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Background: High lipoprotein (a) [Lp(a)] is associated with adverse limb events in patients undergoing lower extremity revascularization. Lp(a) levels are genetically pre-determined, with LPA gene encoding for two apolipoprotein (a) [apo(a)] isoforms. Isoform size variations are driven by the number of kringle IV type 2 (KIV-2) repeats. Lp(a) levels are inversely correlated with isoform size. In this study, we examined the role of Lp(a) levels, apo(a) size, and inflammatory markers with lower extremity revascularization outcomes. Methods: Twenty-five subjects with chronic peripheral arterial disease (PAD) underwent open or endovascular lower extremity revascularization (mean age, 66.7 ± 9.7 years; Female = 12; Male = 13; Black = 8; Hispanic = 5; and White = 12). Pre- and postoperative medical history, self-reported symptoms, ankle-brachial indices (ABIs), and lower extremity duplex ultrasounds were obtained. Plasma Lp(a), apoB100, lipid panel, and pro-inflammatory markers (IL-6, IL-18, hs-CRP, TNFα) were assayed preoperatively. Isoform size was estimated using gel electrophoresis and weighted isoform size (wIS) calculated based on % isoform expression. Firth logistic regression was used to examine the relationship between Lp(a) levels and wIS with procedural outcomes: symptoms (better/worse), early primary patency at 2 to 4 weeks, ABIs, and reintervention within 3 to 6 months. We controlled for age, sex, history of diabetes, smoking, statin, antiplatelet, and anticoagulation use. Results: Median plasma Lp(a) level was 108 (interrquartile range, 44-301) nmol/L. The mean apoB100 level was 168.0 ± 65.8 mg/dL. These values were not statistically different among races. We found no association between Lp(a) levels and wIS with measured plasma pro-inflammatory markers. However, smaller apo(a) wIS was associated with occlusion of the treated lesion(s) in the postoperative period (odds ratio, 1.97; 95% confidence interval, 1.01-3.86; P < .05). The relationship of smaller apo(a) wIS with reintervention was not as strong (odds ratio, 1.57; 95% confidence interval, 0.96-2.56; P = .07). We observed no association between wIS with patient reported symptoms or change in ABIs. Conclusions: In this small study, subjects with smaller apo(a) isoform size undergoing peripheral arterial revascularization were more likely to experience occlusion in the postoperative period and/or require reintervention. Larger cohort studies identifying the mechanism and validating these preliminary data are needed to improve understanding of long-term peripheral vascular outcomes.

BackgroundIn an era in which digital communication technologies play a pivotal role in everyday life, social housing residents remain highly susceptible to digital exclusion. ObjectiveThis study aims to evaluate the feasibility and acceptability of a telephone-based training intervention designed to empower people to confidently use digital communication technologies (ie, video calls and web-based messaging). MethodsConducted in collaboration with a UK social housing association, the intervention was facilitated by a unitary authority’s Digital Inclusion Team during the COVID-19 pandemic. A mixed methods approach was used, encompassing quantitative and qualitative data collection on demand, reach, implementation, and potential outcomes. Demographic and qualitative data on the reasons for undertaking or not undertaking the training were collected via telephone interviews during the recruitment process. Digital competency and well-being data were collected via a self-reported survey before and after the intervention. ResultsAmong the 4485 residents who were offered training, 67 (1.49%) expressed interest, of whom 12 (18%) of the 67 completed the training. The findings indicate a demand for basic digital training among social housing residents. The key findings revolve around the substantial dropout rate among those who were interested in undertaking the training. Barriers were strongly influenced by socioeconomic and health circumstances, reflecting the sociodigital inequalities commonly found in this group. For the training participants, the intervention was acceptable and achieved its goals, demonstrating the potential of tailored, persistent training efforts in overcoming barriers. There were no changes in self-reported well-being or digital competency outcomes (but this was limited by the small sample size). ConclusionsSociodigital inequalities impact the reach, implementation, and acceptability of telephone-based digital training for social housing residents. Barriers to reaching and training digitally excluded groups can be overcome through the use of trusted intermediaries, personalized recruitment approaches, the minimization of administrative barriers, and tailored and agile training programs. Recognizing the resource-intensive nature of such initiatives, this study calls for enhanced recognition of intermediary efforts in national digital inclusion policies.

Aminophospholipids (aPL) such as phosphatidylserine are essential for supporting the activity of coagulation factors, circulating platelets, and blood cells. Phosphatidylthreonine (PT) is an aminophospholipid previously reported in eukaryotic parasites and animal cell cultures, but not yet in human tissues. Here, we evaluated whether PT is present in blood cells and characterized its ability to support coagulation. Several PT molecular species were detected in human blood, washed platelets, extracellular vesicles, and isolated leukocytes from healthy volunteers using liquid chromatography–tandem mass spectrometry. The ability of PT to support coagulation was demonstrated in vitro using biochemical and biophysical assays. In liposomes, PT supported prothrombinase activity in the presence and absence of phosphatidylserine. PT nanodiscs strongly bound FVa and lactadherin (nM affinity) but poorly bound prothrombin and FX, suggesting that PT supports prothrombinase through recruitment of FVa. PT liposomes bearing tissue factor poorly generated thrombin in platelet poor plasma, indicating that PT poorly supports extrinsic tenase activity. On platelet activation, PT is externalized and partially metabolized. Last, PT was significantly higher in platelets and extracellular vesicle from patients with coronary artery disease than in healthy controls. In summary, PT is present in human blood, binds FVa and lactadherin, supports coagulation in vitro through FVa binding, and is elevated in atherosclerotic vascular disease. Our studies reveal a new phospholipid subclass, that contributes to the procoagulant membrane, and may support thrombosis in patients at elevated risk.

PurposeTo investigate heat stress mitigation strategies on productivity and thermoregulatory responses during simulated occupational work in the heat.MethodsThirteen physically active men (age, 25 ± 4 years; body mass,77.8 ± 14.7 kg; VO2peak, 44.5 ± 9.2 ml·kg−1·min−1) completed five randomized-controlled trials in a hot environment (40°C, 40% relative humidity). Each trial was 4.5 h in duration to simulate an outdoor occupational shift. Thermoregulatory responses (heart rate, HR; rectal temperature, Trec; mean skin temperature, Tsk), perceptual responses (rating of perceived exertion, RPE; thermal sensation; thermal comfort; fatigue) and productivity outcomes (box lifting repetitions, time to exhaustion) were examined in the following heat mitigation strategy interventions: (1) simulated solar radiation with limited fluid intake [SUN]; (2) simulated solar radiation with no fluid restrictions [SUN + H2O]; (3) shade (no simulated solar radiation during trial) with no fluid restrictions [SHADE + H2O]; (4) shade and cooling towels during rest breaks with no fluid restrictions [COOL + H2O]; and (5) shade with cooling towels, cooling vest during activity with no fluid restrictions [COOL + VEST + H2O].Results[COOL + VEST + H2O] had lower Trec compared to [SUN] [p = 0.004, effect size(ES) = 1.48], [SUN + H2O] (p 0.05).ConclusionOur results suggest that during a simulated occupational shift in a laboratory setting, additional heat mitigation strategies ([COOL + VEST + H2O] and [COOL + H2O]) reduced physiological strain and improved box lifting performance to a greater degree than [SUN]. These differences may have been attributed to a larger core to skin temperature gradient or reduction in fatigue, thermal sensation, and RPE during [COOL + H2O] and [COOL + VEST + H2O]. These data suggest that body cooling, hydration, and “shade” (removal of simulated radiant heat) as heat stress mitigation strategies should be considered as it reduces physiological strain while producing no additional harm.

