinical trials and aligning with regulatory requirements.

Objectives To determine the feasibility and acceptability of ‘ACTing Minds’, a novel single-player adventure video game based on acceptance and commitment therapy (ACT).Design A single-arm, mixed-methods repeated measures feasibility study.Setting Intervention and questionnaires were completed at home by participants. Semistructured interviews were also conducted at home via the Zoom platform.Participants Thirty-six participants were recruited into the study, 29 completed all phases of the feasibility design. Eligibility criteria required participants to be over the age of 18 and self-reporting experiencing ongoing depression, anxiety or stress.Intervention Participants completed a single session of the ‘ACTing Minds’ video game, lasting approximately 1 hour, designed to educate users on key principles from ACT.Primary outcome measures Participant recruitment and retention, questionnaire completion, long-term intervention adherence and acceptability of the intervention. Reflexive thematic analysis was conducted on semistructured interviews run immediately postintervention and 3 weeks later.Secondary outcome measures Measures of depression, anxiety, stress, psychological flexibility, social connectedness and well-being were assessed at baseline, immediately following intervention completion, and after a 3-week follow-up period. We used a standardised battery of questionnaires.Primary results Twenty-nine participants completed the study. A reflexive thematic analysis indicated that participants responded positively to the intervention and the study at all stages. Themes reflect participants’ desire for an engaging therapeutic experience, use of game for exploring emotions, as well as their perspectives on how they had applied their learning to the real world.Secondary results Quantitative results indicated small to large effect sizes associated with decreases in depression (ηp2 = 0.011), anxiety (ηp2 = 0.096) and stress (ηp2 = 0.108), and increases in psychological flexibility (ηp2 = 0.060), social connectedness (ηp2 = 0.021), well-being (ηp2 = 0.011) and participation in usual activities (ηp2 = .307).Conclusions Implementation of the ‘ACTing Minds’ intervention is warranted, based on both qualitative and quantitative outcomes.Trial registration number NCT04566042 ClinicalTrials.gov

We present the localization and host galaxy of FRB 20190208A, a repeating source of fast radio bursts (FRBs) discovered using CHIME/FRB. As part of the Pinpointing REpeating ChIme Sources with EVN dishes repeater localization program on the European VLBI Network (EVN), we monitored FRB 20190208A for 65.6 hr at ∼1.4 GHz and detected a single burst, which led to its very long baseline interferometry localization with 260 mas uncertainty (2 σ ). Follow-up optical observations with the MMT Observatory ( i ≳ 25.7 mag (AB)) found no visible host at the FRB position. Subsequent deeper observations with the Gran Telescopio Canarias, however, revealed an extremely faint galaxy ( r = 27.32 ± 0.16 mag), very likely (99.95%) associated with FRB 20190208A. Given the dispersion measure of the FRB (∼580 pc cm ^−3 ), even the most conservative redshift estimate ( ${z}_{\max }\sim 0.83$ ) implies that this is the lowest-luminosity FRB host to date (≲10 ^8 L _⊙ ), even less luminous than the dwarf host of FRB 20121102A. We investigate how localization precision and the depth of optical imaging affect host association and discuss the implications of such a low-luminosity dwarf galaxy. Unlike the other repeaters with low-luminosity hosts, FRB 20190208A has a modest Faraday rotation measure of a few tens of rad m ^−2 , and EVN plus Very Large Array observations reveal no associated compact persistent radio source. We also monitored FRB 20190208A for 40.4 hr over 2 yr as part of the Extragalactic Coherent Light from Astrophysical Transients repeating FRB monitoring campaign on the Nançay Radio Telescope and detected one burst. Our results demonstrate that, in some cases, the robust association of an FRB with a host galaxy will require both high localization precision and deep optical follow-up.