Introduction: Hereditary haemorrhagic telangiectasia (HHT) is a rare multi-organ vascular disease. It is characterised by mucocutaneous telangiectasia, epistaxis, and arteriovenous malformations. Some 70% of patients with HHT are thought to have issues with gastrointestinal (GI) bleeding. Traditional management of GI bleeding in HHT includes monitoring for iron deficiency anaemia, iron replacement, antifibrinolytic therapy and control of identifiable bleeding sites with argon photocoagulation during gastrointestinal endoscopy. Blood transfusion may also be required. Case description: Our case describes a man in his 40s with confirmed HHT, with transfusion-dependent anaemia secondary to GI bleeding. He was commenced on fortnightly bevacizumab (5 mg/kg) for 12 weeks in an attempt to reduce his blood transfusion requirement and manage his anaemia. In the months prior to starting bevacizumab, our patient’s transfusion requirement ranged from 3–5 units of packed red cells per month to maintain an Hb >8 g/dl. He had a marked improvement in his symptoms within the first month of treatment and did not require any further blood transfusion during the three months of treatment. He was given one further IV iron infusion in the final month of his 3-month bevacizumab treatment and did not experience any adverse side effects from bevacizumab. Discussion: HHT results from alterations to genes which encode proteins involved in blood vessel formation. This provides the rationale for using anti VEGF drugs such as bevacizumab. Current evidence for this treatment approach is limited. Conclusion: Bevacizumab can be an effective treatment option in patients with HHT refractory to traditional management.

IntroductionSmall Island Developing States have disproportionately high food insecurity rates, related to complex challenges and vulnerabilities. The COVID-19 pandemic highlighted that within these settings, crises often overlap. We aimed to assess the impact of the concurrent COVID-19 pandemic and volcanic eruption on food production and security in St. Vincent and the Grenadines (SVG).MethodsAn interpretive mixed-methods study was conducted among a convenience sample of consenting adults ≥18 years from 100 households in SVG through a cross-sectional survey and participant interviews (10 households) between September 2021 and March 2022. Food insecurity prevalence over the past year was assessed using the Food Insecurity Experience Scale (FIES; Rasch modeling) and impacts to livelihoods from the pandemic and volcanic eruption was assessed using an adapted Caribbean COVID-19 Food Security and Livelihoods Impact Survey (Caribbean COVID-19 FS&L Survey). Data were analyzed using logistic regression.ResultsDuring the pandemic, 59% of the participants reported decreased income, 63% had no access to markets, 81% had no access to food aid; 34% of the participants had a change in food sources, and 81% reported that food production was negatively impacted by the volcanic eruptions, of which 68% reported decreased food production. The interviews highlighted that access to markets were restricted by fear of leaving home and contracting the COVID-19 virus, and participants who received food aid stated that the number of items were not sufficient for larger families. Almost half of the participants were severely food insecure [48% (95% C.I. 31.2,57.8)]; almost two thirds were moderately to severely food insecure [64% (95% C.I. 50.0, 74.2)]; mean FIES score 5.31 (95% C.I. 5.0,5.6). After adjusting for gender, age, education, and household size, moderate to severe food insecurity was associated with no access to food aid during the pandemic and post-eruptions (odds ratio 3.7; 95% confidence interval 1.5, 9.1; p = 0.004).ConclusionFood insecurity rates were high during the COVID-19 pandemic, exacerbated by volcanic eruptions and insufficient access to food aid. Our results suggest the need for the development of strategies and interventions aimed at increasing the resilience of food systems to mitigate the effects of future disasters.

Macrophages destroy pathogens and diseased cells through Fcγ receptor (FcγR)-driven phagocytosis of antibody-opsonized targets. Phagocytosis requires activation of multiple FcγRs, but the mechanism controlling the threshold for response is unclear. We developed a DNA origami-based engulfment system that allows precise nanoscale control of the number and spacing of ligands. When the number of ligands remains constant, reducing ligand spacing from 17.5 nm to 7 nm potently enhances engulfment, primarily by increasing efficiency of the engulfment-initiation process. Tighter ligand clustering increases receptor phosphorylation, as well as proximal downstream signals. Increasing the number of signaling domains recruited to a single ligand-receptor complex was not sufficient to recapitulate this effect, indicating that clustering of multiple receptors is required. Our results suggest that macrophages use information about local ligand densities to make critical engulfment decisions, which has implications for the mechanism of antibody-mediated phagocytosis and the design of immunotherapies.

Predation structures food webs, influences energy flow, and alters rates and pathways of nutrient cycling through ecosystems, effects that are well documented for macroscopic predators. In the microbial world, predatory bacteria are common, yet little is known about their rates of growth and roles in energy flows through microbial food webs, in part because these are difficult to quantify. Here, we show that growth and carbon uptake were higher in predatory bacteria compared to nonpredatory bacteria, a finding across 15 sites, synthesizing 82 experiments and over 100,000 taxon-specific measurements of element flow into newly synthesized bacterial DNA. Obligate predatory bacteria grew 36% faster and assimilated carbon at rates 211% higher than nonpredatory bacteria. These differences were less pronounced for facultative predators (6% higher growth rates, 17% higher carbon assimilation rates), though high growth and carbon assimilation rates were observed for some facultative predators, such as members of the genera Lysobacter and Cytophaga, both capable of gliding motility and wolf-pack hunting behavior. Added carbon substrates disproportionately stimulated growth of obligate predators, with responses 63% higher than those of nonpredators for the Bdellovibrionales and 81% higher for the Vampirovibrionales, whereas responses of facultative predators to substrate addition were no different from those of nonpredators. This finding supports the ecological theory that higher productivity increases predator control of lower trophic levels. These findings also indicate that the functional significance of bacterial predators increases with energy flow and that predatory bacteria influence element flow through microbial food webs.IMPORTANCE The word "predator" may conjure images of leopards killing and eating impala on the African savannah or of great white sharks attacking elephant seals off the coast of California. But microorganisms are also predators, including bacteria that kill and eat other bacteria. While predatory bacteria have been found in many environments, it has been challenging to document their importance in nature. This study quantified the growth of predatory and nonpredatory bacteria in soils (and one stream) by tracking isotopically labeled substrates into newly synthesized DNA. Predatory bacteria were more active than nonpredators, and obligate predators, such as Bdellovibrionales and Vampirovibrionales, increased in growth rate in response to added substrates at the base of the food chain, strong evidence of trophic control. This work provides quantitative measures of predator activity and suggests that predatory bacteria-along with protists, nematodes, and phages-are active and important in microbial food webs.

Lineage plasticity, the ability of a cell to alter its identity, is an increasingly common mechanism of adaptive resistance to targeted therapy in cancer. An archetypal example is the development of neuroendocrine prostate cancer (NEPC) after treatment of prostate adenocarcinoma (PRAD) with inhibitors of androgen signaling. NEPC is an aggressive variant of prostate cancer that aberrantly expresses genes characteristic of neuroendocrine (NE) tissues and no longer depends on androgens. Here, we investigate the epigenomic basis of this resistance mechanism by profiling histone modifications in NEPC and PRAD patient-derived xenografts (PDXs) using chromatin immunoprecipitation and sequencing (ChIP-seq). We identify a vast network of cis-regulatory elements (N~15,000) that are recurrently activated in NEPC. The FOXA1 transcription factor (TF), which pioneers androgen receptor (AR) chromatin binding in the prostate epithelium, is reprogrammed to NE-specific regulatory elements in NEPC. Despite loss of dependence upon AR, NEPC maintains FOXA1 expression and requires FOXA1 for proliferation and expression of NE lineage-defining genes. Ectopic expression of the NE lineage TFs ASCL1 and NKX2-1 in PRAD cells reprograms FOXA1 to bind to NE regulatory elements and induces enhancer activity as evidenced by histone modifications at these sites. Our data establish the importance of FOXA1 in NEPC and provide a principled approach to identifying cancer dependencies through epigenomic profiling.

Abstract The global COVID-19 pandemic brought considerable public and policy attention to the field of infectious disease modelling. A major hurdle that modellers must overcome, particularly when models are used to develop policy, is quantifying the uncertainty in a model’s predictions. By including the most recent available data in a model, the quality of its predictions can be improved and uncertainties reduced. This paper adapts an existing, large-scale, individual-based COVID-19 model to explore the benefits of updating the model in pseudo-real time. We use Approximate Bayesian Computation (ABC) to dynamically recalibrate the model’s parameter values as new data emerge. ABC offers advantages over alternative calibration methods by providing information about the uncertainty associated with particular parameter values and the resulting COVID-19 predictions through posterior distributions. Analysing such distributions is crucial in fully understanding a model and its outputs. We find that forecasts of future disease infection rates are improved substantially by incorporating up-to-date observations and that the uncertainty in forecasts drops considerably in later simulation windows (as the model is provided with additional data). This is an important outcome because the uncertainty in model predictions is often overlooked when models are used in policy.

Abstract Current treatments to prevent thrombosis, namely anticoagulants and platelets antagonists, remain complicated by the persistent risk of bleeding. Improved therapeutic strategies that diminish this risk would have a huge clinical impact. Antithrombotic agents that neutralize and inhibit polyphosphate (polyP) can be a powerful approach towards such a goal. Here, we report a design concept towards polyP inhibition, termed macromolecular polyanion inhibitors (MPI), with high binding affinity and specificity. Lead antithrombotic candidates are identified through a library screening of molecules which possess low charge density at physiological pH but which increase their charge upon binding to polyP, providing a smart way to enhance their activity and selectivity. The lead MPI candidates demonstrates antithrombotic activity in mouse models of thrombosis, does not give rise to bleeding, and is well tolerated in mice even at very high doses. The developed inhibitor is anticipated to open avenues in thrombosis prevention without bleeding risk, a challenge not addressed by current therapies.

Abstract Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a cell surface antigen for therapeutic targeting in prostate cancer. Here, we report broad expression of STEAP1 relative to prostate-specific membrane antigen (PSMA) in lethal metastatic prostate cancers and the development of a STEAP1-directed chimeric antigen receptor (CAR) T cell therapy. STEAP1 CAR T cells demonstrate reactivity in low antigen density, antitumor activity across metastatic prostate cancer models, and safety in a human STEAP1 knock-in mouse model. STEAP1 antigen escape is a recurrent mechanism of treatment resistance and is associated with diminished tumor antigen processing and presentation. The application of tumor-localized interleukin-12 (IL-12) therapy in the form of a collagen binding domain (CBD)-IL-12 fusion protein combined with STEAP1 CAR T cell therapy enhances antitumor efficacy by remodeling the immunologically cold tumor microenvironment of prostate cancer and combating STEAP1 antigen escape through the engagement of host immunity and epitope spreading.

Abstract Silicon photonics has emerged as a mature technology that is expected to play a key role in critical emerging applications, including very high data rate optical communications, distance sensing for autonomous vehicles, photonic-accelerated computing, and quantum information processing. The success of silicon photonics has been enabled by the unique combination of performance, high yield, and high-volume capacity that can only be achieved by standardizing manufacturing technology. Today, standardized silicon photonics technology platforms implemented by foundries provide access to optimized library components, including low-loss optical routing, fast modulation, continuous tuning, high-speed germanium photodiodes, and high-efficiency optical and electrical interfaces. However, silicon’s relatively weak electro-optic effects result in modulators with a significant footprint and thermo-optic tuning devices that require high power consumption, which are substantial impediments for very large-scale integration in silicon photonics. Microelectromechanical systems (MEMS) technology can enhance silicon photonics with building blocks that are compact, low-loss, broadband, fast and require very low power consumption. Here, we introduce a silicon photonic MEMS platform consisting of high-performance nano-opto-electromechanical devices fully integrated alongside standard silicon photonics foundry components, with wafer-level sealing for long-term reliability, flip-chip bonding to redistribution interposers, and fibre-array attachment for high port count optical and electrical interfacing. Our experimental demonstration of fundamental silicon photonic MEMS circuit elements, including power couplers, phase shifters and wavelength-division multiplexing devices using standardized technology lifts previous impediments to enable scaling to very large photonic integrated circuits for applications in telecommunications, neuromorphic computing, sensing, programmable photonics, and quantum computing.

A capstone experience is a final opportunity for master's of social work students to practice competencies they will apply in the field. To support the transition, we designed and evaluated a capstone course using ethically challenging cases in the Decision Case Method approach, as well as integrating active, embodied participation through Theatre of the Oppressed Forum Theatre. Feedback from students was mixed, with more positive feedback for the Decision Case Method classes. In this teaching note, we present how we researched and designed the course, feedback we received, reasons for the mixed feedback, and lessons learned that will likely be helpful to other social work programs designing capstone experiences.

Snow crab replaced groundfish fisheries as the primary focus of the Newfoundland and Labrador (NL) fishing industry in the mid-1990s. Over the past three decades, management philosophies in this male-only fishery have shifted from promoting industry expansion to promoting industry rationalization to implementing Precautionary Approach (PA) management. Until the mid-2010s, there were regionalized management strategies characterized by higher exploitation rates in northern than southern sub-stock units along the NL marine shelves. However, in the late 2010s, exploitation rates were permitted to elevate to high levels across the entire stock range in association with a large resource decline, and evidence of biological harm through fishing emerged in chronically depleted areas. In 2019, when stock and fishery productivity were near historical lows, a multi-indicator PA system was informally introduced into the management of the resource. This event coincided with anticipated improvements in stock and fishery performance. This paper examines the extent to which the multi-indicator PA management system, focused on the promotion of both biological protection and maximization of fishing efficiency, may have contributed to recent improvements in stock and fishery status. A suite of indicators from areas implementing PA guidance into management in 2019 prior to the formal adoption of the PA system in 2023 suggest the system has been highly beneficial in promoting rapid recovery and improving stock and fishery performance metrics to levels matching or exceeding historical levels under similar conditions. We discuss the capacity of the system to better safeguard biological aspects of resource and fisheries productivity moving forward under a scenario of an expectant resource decline.

Being able to represent and remember verbally-encoded information about spatial environments from different perspectives is important for numerous daily activities. The present study examined how frequently individuals spontaneously engage in visual mental imagery and verbal rehearsal strategies in memory recall of spatial descriptions, and whether using certain strategies is associated with better recall performance. Memory recall for route (person-centred) and survey (object-centred) spatial descriptions was examined in a sample of 105 neurotypical individuals, who also reported to what extent they used route- and survey-based mental imagery and verbal rehearsal strategies in each description. Results showed that participants favoured a path visualisation strategy to recall the route description and a map visualisation strategy to recall the survey description. Regression models further showed that employing both imagery and verbal strategies was associated with better recall for both route and survey descriptions, although imagery strategies held a higher predictive power. The present findings highlight the fact that the spontaneous use of internal strategies in the form of visual imagery and verbal rehearsal is ubiquitous when recalling spatial descriptions and a core part of efficient spatial memory functioning.