Research on visually driven behavior in anurans has often focused on Dendrobatoidea, a clade with extensive variation in skin reflectance, which is perceived to range from cryptic to conspicuous coloration. Because these skin patterns are important in intraspecific and interspecific communication, we hypothesized that the visual spectral sensitivity of dendrobatids should vary with conspecific skin spectrum. We predicted that the physiological response of frog retinas would be tuned to portions of the visible light spectrum that match their body reflectance. Using wavelength-specific electroretinograms (ERGs; from 350-650 nm), spectrometer measurements, and color-calibrated photography of the skin, we compared retinal sensitivity and reflectance of two cryptic species (Allobates talamancae and Silverstoneia flotator), two intermediate species (Colostethus panamansis and Phyllobates lugubris), and two conspicuous aposematic species (Dendrobates tinctorius and Oophaga pumilio). Consistent with the matched filter hypothesis, the retinae of cryptic and intermediate species were sensitive across the spectrum, without evidence of spectral tuning to specific wavelengths, yielding low-threshold broadband sensitivity. In contrast, spectral tuning was found to be different between morphologically distinct populations of O. pumilio, where frogs exhibited retinal sensitivity better matching their morph's reflectance. This sensory specialization is particularly interesting given the rapid phenotypic divergence exhibited by this species and their behavioral preference for sympatric skin reflectances. Overall, this study suggests that retinal sensitivity is coevolving with reflective strategy and spectral reflectance in dendrobatids.

FRB 20220610A is a high-redshift fast radio burst (FRB) that has not been observed to repeat. Here, we present rest-frame UV and optical Hubble Space Telescope observations of the field of FRB 20220610A. The imaging reveals seven extended sources, one of which we identify as the most likely host galaxy with a spectroscopic redshift of z = 1.017. We spectroscopically confirm three additional sources to be at the same redshift and identify the system as a compact galaxy group with possible signs of interaction among group members. We determine the host of FRB 20220610A to be a star-forming galaxy with a stellar mass of ≈10 ^9.7 M _⊙ , mass-weighted age of ≈2.6 Gyr, and star formation rate (integrated over the last 100 Myr) of ≈1.7 M _⊙ yr ^−1 . These host properties are commensurate with the star-forming field galaxy population at z ∼ 1 and trace their properties analogously to the population of low- z FRB hosts. Based on estimates of the total stellar mass of the galaxy group, we calculate a fiducial contribution to the observed dispersion measure from the intragroup medium of ≈90–182 pc cm ^−3 (rest frame). This leaves a significant excess of ${515}_{-272}^{+122}$ pc cm ^−3 (in the observer frame); further observation will be required to determine the origin of this excess. Given the low occurrence rates of galaxies in compact groups, the discovery of an FRB in one demonstrates a rare, novel environment in which FRBs can occur. As such groups may represent ongoing or future mergers that can trigger star formation, this supports a young stellar progenitor relative to star formation.

Introduction Almost all patients receiving mechanical ventilation (MV) in intensive care units (ICUs) require analgesia and sedation. The most widely used sedative drug is propofol, but there is uncertainty whether alpha2-agonists are superior. The alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B) trial aims to determine whether clonidine or dexmedetomidine (or both) are clinically and cost-effective in MV ICU patients compared with usual care.Methods and analysis Adult ICU patients within 48 hours of starting MV, expected to require at least 24 hours further MV, are randomised in an open-label three arm trial to receive propofol (usual care) or clonidine or dexmedetomidine as primary sedative, plus analgesia according to local practice. Exclusions include patients with primary brain injury; postcardiac arrest; other neurological conditions; or bradycardia. Unless clinically contraindicated, sedation is titrated using weight-based dosing guidance to achieve a Richmond-Agitation-Sedation score of −2 or greater as early as considered safe by clinicians. The primary outcome is time to successful extubation. Secondary ICU outcomes include delirium and coma incidence/duration, sedation quality, predefined adverse events, mortality and ICU length of stay. Post-ICU outcomes include mortality, anxiety and depression, post-traumatic stress, cognitive function and health-related quality of life at 6-month follow-up. A process evaluation and health economic evaluation are embedded in the trial.The analytic framework uses a hierarchical approach to maximise efficiency and control type I error. Stage 1 tests whether each alpha2-agonist is superior to propofol. If either/both interventions are superior, stages 2 and 3 testing explores which alpha2-agonist is more effective. To detect a mean difference of 2 days in MV duration, we aim to recruit 1437 patients (479 per group) in 40–50 UK ICUs.Ethics and dissemination The Scotland A REC approved the trial (18/SS/0085). We use a surrogate decision-maker or deferred consent model consistent with UK law. Dissemination will be via publications, presentations and updated guidelines.Trial registration number ClinicalTrials.gov NCT03653832.

No abstract available.

Objectives The objective of this study is to explore patient, relative/carer and clinician perceptions of barriers to early physical rehabilitation in intensive care units (ICUs) within an associated group of hospitals in the UK and how they can be overcome.Design Qualitative study using semi-structured interviews and thematic framework analysis.Setting Four ICUs over three hospital sites in London, UK.Participants Former ICU patients or their relatives/carers with personal experience of ICU rehabilitation. ICU clinicians, including doctors, nurses, physiotherapists and occupational therapists, involved in the delivery of physical rehabilitation or decisions over its initiation.Primary and secondary outcomes measures Views and experiences on the barriers and facilitators to ICU physical rehabilitation.Results Interviews were carried out with 11 former patients, 3 family members and 16 clinicians. The themes generated related to: safety and physiological concerns, patient participation and engagement, clinician experience and knowledge, teamwork, equipment and environment and risks and benefits of rehabilitation in intensive care. The overarching theme for overcoming barriers was a change in working model from ICU clinicians having separate responsibilities (a multidisciplinary approach) to one where all parties have a shared aim of providing patient-centred ICU physical rehabilitation (an interdisciplinary approach).Conclusions The results have revealed barriers that can be modified to improve rehabilitation delivery in an ICU. Interdisciplinary working could overcome many of these barriers to optimise recovery from critical illness.

Global surgery is developing as new discipline in many countries. Global surgery primarily aims to improve access to quality surgery in low-and-middle Income countries (LMICs). Thus, ensuring appropriate LMIC representation and leadership in global surgery research, projects, and innovations, is essential. There is a paucity of pathways for students and young clinicians in LMICs to attain training in and exposure to global surgery research and projects. If equity in global surgery leadership and scholarship is truly desired, steps need to be taken to ensure that more students and young clinicians in LMICs are exposed to global surgery as an academic discipline and are offered pathways to practice and leadership. This paper explores ways of ensuring this through increased exposure, increased training and increased funding.

We present high-resolution 1.5–6 GHz Karl G. Jansky Very Large Array and Hubble Space Telescope (HST) optical and infrared observations of the extremely active repeating fast radio burst (FRB) FRB 20201124A and its barred spiral host galaxy. We constrain the location and morphology of star formation in the host and search for a persistent radio source (PRS) coincident with FRB 20201124A. We resolve the morphology of the radio emission across all frequency bands and measure a star formation rate (SFR) ≈ 8.9 M _⊙ yr ^−1 , approximately ≈2.5–6 times larger than optically inferred SFRs, demonstrating dust-obscured star formation throughout the host. Compared to a sample of all known FRB hosts with radio emission, the host of FRB 20201124A has the most significantly obscured star formation. While HST observations show the FRB to be offset from the bar or spiral arms, the radio emission extends to the FRB location. We propose that the FRB progenitor could have formed in situ (e.g., a magnetar born from a massive star explosion). It is still plausible, although less likely, that the progenitor of FRB 20201124A migrated from the central bar of the host. We further place a limit on the luminosity of a putative PRS at the FRB position of L _6.0GHz ≲ 1.8 ×10 ^27 erg s ^−1 Hz ^−1 , among the deepest PRS luminosity limits to date. However, this limit is still broadly consistent with both magnetar nebulae and hypernebulae models assuming a constant energy injection rate of the magnetar and an age of ≳10 ^5 yr in each model, respectively.