This conceptual model paper uses systems theory to explain how key elements in the Australian policy and regulatory context lead to three issues of concern in childcare centre physical environments: siting of centres on busy roads; lack of outdoor space; and, emergency evacuation in high-rise buildings. Drawing on evidence from prior studies and policy documents through desktop research, as well as childcare centre visits and communications with stakeholders and experts, we confirmed these issues as threats to children's health, safety, development and well-being. Adapting Goekler's 'iceberg model' of systems theory, we identified a dominance of commercial childcare property interests and complex and conflicting policy and regulatory structures, as explanatory elements leading to outcomes that conflict with children's best interests.

Background Evidence indicates that the reporting of serious injury in long-term residential care has increased substantially over the past decade. However, what constitutes a serious injury in residential care is poorly and inconsistently defined. This may result in incidences being unnecessarily reported as a serious injury. It is therefore, crucial to develop a consistent definition of serious injury to reduce reporting burden and to facilitate comparison between different residential care settings and across jurisdictions. This protocol describes the methods for a systematic review of existing definitions from the literature to inform the development of a consistent definition of serious injury in long-term residential care. Methods A wide range of published peer-reviewed and grey literature will be sought for this review, including guidance and policy documents. Searches will be conducted of databases including MEDLINE, CINAHL, SocINDEX, Academic Search Ultimate, and Westlaw International. Grey literature database searches will include Trip and Social Care Online. Country specific searches of government and health and social care websites will be conducted. Quality appraisal will be facilitated using the Quality Assessment for Diverse Studies (QuADS) tool and Tyndall’s checklist. The level of confidence in the findings will be assessed using the GRADE CERQual approach. A customised data extraction form will be used to extract data to reduce the risk of bias. Conceptual content analysis of data will facilitate identification of definitions of serious injury and their frequency within texts. Conclusion The findings will inform the development of a consistent definition of serious injury in long-term residential care that will reduce reporting burden, facilitate the accuracy of data collected and allow for comparison across jurisdictions. A more universal and consistent definition will enable regulators, policy makers, service providers and researchers to develop policy and practical interventions to prevent the occurrence of serious injury in long-term residential care.

Summary: Background: New and emerging risks for invasive aspergillosis (IA) bring the need for contemporary analyses of the epidemiology and outcomes of IA, in order to improve clinical practice. Methods: The study was a retrospective, multicenter, cohort design of proven and probable IA in adults from 10 Australasian tertiary centres (January 2017–December 2020). Descriptive analyses were used to report patients’ demographics, predisposing factors, mycological characteristics, diagnosis and management. Accelerated failure-time model was employed to determine factor(s) associated with 90-day all-cause mortality (ACM). Findings: Of 382 IA episodes, 221 (in 221 patients) fulfilled inclusion criteria – 53 proven and 168 probable IA. Median patient age was 61 years (IQR 51–69). Patients with haematologic malignancies (HM) comprised 49.8% of cases. Fifteen patients (6.8%) had no pre-specified immunosuppression and eleven patients (5.0%) had no documented comorbidity. Only 30% of patients had neutropenia. Of 170 isolates identified, 40 (23.5%) were identified as non-Aspergillus fumigatus species complex. Azole-resistance was present in 3/46 (6.5%) of A. fumigatus sensu stricto isolates. Ninety-day ACM was 30.3%. HM (HR 1.90; 95% CI 1.04–3.46, p = 0.036) and ICU admission (HR 4.89; 95% CI 2.93–8.17, p