The Dark Energy Spectroscopic Instrument (DESI) was designed to conduct a survey covering 14,000 deg ^2 over 5 yr to constrain the cosmic expansion history through precise measurements of baryon acoustic oscillations (BAO). The scientific program for DESI was evaluated during a 5 month survey validation (SV) campaign before beginning full operations. This program produced deep spectra of tens of thousands of objects from each of the stellar Milky Way Survey (MWS), Bright Galaxy Survey (BGS), luminous red galaxy (LRG), emission line galaxy (ELG), and quasar target classes. These SV spectra were used to optimize redshift distributions, characterize exposure times, determine calibration procedures, and assess observational overheads for the 5 yr program. In this paper, we present the final target selection algorithms, redshift distributions, and projected cosmology constraints resulting from those studies. We also present a One-Percent Survey conducted at the conclusion of SV covering 140 deg ^2 using the final target selection algorithms with exposures of a depth typical of the main survey. The SV indicates that DESI will be able to complete the full 14,000 deg ^2 program with spectroscopically confirmed targets from the MWS, BGS, LRG, ELG, and quasar programs with total sample sizes of 7.2, 13.8, 7.46, 15.7, and 2.87 million, respectively. These samples will allow exploration of the Milky Way halo, clustering on all scales, and BAO measurements with a statistical precision of 0.28% over the redshift interval z < 1.1, 0.39% over the redshift interval 1.1 < z < 1.9, and 0.46% over the redshift interval 1.9 < z < 3.5.

The Dark Energy Spectroscopic Instrument (DESI) completed its 5 month Survey Validation in 2021 May. Spectra of stellar and extragalactic targets from Survey Validation constitute the first major data sample from the DESI survey. This paper describes the public release of those spectra, the catalogs of derived properties, and the intermediate data products. In total, the public release includes good-quality spectral information from 466,447 objects targeted as part of the Milky Way Survey, 428,758 as part of the Bright Galaxy Survey, 227,318 as part of the Luminous Red Galaxy sample, 437,664 as part of the Emission Line Galaxy sample, and 76,079 as part of the Quasar sample. In addition, the release includes spectral information from 137,148 objects that expand the scope beyond the primary samples as part of a series of secondary programs. Here, we describe the spectral data, data quality, data products, Large-Scale Structure science catalogs, access to the data, and references that provide relevant background to using these spectra.

We present 1–12 GHz Karl G. Jansky Very Large Array observations of nine off-nuclear persistent radio sources (PRSs) in nearby ( z ≲ 0.055) dwarf galaxies, along with high-resolution European VLBI Network observations for one of them at 1.7 GHz. We explore the plausibility that these PRSs are associated with fast radio burst (FRB) sources by examining their properties—physical sizes, host-normalized offsets, spectral energy distributions (SEDs), radio luminosities, and light curves—and compare them to those of the PRSs associated with FRB 20121102A and FRB 20190520B, two known active galactic nuclei (AGN), and one likely AGN in our sample with comparable data, as well as other radio transients exhibiting characteristics analogous to FRB-PRSs. We identify a single source in our sample, J1136+2643, as the most promising FRB-PRS, based on its compact physical size and host-normalized offset. We further identify two sources, J0019+1507 and J0909+5655, with physical sizes comparable to FRB-PRSs, but which exhibit large offsets and flat spectral indices potentially indicative of a background AGN origin. We test the viability of neutron star wind nebula and hypernebula models for J1136+2643 and find that the physical size, luminosity, and SED of J1136+2643 are broadly consistent with these models. Finally, we discuss the alternative interpretation that the radio sources are instead powered by accreting massive black holes, and we outline future prospects and follow-up observations for differentiating between these scenarios.

The dispersion measure of fast radio bursts (FRBs), arising from the interactions with free electrons along the propagation path, constitutes a unique probe of the cosmic baryon distribution. Their constraining power is further enhanced in combination with observations of the foreground large-scale structure and intervening galaxies. In this work, we present the first constraints on the partition of the cosmic baryons between the intergalactic medium (IGM) and circumgalactic medium (CGM), inferred from the FLIMFLAM spectroscopic survey. In its first data release, the FLIMFLAM survey targeted galaxies in the foreground of eight localized FRBs. Using Bayesian techniques, we reconstruct the underlying ∼Mpc-scale matter density field that is traced by the IGM gas. Simultaneously, deeper spectroscopy of intervening foreground galaxies (at impact parameters b _⊥ ≲ r _200 ) and the FRB host galaxies constrains the contribution from the CGM. Applying Bayesian parameter inference to our data and assuming a fiducial set of priors, we infer the IGM cosmic baryon fraction to be ${f}_{\mathrm{igm}}={0.59}_{-0.10}^{+0.11}$ and a CGM gas fraction of ${f}_{\mathrm{gas}}={0.55}_{-0.29}^{+0.26}$ for 10 ^10 M _⊙ ≲ M _halo ≲ 10 ^13 M _⊙ halos. The mean FRB host dispersion measure (rest-frame) in our sample is $\langle {\mathrm{DM}}_{\mathrm{host}}\rangle ={90}_{-19}^{+29}\,\mathrm{pc}\ \ {\mathrm{cm}}^{-3}$ , of which $\langle {\mathrm{DM}}_{\mathrm{host}}^{\mathrm{unk}}\rangle ={69}_{-19}^{+28}\,\mathrm{pc}\ \ {\mathrm{cm}}^{-3}$ arises from the host galaxy interstellar medium (ISM) and/or the FRB progenitor environment. While our current f _igm and f _gas uncertainties are too broad to constrain most galactic feedback models, this result marks the first measurement of the IGM and CGM baryon fractions, as well as the first systematic separation of the FRB host dispersion measure into two components: arising from the halo and from the inner ISM/FRB engine.

The serpentine mineral lizardite displays strong Raman anisotropy in the OH-stretching region, resulting in significant wavenumber shifts (up to ca. 14.5 cm−1) that depend on the orientation of the impinging excitation laser relative to the crystallographic axes. We quantified the relationship between crystallographic orientation and Raman wavenumber using well-characterised samples of Monte Fico lizardite by applying Raman spectroscopy and electron backscatter diffraction (EBSD) mapping on thin sections of polycrystalline samples and grain mounts of selected single crystals, as well as by a spindle stage Raman study of an oriented cylinder drilled from a single crystal. We demonstrate that the main band in the OH-stretching region undergoes a systematic shift that depends on the inclination of the c-axis of the lizardite crystal. The data are used to derive an empirical relationship between the position of this main band and the c-axis inclination of a measured lizardite crystal: y=14.5cos 4 (0.013x+0.02)+(3670±1), where y is the inclination of the c-axis with respect to the normal vector (in degrees), and x is the main band position (wavenumber in cm −1) in the OH-stretching region. This new method provides a simple and cost-effective technique for measuring and quantifying the crystallographic orientation of lizardite-bearing serpentinite fault rocks, which can be difficult to achieve using EBSD alone. In addition to the samples used to determine the above empirical relationship, we demonstrate the applicability of the technique by mapping the orientations of lizardite in a more complex sample of deformed serpentinite from Elba Island, Italy.