Background Tendinopathy is a common, painful and functionally limiting condition, primarily managed conservatively using exercise therapy. Review questions (i) What exercise interventions have been reported in the literature for which tendinopathies? (ii) What outcomes have been reported in studies investigating exercise interventions for tendinopathy? (iii) Which exercise interventions are most effective across all tendinopathies? (iv) Does type/location of tendinopathy or other specific covariates affect which are the most effective exercise therapies? (v) How feasible and acceptable are exercise interventions for tendinopathies? Methods A scoping review mapped exercise interventions for tendinopathies and outcomes reported to date (questions i and ii). Thereafter, two contingent systematic review workstreams were conducted. The first investigated a large number of studies and was split into three efficacy reviews that quantified and compared efficacy across different interventions (question iii), and investigated the influence of a range of potential moderators (question iv). The second was a convergent segregated mixed-method review (question v). Searches for studies published from 1998 were conducted in library databases (n = 9), trial registries (n = 6), grey literature databases (n = 5) and Google Scholar. Scoping review searches were completed on 28 April 2020 with efficacy and mixed-method search updates conducted on 19 January 2021 and 29 March 2021. Results Scoping review – 555 included studies identified a range of exercise interventions and outcomes across a range of tendinopathies, most commonly Achilles, patellar, lateral elbow and rotator cuff-related shoulder pain. Strengthening exercise was most common, with flexibility exercise used primarily in the upper limb. Disability was the most common outcome measured in Achilles, patellar and rotator cuff-related shoulder pain; physical function capacity was most common in lateral elbow tendinopathy. Efficacy reviews – 204 studies provided evidence that exercise therapy is safe and beneficial, and that patients are generally satisfied with treatment outcome and perceive the improvement to be substantial. In the context of generally low and very low-quality evidence, results identified that: (1) the shoulder may benefit more from flexibility (effect sizeResistance:Flexibility = 0.18 [95% CrI 0.07 to 0.29]) and proprioception (effect sizeResistance:Proprioception = 0.16 [95% CrI −1.8 to 0.32]); (2) when performing strengthening exercise it may be most beneficial to combine concentric and eccentric modes (effect sizeEccentricOnly:Concentric+Eccentric = 0.48 [95% CrI −0.13 to 1.1]; and (3) exercise may be most beneficial when combined with another conservative modality (e.g. injection or electro-therapy increasing effect size by ≈0.1 to 0.3). Mixed-method review – 94 studies (11 qualitative) provided evidence that exercise interventions for tendinopathy can largely be considered feasible and acceptable, and that several important factors should be considered when prescribing exercise for tendinopathy, including an awareness of potential barriers to and facilitators of engaging with exercise, patients’ and providers’ prior experience and beliefs, and the importance of patient education, self-management and the patient-healthcare professional relationship. Limitations Despite a large body of literature on exercise for tendinopathy, there are methodological and reporting limitations that influenced the recommendations that could be made. Conclusion The findings provide some support for the use of exercise combined with another conservative modality; flexibility and proprioception exercise for the shoulder; and a combination of eccentric and concentric strengthening exercise across tendinopathies. However, the findings must be interpreted within the context of the quality of the available evidence. Future work There is an urgent need for high-quality efficacy, effectiveness, cost-effectiveness and qualitative research that is adequately reported, using common terminology, definitions and outcomes. Study registration This project is registered as DOI: 10.11124/JBIES-20-00175 (scoping review); PROSPERO CRD 42020168187 (efficacy reviews); https://osf.io/preprints/sportrxiv/y7sk6/ (efficacy review 1); https://osf.io/preprints/sportrxiv/eyxgk/ (efficacy review 2); https://osf.io/preprints/sportrxiv/mx5pv/ (efficacy review 3); PROSPERO CRD42020164641 (mixed-method review). Funding This project was funded by the National Institute for Health and Care Research (NIHR) HTA programme and will be published in full in HTA Journal; Vol. 27, No. 24. See the NIHR Journals Library website for further project information. Plain language summary Tendons are cords of strong, flexible tissue that attach muscles to bones, allowing joints to move. Tendinopathy is a common condition that can affect any tendon in the body, causing pain and limiting function. Exercise is often used to treat tendinopathy. We examined over 500 research papers on exercise for tendinopathy. The most common tendons to be studied were the calf (Achilles), knee (patellar), elbow and shoulder. Strengthening exercise was studied most often, especially in lower-limb tendinopathy. Other types of exercise such as stretching, balance and aerobic activity were less common, but were used to some extent in the upper and lower limbs. We found that exercise therapy is safe and beneficial for the tendinopathies that have been studied to date. Exercise may be most beneficial when combined with another intervention such as injection or electro-therapy. Strengthening exercise may be most beneficial for lower-limb tendinopathies. However, more research is needed on the type of strengthening and the dosage, such as how many exercises and how much resistance to use. Shoulder tendinopathies may benefit from exercise that targets joint flexibility and position more than strengthening. We also found that people who receive exercise therapy for tendinopathy are generally satisfied with the effect it has on their symptoms. Finally, we found that an individualised, person-centred approach to delivering exercise therapy is valued by people with tendinopathy. They also believe that the patient-healthcare provider relationship is important for promoting the confidence and motivation people need to continue with exercise programmes, especially when they complete them independently. Although we examined a lot of papers, many of the studies were low quality. This means there is still a need for high-quality studies to tell us how effective specific types of exercise are for specific tendinopathies. There is also a need for more studies on patients’ and professionals’ experiences of receiving or providing exercise for tendinopathy. Scientific summary Background Tendinopathy refers to a spectrum of changes in damaged or diseased tendons leading to pain and functional impairment, often chronic or recurrent in nature. Tendinopathy can affect any muscle-tendon unit in the body but is most reported in the Achilles, patellar, lateral elbow, rotator cuff and hip tendons. Tendinopathy is common, affects all age-groups and, although often associated with athletic populations, it is also prevalent in non-athletic and sedentary populations. Tendinopathy is primarily managed conservatively using exercise therapy that may consist of one or more types of exercise including resistance, flexibility, proprioception, balance and whole-body exercise. A substantive number of studies and systematic reviews have been conducted on various aspects of exercise for tendinopathy. These mostly comprise efficacy studies, with a growing trend towards qualitative studies of lived experience. Previous systematic reviews have typically focussed on individual tendinopathies and included small numbers of homogeneous studies. Driven by the need for clear evidence-based guidance to inform clinical practice in this field, the current mixed-methods evidence synthesis project was designed to comprehensively map the research conducted to date, and to take an inclusive approach to synthesising the evidence on efficacy, feasibility and acceptability of exercise for tendinopathy, to make recommendations for practice and research. Review questions The specific review questions were as follows: (1) What exercise interventions have been reported in the literature and for which tendinopathies? (2) What outcomes have been reported in studies investigating exercise interventions for tendinopathies? (3) Which exercise interventions are most effective across all tendinopathies? (4) Does type/location of tendinopathy or other specific covariates affect which are the most effective exercise therapies? And (5) how feasible and acceptable are exercise interventions for tendinopathies? Methods We conducted an initial scoping review to address questions 1 and 2, followed by an efficacy workstream consisting of three systematic reviews with meta-analyses to address questions 3 and 4, and a convergent segregated mixed-method systematic review to address question 5. All reviews are reported according to the PRISMA 2020 statement and relevant extensions. Scoping review: Using Joanna Briggs Institute (JBI) methodology and an a priori protocol made publicly available on Open Science Framework (OSF) and published in JBI Evidence Synthesis, we searched for studies and systematic reviews on any exercise therapy for any tendinopathy experienced by people of any age or sex. Inclusion was limited to studies published in any language from 1998 onwards and conducted in countries with very high human development (as defined by the United Nations Development Programme). In April 2020 we searched MEDLINE, CINAHL, AMED and SPORTDiscus via EBSCOhost, EMBase via Ovid, the Cochrane library (controlled trials, systematic reviews), JBI Evidence Synthesis, PEDRo and Epistemonikos. We also searched six trial registries, five grey literature databases and Google Scholar. Search results were deduplicated in Proquest® RefWorks. They were then imported to Covidence systematic review software (Melbourne, Australia) where title/abstract followed by full-text screening was conducted by two reviewers independently, with conflicts resolved by a third reviewer. Data were extracted from included studies using a bespoke data-extraction tool developed by the review team using Microsoft Excel®. Efficacy reviews: Using effectiveness review methodology and a priori protocols registered on PROSPERO (overarching methodology) and OSF (review-specific methods), three efficacy reviews were conducted. Efficacy review 1 quantified efficacy through calculation of a range of effect sizes from exercise-only interventions. In efficacy review 2, pairwise effect sizes were calculated to quantify comparative efficacy between different exercise therapies based on their dominant therapy class (e.g. resistance, flexibility, proprioception) and their dominant therapy type (e.g. eccentric-only, static stretching, joint position sense). In efficacy review 3, pairwise effect sizes were calculated between exercise-only therapies, non-exercise therapies (e.g. surgery, injection, manual therapy (MT)) and combined therapies to quantify comparative efficacy across a range of therapy classes frequently used in the management of tendinopathy. Studies were identified from the scoping review search, a search update (19 January 2021) and reference and citation searching of systematic reviews included in the scoping review. Screening was conducted as described above. Risk of bias and data extraction were completed by two independent reviewers. The Grading of Recommendations, Assessment, Development and Evaluations framework was used to assess the strength of evidence. Mixed-method review: Using JBI methodology and an a priori protocol (PROSPERO) we searched for quantitative, qualitative and mixed-methods studies exploring any aspect of feasibility or acceptability of exercise for tendinopathy from patients’ or providers’ perspectives. Studies were identified from the scoping review and effectiveness update searches, and a further search (29 March 2021) to locate additional studies. Screening was conducted as described above and methodological quality was assessed by two reviewers independently using JBI critical appraisal tools, with conflicts at each stage resolved by discussion or a third reviewer. Data were extracted from quantitative studies using a bespoke data-extraction tool developed by the review team in Microsoft Excel®. Data were extracted from qualitative studies using the data-extraction tool in JBI SUMARI software. Data extraction for both data types was conducted by two reviewers independently with conflicts resolved by discussion or a third reviewer. A convergent segregated approach to data synthesis was applied, where each data type was synthesised independently, followed by integration of findings from the quantitative and qualitative syntheses using comparative analysis. Data synthesis was an iterative process involving four reviewers. Results Scoping review: The search identified 13,729 unique studies. Following screening, 555 studies were included in the review, 119 of which were systematic reviews. A range of exercise interventions were reported across multiple tendinopathies, with Achilles, lateral elbow, patellar and rotator cuff-related shoulder pain (RCRSP) the most studied. Strengthening exercise was most frequently reported (84%), with eccentric exercise the most common mode for Achilles (89%), patellar (85%) and lateral elbow tendinopathies (44%). Flexibility exercise was more commonly reported in the upper (≈60%) than lower limb (≈25%). Exercise therapies for RCRSP showed the greatest range with respect to mode of exercise. Reporting of exercise interventions was highly variable such that few were identified as being replicable. A range of health domains and outcome measurement tools were reported, with lack of consensus a key finding in this review. Disability was the most common primary health domain for RCRSP (65%), Achilles (68%) and patellar tendinopathies (75%), and physical function capacity was most common for lateral elbow tendinopathy (49%). Impairment-based outcome measures were dominant across tendinopathies, with psychosocial outcomes rarely reported. Few true effectiveness studies were identified, with most studies being conducted under controlled circumstances. Therefore, efficacy, rather than effectiveness, was explored in the contingent reviews. Efficacy reviews: 204 studies comprising 467 treatment arms (TAs) and 12,081 participants were identified that met the inclusion criteria to be included in at least one of the reviews (review 1: 125 studies/188 TAs; review 2: 55 studies; review 3: 201 studies). In the context of low and often very low strength of evidence, the efficacy reviews concluded that exercise therapy is safe and efficacious, and that patients are generally satisfied with the outcome and perceive their improvements to be substantive. RCRSP may benefit from exercise interventions that focus on flexibility and proprioception more than strengthening. Resistance training that combines both concentric and eccentric exercise may be most beneficial given the intensities and frequencies commonly adopted in practice. Combining exercise with a non-exercise adjunct such as electro-therapy, injection or taping may be most beneficial and could be considered in the early phase of management. Mixed-method review: 96 reports from 94 studies were included in the review (85 quantitative, 11 qualitative). Quantitative findings: For feasibility, measures of adherence, attendance and fidelity were reported in 75, 13 and 3 studies respectively. Self-reported exercise adherence was good (at least 70%) and attendance to supervised exercise sessions excellent (90%). Different approaches to measuring fidelity were used in the three studies, with a range of findings reported. Acceptability was reported in 17 studies as tolerability (n = 15), satisfaction with exercise (n = 2), willingness to do the exercise (n = 2), helpfulness (n = 1) and how easy it was to fit into daily activities (n = 1), with some studies including more than one measure. The findings provide evidence that exercise for tendinopathy is acceptable, but heterogeneity in defining, measuring and reporting the various dimensions of acceptability combined with the limited number of studies reporting acceptability limits our ability to draw firm conclusions. Qualitative findings: 68 findings from 11 studies generated two synthesised findings: (1) patients and healthcare professionals report a range of highly personalised experiences and opinions of exercise therapies along with several barriers and facilitators to adhering to exercise; therefore, a person-centred, individualised approach should be used when delivering such interventions to people with tendinopathy; and (2) patients and healthcare professionals place value on appropriate and timely patient education facilitated by an effective ‘therapeutic alliance’ between patient and physiotherapist, to promote motivation and confidence in the exercise therapy being undertaken. Integration of quantitative and qualitative findings: The qualitative findings largely supported and explained the quantitative findings. For example, qualitative findings explain the factors that can influence adherence, including barriers, facilitators, beliefs, previous experiences and the ‘therapeutic alliance’. They provide explanation for supervised exercise being adhered to more than unsupervised, due to levels of confidence. They also help to explain the range of tolerability reported: beliefs about the pain–exercise relationship, the individualised response to pain, and the impact of symptomatic response all moderate an individual’s tolerability of therapeutic exercise. Environmental factors including group-based exercise and remote supervision via telehealth had been explored in the qualitative but not quantitative studies. Strengths and limitations Strengths: All tendinopathies and all forms of exercise were included in this evidence synthesis, allowing a large amount of data to be included. The modelling approaches featured in both the efficacy and mixed-methods reviews attempted to synthesise these data, identifying general results and where possible exploring heterogeneity to generate novel and clinically relevant findings. In addition, the inclusive approach with regard to tendinopathies, participants, therapies and outcomes enabled the review to synthesise diverse sets of information from both the providers’ and patients’ perspectives to provide the most comprehensive summary of the field to date. We excluded few studies based on language of publication, as we used both automated and personal translation where possible. Limitations: Restricting inclusion to studies conducted in countries with very high human development, by applying the Human Development Index, may have excluded some potentially relevant studies but does make the findings more relevant to the UK context. Several limitations in the available body of evidence were identified through conducting this project and include low-quality evidence, lack of agreed definitions (e.g. adherence), lack of standardised measurements (e.g. feasibility, acceptability), lack of consensus on outcome domains and measurement tools, poor reporting of exercise interventions and patient factors, and a lack of qualitative research. Conclusions and recommendations In conclusion, this comprehensive, robust, inclusive mixed-methods evidence synthesis has provided an extensive map of the contemporary research on exercise for tendinopathy, evaluated the efficacy and comparative efficacy of exercise across the common tendinopathies and identified what is known about the feasibility and acceptability of exercise therapy for the management of tendinopathy from patients’ and providers’ perspectives. The following recommendations can be made. Practice recommendations: Outcome domains are important to consider when evaluating the outcome of specific exercise interventions, with subjective measures likely to result in larger relative improvements compared to objective outcomes. Gathering information on patient satisfaction, including reasons for (dis)satisfaction, would be useful to inform practice. Resistance training should be prescribed at an appropriate intensity and frequency to increase muscle strength and subsequent positive adaptations to tendons. Use of flexibility and proprioceptive exercise should be considered for RCRSP rather than using resistance exercise in isolation; flexibility regimes may also be considered for Achilles tendinopathy. A focus on eccentric resistance exercise above all other treatments does not appear warranted. Given the loading protocols commonly used, it is likely that standard resistance exercise practices that combine concentric and eccentric exercise will be superior to eccentric-only and easier to implement in practice. Exercise could be combined with other non-exercise adjuncts earlier in the rehabilitative process. An individualised, person-centred approach should be taken when delivering exercise therapy to people with tendinopathy. Research recommendations: There is still a need for high-quality adequately powered research in the following areas: dose parameters and their interactions with patient characteristics; cost-effectiveness, which may also investigate models that include multiple modalities earlier in the therapeutic process; true effectiveness studies such as pragmatic trials to better quantify the effectiveness of current and developing therapeutic models. There is a need for exercise interventions to be carefully developed and tested, including their feasibility and acceptability, prior to moving to studies of efficacy and effectiveness. There is also a need for further high-quality qualitative research on patients’ and healthcare professionals’ perceptions and experiences of exercise for tendinopathy to generate a greater depth of understanding of the factors that influence efficacy of exercise therapy and implementation in the real-world clinical setting. Standard reporting of exercise for tendinopathy requires considerable improvement, including the development of, or consensus agreement on, definitions (e.g. of exercise types, intervention components, adherence, feasibility), the use of core outcome sets, and full and transparent reporting in compliance with reporting checklists. Development of a taxonomy for guidance on reporting exercise therapy for tendinopathy, which is introduced in this project, would benefit from further research involving all key stakeholders (e.g. people with experience of exercise for tendinopathy, clinicians, academics, researchers). Policy recommendations: Research funders and service providers need to fund and facilitate research within different care settings to enable cost-effectiveness, acceptability and adherence comparisons between different modes of delivery of exercise interventions for tendinopathy to be conducted. Service provision may need to be adapted and funded to enable a person-centred approach to care and access to additional non-exercise treatment modalities when appropriate. This may include the need for extended periods of intervention to be enabled in order that the timescales of physiological tendon change are reflected in interventions. The use of technologies that facilitate better patient engagement with exercise therapy and more consistent self-reporting of adherence, outcomes and side effects should be explored. Study registration This project is registered as: DOI: 10.11124/JBIES-20-00175 (scoping review) PROSPERO CRD42020168187 (efficacy reviews overarching methodology) https://osf.io/preprints/sportrxiv/y7sk6/ (efficacy review 1) https://osf.io/preprints/sportrxiv/eyxgk/ (efficacy review 2) https://osf.io/preprints/sportrxiv/mx5pv/ (efficacy review 3) PROSPERO CRD42020164641 (mixed-method review). Funding This project was funded by the National Institute for Health and Care Research (NIHR) HTA programme and will be published in full in the HTA Journal; Vol. 27, No. 24. See the NIHR Journals Library website for further project information.