Abstract Purpose To perform precision dosimetry in yttrium-90 radioembolization through CT imaging of radiopaque microspheres in a rabbit liver model and to compare extracted dose metrics to those produced from conventional PET-based dosimetry. Materials and methods A CT calibration phantom was designed containing posts with nominal microsphere concentrations of 0.5 mg/mL, 5.0 mg/mL, and 25.0 mg/mL. The mean Hounsfield unit was extracted from the post volumes to generate a calibration curve to relate Hounsfield units to microsphere concentration. A nominal bolus of 40 mg of microspheres was administered to the livers of eight rabbits, followed by PET/CT imaging. A CT-based activity distribution was calculated through the application of the calibration curve to the CT liver volume. Post-treatment dosimetry was performed through the convolution of yttrium-90 dose-voxel kernels and the PET- and CT-based cumulated activity distributions. The mean dose to the liver in PET- and CT-based dose distributions was compared through linear regression, ANOVA, and Bland–Altman analysis. Results A linear least-squares fit to the average Hounsfield unit and microsphere concentration data from the calibration phantom confirmed a strong correlation (r 2 > 0.999) with a slope of 14.13 HU/mg/mL. A poor correlation was found between the mean dose derived from CT and PET (r 2 = 0.374), while the ANOVA analysis revealed statistically significant differences (p

Abstract Background Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX ). Methods In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung–Knapp–Sidik–Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. Results A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. Conclusions Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.

Objectives Establishing confidence in the safety of Artificial Intelligence (AI)-based clinical decision support systems is important prior to clinical deployment and regulatory approval for systems with increasing autonomy. Here, we undertook safety assurance of the AI Clinician, a previously published reinforcement learning-based treatment recommendation system for sepsis.Methods As part of the safety assurance, we defined four clinical hazards in sepsis resuscitation based on clinical expert opinion and the existing literature. We then identified a set of unsafe scenarios, intended to limit the action space of the AI agent with the goal of reducing the likelihood of hazardous decisions.Results Using a subset of the Medical Information Mart for Intensive Care (MIMIC-III) database, we demonstrated that our previously published ‘AI clinician’ recommended fewer hazardous decisions than human clinicians in three out of our four predefined clinical scenarios, while the difference was not statistically significant in the fourth scenario. Then, we modified the reward function to satisfy our safety constraints and trained a new AI Clinician agent. The retrained model shows enhanced safety, without negatively impacting model performance.Discussion While some contextual patient information absent from the data may have pushed human clinicians to take hazardous actions, the data were curated to limit the impact of this confounder.Conclusion These advances provide a use case for the systematic safety assurance of AI-based clinical systems towards the generation of explicit safety evidence, which could be replicated for other AI applications or other clinical contexts, and inform medical device regulatory bodies.

Background: During anterior approach total hip arthroplasty (THA), the femur may be an impediment for acetabular access, pushing reamers proximally and consequently altering the hip center. In an effort to address this, the senior author changed the surgical workflow from acetabulum first (AF) to femur first (FF). The objective of this study was to compare the precision of biomechanical hip reconstruction and clinical outcomes between the FF and AF techniques. Methods: This is a retrospective, case-control study of 267 anterior THAs (132 AF and 135 FF). A normal, contralateral hip was used to determine the native biomechanical parameters. Using a calibrated software program, radiographic measurements were performed to calculate the hip center position, femoral offset, global offset, and leg length of the operative and native hips using 2-week postoperative anteroposterior pelvis radiographs. Demographics, operative information, hemoglobin change, and complication data were obtained. Functional outcomes were assessed with the Hip Dysfunction and Osteoarthritis Outcome Score for Joint Replacement survey at 1 year postoperatively. Results: The groups exhibited similar demographic characteristics. The FF group demonstrated significantly more accurate and more precise reconstruction of horizontal and vertical hip centers, femoral offset, and leg length. There was no significant difference in operative time, hemoglobin change, complication rate, or Hip Disability and Osteoarthritis Outcome Score, Joint Replacement scores between groups. Conclusions: The FF technique allowed for more accurate and precise reconstruction of the hip center, leg length, and offset in THA than the AF workflow. Furthermore, the FF approach demonstrated no significant differences in complication rate or blood loss, nor in clinical outcomes. Level of Evidence: Therapeutic Study Level III.