Introduction COVID-19 is an unprecedented public health threat in modern times, especially for older adults or those with chronic illness. Beyond the threat of infection, the pandemic may also have longer-term impacts on mental and physical health. The COVID-19 & Chronic Conditions (‘C3’) study offers a unique opportunity to assess psychosocial and health/healthcare trajectories over 5 years among a diverse cohort of adults with comorbidities well-characterised from before the pandemic, at its onset, through multiple surges, vaccine rollouts and through the gradual easing of restrictions as society slowly returns to ‘normal’.Methods and analysis The C3 study is an extension of an ongoing longitudinal cohort study of ‘high-risk’ adults (aged 23–88 at baseline) with one or more chronic medical conditions during the COVID-19 pandemic. Five active studies with uniform data collection prior to COVID-19 were leveraged to establish the C3 cohort; 673 adults in Chicago were interviewed during the first week of the outbreak. The C3 cohort has since expanded to include 1044 participants across eight survey waves (T1–T8). Four additional survey waves (T9–T12) will be conducted via telephone interviews spaced 1 year apart and supplemented by electronic health record and pharmacy fill data, for a total of 5 years of data post pandemic onset. Measurement will include COVID-19-related attitudes/behaviours, mental health, social behaviour, lifestyle/health behaviours, healthcare use, chronic disease self-management and health outcomes. Mental health trajectories and associations with health behaviours/outcomes will be examined in a series of latent group and mixed effects modelling, while also examining mediating and moderating factors.Ethics and dissemination This study was approved by Northwestern University’s Feinberg School of Medicine Institutional Review Board (STU00215360). Results will be published in international peer-reviewed journals and summaries will be provided to the funders of the study.

BackgroundSocial risk screening rates in many US primary care settings remain low. This realist-informed evaluation explored the mechanisms through which a tailored coaching and technical training intervention impacted social risk screening uptake in 26 community clinics across the United States.MethodsEvaluation data sources included the documented content of interactions between the clinics and implementation support team and electronic health record (EHR) data. Following the realist approach, analysis was composed of iterative cycles of developing, testing and refining program theories about how the intervention did—or didn't—work, for whom, under what circumstances. Normalization Process Theory was applied to the realist program theories to enhance the explanatory power and transferability of the results.ResultsAnalysis identified three overarching realist program theories. First, clinic staff perceptions about the role of standardized social risk screening in person-centered care—considered “good” care and highly valued—strongly impacted receptivity to the intervention. Second, the physicality of the intervention materials facilitated collaboration and impacted clinic leaders' perception of the legitimacy of the social risk screening implementation work. Third, positive relationships between the implementation support team members, between the support team and clinic champions, and between clinic champions and staff motivated and inspired clinic staff to engage with the intervention and to tailor workflows to their settings' needs. Study clinics did not always exhibit the social risk screening patterns anticipated by the program theories due to discrepant definitions of success between clinic staff (improved ability to provide contextualized, person-centered care) and the trial (increased rates of EHR-documented social risk screening). Aligning the realist program theories with Normalization Process Theory constructs clarified that the intervention as implemented emphasized preparation over operationalization and appraisal, providing insight into why the intervention did not successfully embed sustained systematic social risk screening in participating clinics.ConclusionThe realist program theories highlighted the effectiveness and importance of intervention components and implementation strategies that support trusting relationships as mechanisms of change. This may be particularly important in social determinants of health work, which requires commitment and humility from health care providers and vulnerability on the part of patients.

Introduction Many older adults receive assistance in managing chronic conditions. Yet complicating the utility of caregiver support is whether caregivers have sufficient skills to aid in a patient’s self-care. Health literacy and cognition are important determinants of older adults’ health outcomes, but few studies have examined caregiver health literacy, cognition and self-care skills and their relations to patient outcomes.Methods and analysis We will expand an ongoing cognitive ageing cohort study (LitCog) to enroll a parallel caregiver cohort. Caregivers are eligible if they are (1) ≥18 years of age, (2) provided care for ≥6 months and (3) assisted with at least one activity of daily living, instrumental activity of daily living or health management task. Caregivers will complete interviews at time points corresponding with the LitCog participant interviews. Caregivers will complete assessments of health literacy, self-care skills, cognitive function, caregiver healthcare task difficulty, caregiver burden, caregiver self-efficacy, activation, technology use, busyness and routine and relationship quality. Caregivers will self-report the nature and intensity of care provided, and their own health status. Associations between caregiver presence and caregiver capacity with patient outcomes will be examined in a series of regression models, and mediating and moderating factors will be tested.Ethics and dissemination The Institutional Review Board at Northwestern University has approved the study protocol (STU00026255). Results will be published in peer-reviewed journals and summaries will be provided to the funders of the study as well as patients and caregivers.

BackgroundHigh-quality clinical care requires excellent interdisciplinary communication, especially during emergencies, and no tools exist to evaluate communication in critical care. We describe the development of a pragmatic tool focusing on interdisciplinary communication during patient deterioration (CritCom).MethodsThe preliminary CritCom tool was developed after a literature review and consultation with a multidisciplinary panel of global experts in communication, pediatric oncology, and critical care to review the domains and establish content validity iteratively. Face and linguistic validity were established through cognitive interviews, translation, and linguistic synthesis. We conducted a pilot study among an international group of clinicians to establish reliability and usability.ResultsAfter reviewing 105 potential survey items, we identified 52 items across seven domains. These were refined through cognitive interviews with 36 clinicians from 15 countries. CritCom was piloted with 433 clinicians (58% nurses, 36% physicians, and 6% other) from 42 hospitals in 22 countries. Psychometric testing guided the refinement of the items for the final tool. CritCom comprised six domains with five items each (30 total). The final tool has excellent reliability (Cronbach’s alpha 0.81-0.86), usability (93% agree or strongly agree that the tool is easy to use), and similar performance between English and Spanish tools. Confirmatory factor analysis was used to establish the final 6-domain structure.ConclusionsCritCom is a reliable and pragmatic bilingual tool to assess the quality of interdisciplinary communication around patient deterioration for children in diverse resource levels globally. Critcom results can be used to design and evaluate interventions to improve team communication.

BackgroundIdentifying and managing serious spinal pathology (SSP) such as cauda equina syndrome or spinal infection in patients presenting with low back pain is challenging. Traditional red flag questioning is increasingly criticized, and previous studies show that many clinicians lack confidence in managing patients presenting with red flags. Improving decision-making and reducing the variability of care for these patients is a key priority for clinicians and researchers. ObjectiveWe aimed to improve SSP identification by constructing and validating a decision support tool using a Bayesian network (BN), which is an artificial intelligence technique that combines current evidence and expert knowledge. MethodsA modified RAND appropriateness procedure was undertaken with 16 experts over 3 rounds, designed to elicit the variables, structure, and conditional probabilities necessary to build a causal BN. The BN predicts the likelihood of a patient with a particular presentation having an SSP. The second part of this study used an established framework to direct a 4-part validation that included comparison of the BN with consensus statements, practice guidelines, and recent research. Clinical cases were entered into the model and the results were compared with clinical judgment from spinal experts who were not involved in the elicitation. Receiver operating characteristic curves were plotted and area under the curve were calculated for accuracy statistics. ResultsThe RAND appropriateness procedure elicited a model including 38 variables in 3 domains: risk factors (10 variables), signs and symptoms (17 variables), and judgment factors (11 variables). Clear consensus was found in the risk factors and signs and symptoms for SSP conditions. The 4-part BN validation demonstrated good performance overall and identified areas for further development. Comparison with available clinical literature showed good overall agreement but suggested certain improvements required to, for example, 2 of the 11 judgment factors. Case analysis showed that cauda equina syndrome, space-occupying lesion/cancer, and inflammatory condition identification performed well across the validation domains. Fracture identification performed less well, but the reasons for the erroneous results are well understood. A review of the content by independent spinal experts backed up the issues with the fracture node, but the BN was otherwise deemed acceptable. ConclusionsThe RAND appropriateness procedure and validation framework were successfully implemented to develop the BN for SSP. In comparison with other expert-elicited BN studies, this work goes a step further in validating the output before attempting implementation. Using a framework for model validation, the BN showed encouraging validity and has provided avenues for further developing the outputs that demonstrated poor accuracy. This study provides the vital first step of improving our ability to predict outcomes in low back pain by first considering the problem of SSP. International Registered Report Identifier (IRRID)RR2-10.2196/21804