Abstract Individuals with autism spectrum disorder (ASD) and their first-degree relatives demonstrate automaticity deficits reflected in reduced eye-voice coordination during rapid automatized naming (RAN), suggesting that RAN deficits may be a genetically meaningful marker of ASD language-related impairments. This study investigated whether RAN deficits in ASD extend to a language typologically distinct from English. Participants included 23 Cantonese-speaking individuals with ASD and 39 controls from Hong Kong (HK), and age- and IQ-comparable groups of previously-studied English-speaking individuals with ASD (n = 45) and controls (n = 44) from the US. Participants completed RAN on an eye tracker. Analyses examined naming time, error rate, measures of eye movement reflecting language automaticity, including eye-voice span (EVS; location of eyes versus the named item) and refixations. The HK-ASD group exhibited longer naming times and more refixations than HK-Controls, in a pattern similar to that observed in the US-ASD group. Cultural effects revealed that both HK groups showed longer EVS and more fixations than US groups. Naming time and refixation differences may be ASD-specific impairments spanning cultures/languages, whereas EVS and fixation frequency may be more variably impacted. A potential underlying mechanism of visual “stickiness” may be contributing to this breakdown in language automaticity in ASD.

Abstract The pro-homeostatic lipid mediators elovanoids (ELVs) attenuate cell binding and entrance of the SARS-CoV-2 receptor-binding domain (RBD) as well as of the SARS-CoV-2 virus in human primary alveoli cells in culture. We uncovered that very-long-chain polyunsaturated fatty acid precursors (VLC-PUFA, n-3) activate ELV biosynthesis in lung cells. Both ELVs and their precursors reduce the binding to RBD. ELVs downregulate angiotensin-converting enzyme 2 (ACE2) and enhance the expression of a set of protective proteins hindering cell surface virus binding and upregulating defensive proteins against lung damage. In addition, ELVs and their precursors decreased the signal of spike (S) protein found in SARS-CoV-2 infected cells, suggesting that the lipids curb viral infection. These findings open avenues for potential preventive and disease-modifiable therapeutic approaches for COVID-19.

Abstract Sustained brain chronic inflammation in Alzheimer’s disease (AD) includes glial cell activation, an increase in cytokines and chemokines, and lipid mediators (LMs), concomitant with decreased pro-homeostatic mediators. The inflammatory response at the onset of pathology engages activation of pro-resolving, pro-homeostatic LMs followed by a gradual decrease. We used an APP knock-in (App KI) AD mouse that accumulates β-amyloid (Aβ) and presents cognitive deficits (at 2 and 6 months of age, respectively) to investigate LMs, their precursors, biosynthetic enzymes and receptors, glial activation, and inflammatory proteins in the cerebral cortex and hippocampus at 2-, 4-, 8- and 18-month-old in comparison with wild-type (WT) mice. We used LC-mass-spectrometry and MALDI molecular imaging to analyze LMs and phospholipids, and immunochemistry for proteins. Our results revealed an age-specific lipid and cytokine profile, and glial activation in the App KI mice. Despite an early onset of Aβ pathology, pro-inflammatory and pro-resolving LMs were prominently increased only in the oldest age group. Furthermore, the LM biosynthetic enzymes increased, and their receptor expression decreased in the aged App KI mice. Arachidonic acid (AA)-containing phospholipid molecular species were elevated, correlating with decreased cPLA2 activity. MALDI molecular imaging depicted differential distribution of phospholipids according to genotype in hippocampal layers. Brain histology disclosed increased microglia proliferation starting from young age in the App KI mice, while astrocyte numbers were enhanced in older ages. Our results demonstrate that the brain lipidome is modified preferentially during aging as compared to amyloid pathology in the model studied here. However, alterations in phospholipids signal early pathological changes in membrane composition.