Abstract Future exploration efforts of the Moon, Mars, and other bodies are poised to focus heavily on persistent and sustainable survey and research efforts, especially given the recent interest in a long‐term sustainable human presence at the Moon. Key to these efforts understands a number of important processes on the lunar surface for both scientific and operational purposes. We discuss the potential value of in situ artificial substrate witness plates, powerful tools that can supplement familiar remote sensing and sample acquisition techniques and provide a sustainable way of monitoring processes in key locations on planetary surfaces while maintaining a low environmental footprint. These tools, which we call Biscuits, can use customized materials as wide ranging as zircon‐based spray coatings to metals potentially useable for surface structures, to target specific processes/questions as part of a small, passive witness plate that can be flexibly placed with respect to location and total time duration. We examine and discuss unique case studies to show how processes such as water presence/transport, presence and contamination of biologically relevant molecules, solar activity related effects, and other processes can be measured using Biscuits. Biscuits can yield key location sensitive, time integrated measurements on these processes to inform scientific understanding of the Moon and enable operational goals in lunar exploration. While we specifically demonstrate this on a simulated traverse and for selected examples, we stress all groups interested in planetary surfaces should consider these adaptable, low footprint, and highly informative tools for future exploration.

The addition of glucose to soil has long been used to study the metabolic activity of microbes in soil; however, the response of the microbial ecophysiology remains poorly characterized. To address this, we sequenced the metagenomes and metatranscriptomes of glucose-amended soil microbial communities in a laboratory incubation.

ObjectiveDuring the COVID-19 pandemic, central venous access line teams were implemented at many hospitals throughout the world to provide access for critically ill patients. The objective of this study was to describe the structure, practice patterns, and outcomes of these vascular access teams during the COVID-19 pandemic.MethodsWe conducted a cross-sectional, self-reported study of central venous access line teams in hospitals afflicted with the COVID-19 pandemic. To participate in the study, hospitals were required to meet one of the following criteria: development of a formal plan for a central venous access line team during the pandemic; implementation of a central venous access line team during the pandemic; placement of central venous access by a designated practice group during the pandemic as part of routine clinical practice; or management of an iatrogenic complication related to central venous access in a patient with COVID-19.ResultsParticipants from 60 hospitals in 13 countries contributed data to the study. Central venous line teams were most commonly composed of vascular surgery and general surgery attending physicians and trainees. Twenty sites had 2657 lines placed by their central venous access line team or designated practice group. During that time, there were 11 (0.4%) iatrogenic complications associated with central venous access procedures performed by the line team or group at those 20 sites. Triple lumen catheters, Cordis (Santa Clara, Calif) catheters, and nontunneled hemodialysis catheters were the most common types of central venous lines placed by the teams. Eight (14%) sites reported experience in placing central venous lines in prone, ventilated patients with COVID-19. A dedicated line cart was used by 35 (59%) of the hospitals. Less than 50% (24 [41%]) of the participating sites reported managing thrombosed central lines in COVID-19 patients. Twenty-three of the sites managed 48 iatrogenic complications in patients with COVID-19 (including complications caused by providers outside of the line team or designated practice group).ConclusionsImplementation of a dedicated central venous access line team during a pandemic or other health care crisis is a way by which physicians trained in central venous access can contribute their expertise to a stressed health care system. A line team composed of physicians with vascular skill sets provides relief to resource-constrained intensive care unit, ward, and emergency medicine teams with a low rate of iatrogenic complications relative to historical reports. We recommend that a plan for central venous access line team implementation be in place for future health care crises.

The increased treatment of metastatic castration-resistant prostate cancer (mCRPC) with second-generation antiandrogen therapies (ADT) has coincided with a greater incidence of lethal, aggressive variant prostate cancer (AVPC) tumors that have lost dependence on androgen receptor (AR) signaling. These AR-independent tumors may also transdifferentiate to express neuroendocrine lineage markers and are termed neuroendocrine prostate cancer (NEPC). Recent evidence suggests kinase signaling may be an important driver of NEPC. To identify targetable kinases in NEPC, we performed global phosphoproteomics comparing several AR-independent to AR-dependent prostate cancer cell lines and identified multiple altered signaling pathways, including enrichment of RET kinase activity in the AR-independent cell lines. Clinical NEPC patient samples and NEPC patient-derived xenografts displayed upregulated RET transcript and RET pathway activity. Genetic knockdown or pharmacologic inhibition of RET kinase in multiple mouse and human models of NEPC dramatically reduced tumor growth and decreased cell viability. Our results suggest that targeting RET in NEPC tumors with high RET expression could be an effective treatment option. Currently, there are limited treatment options for patients with aggressive neuroendocrine prostate cancer and none are curative. IMPLICATIONS: Identification of aberrantly expressed RET kinase as a driver of tumor growth in multiple models of NEPC provides a significant rationale for testing the clinical application of RET inhibitors in patients with AVPC.

CD47 acts as a "don't eat me" signal that protects cells from phagocytosis by binding and activating its receptor SIPRA on macrophages. CD47 suppresses multiple different pro-engulfment "eat me" signals, including immunoglobulin G (IgG), complement, and calreticulin, on distinct target cells. This complexity has limited understanding of how the "don't eat me" signal is transduced biochemically. Here, we utilized a reconstituted system with a defined set of signals to interrogate the mechanism of SIRPA activation and its downstream targets. CD47 ligation altered SIRPA localization, positioning SIRPA for activation at the phagocytic synapse. At the phagocytic synapse, SIRPA inhibited integrin activation to limit macrophage spreading across the surface of the engulfment target. Chemical reactivation of integrin bypassed CD47-mediated inhibition and rescued engulfment, similar to the effect of a CD47 function-blocking antibody. Thus, the CD47-SIRPA axis suppresses phagocytosis by inhibiting inside-out activation of integrin signaling in the macrophage, with implications to cancer immunotherapy applications.

Microbial activity increases after rewetting dry soil, resulting in a pulse of carbon mineralization and nutrient availability. The biogeochemical responses to wet-up are reasonably well understood and known to be microbially mediated. Yet, the population level dynamics, and the resulting changes in microbial community patterns, are not well understood as ecological phenomena. Here, we used sequencing of 16S rRNA genes coupled with heavy water (H218O) DNA quantitative stable isotope probing to estimate population-specific rates of growth and mortality in response to a simulated wet-up event in a California annual grassland soil. Bacterial growth and mortality responded rapidly to wet-up, within 3 h, and continued throughout the 168 h incubation, with patterns of sequential growth observed at the phylum level. Of the 37 phyla detected in the prewet community, growth was found in 18 phyla while mortality was measured in 26 phyla. Rapid growth and mortality rates were measurable within 3 h of wet-up but had contrasting characteristics; growth at 3 h was dominated by select taxa within the Proteobacteria and Firmicutes, whereas mortality was taxonomically widespread. Furthermore, across the community, mortality exhibited density-independence, consistent with the indiscriminate shock resulting from dry-down and wet-up, whereas growth was density-dependent, consistent with control by competition or predation. Total aggregated growth across the community was highly correlated with total soil CO2 production. Together, these results illustrate how previously "invisible" population responses can translate quantitatively to emergent observations of ecosystem-scale biogeochemistry.