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The deep continental biosphere is supported by chemolithoautotrophy and depends on rock-derived substrates for energy. The majority of microorganisms in these crustal environments are likely attached to mineral surfaces within rock fractures, making characterization of deep life challenging. To better understand both biogeochemical cycling and mineral-hosted microbial communities in the deep subsurface, we characterized naturally occurring mineral particulate and associated biomass collected from boreholes drilled into a 2.7 Ga banded iron formation within the southern Canadian Shield. Particulate mineralogy was characterized via X-ray diffraction and Fe X-ray absorption near edge structure (XANES) spectroscopy. The particulate in one borehole was identified as a mixture of hematite and quartz, while the other borehole contained a mixture of the iron sulfides mackinawite and greigite, suggesting an active sulfur cycle mediated by microbial activity. Carbon associated with the particulate was imaged via scanning transmission X-ray microscopy and characterized via C XANES spectroscopy. In both boreholes, the particulate was colonized by microbial cells; many samples contained abundant biofilm. The cells and biofilm were chemically distinct, with the C XANES spectra for the cells consisting primarily of a protein-like signal and the biofilm resembling a mixture of protein, saccharide, and lipid. In the borehole containing the sulfidic particulate, the abundance of cells and biofilm increased with sample depth. Mineral particulate found in boreholes, whether forming in situ or as a result of drilling and weathering, are a valuable way to access the deep subsurface without the contamination and disturbance caused by drilling new cores. To better understand the microbial community composition and function associated with the particulate-biofilm aggregates and surrounding groundwater, filtered-water and particulate samples were characterized via shotgun metagenomic sequencing. Metagenomic analyses showed that while microbial communities were distinct between boreholes, all communities contained the genetic potential for the oxidation and reduction of a variety of sulfur phases. This suggests that the biogeochemical cycling of S, potentially connected to Fe cycling in this iron-rich habitat, could be fueling life in deep crustal environments.

This cross-cultural ethnography explored the global student mobility patterns of international students from English-speaking countries in China and asked research questions about (a) their motivational factors and acculturation expectations before arrival; (b) linguistic factors influencing their acculturative stressors in the host group community's culture and its academic, social, and public systems after arrival; and (c) their reflections on intergroup ideologies with the host community after graduation, based on looking ahead. This study collected data through fieldwork by observing and interacting with approximately 80 individuals from the United Kingdom, the United States, Canada, Australia, and New Zealand in university towns in East China during the academic years from 2012 to 2023. In turn, 17 individuals who graduated before 2021 were selected as the final sample to conduct in-depth interviews. The study placed the concepts of acculturation expectations and intergroup ideologies at the nexus of linguistic hegemony, symbolic power, and social space. The overarching findings showed that despite positive motivations to visit China, language barriers led participants to express confusion, culture shock, anxiety, and perceived discrimination in their academic, social, and public domains. However, some participants who remained in China after graduation expressed their authentic voices regarding changes in attitude toward the host community culture and their heritage language. Therefore, this study focused on a different dimension of acculturation and linguistic ideology by examining how a linguistically and culturally dominant cohort faced acculturative challenges and negotiated to cope with their stressors in power dynamics.

Background People with suspected prostate cancer are usually offered either a local anaesthetic transrectal ultrasound-guided prostate biopsy or a general anaesthetic transperineal prostate biopsy. Transperineal prostate biopsy is often carried out under general anaesthetic due to pain caused by the procedure. However, recent studies suggest that performing local anaesthetic transperineal prostate biopsy may better identify cancer in particular regions of the prostate and reduce infection rates, while being carried out in an outpatient setting. Devices to assist with freehand methods of local anaesthetic transperineal prostate may also help practitioners performing prostate biopsies. Objectives To evaluate the clinical effectiveness and cost-effectiveness of local anaesthetic transperineal prostate compared to local anaesthetic transrectal ultrasound-guided prostate and general anaesthetic transperineal prostate biopsy for people with suspected prostate cancer, and local anaesthetic transperineal prostate with specific freehand devices in comparison with local anaesthetic transrectal ultrasound-guided prostate and transperineal prostate biopsy conducted with a grid and stepping device conducted under local or general anaesthetic. Data sources and methods We conducted a systematic review of studies comparing the diagnostic yield and clinical effectiveness of different methods for performing prostate biopsies. We used pairwise and network meta-analyses to pool evidence on cancer detection rates and structured narrative synthesis for other outcomes. For the economic evaluation, we reviewed published and submitted evidence and developed a model to assess the cost-effectiveness of the different biopsy methods. Results We included 19 comparative studies (6 randomised controlled trials and 13 observational comparative studies) and 4 single-arm studies of freehand devices. There were no statistically significant differences in cancer detection rates for local anaesthetic transperineal prostate (any method) compared to local anaesthetic transrectal ultrasound-guided prostate (relative risk 1.00, 95% confidence interval 0.85 to 1.18) (n = 5 randomised controlled trials), as was the case for local anaesthetic transperineal prostate with a freehand device compared to local anaesthetic transrectal ultrasound-guided prostate (relative risk 1.40, 95% confidence interval 0.96 to 2.04) (n = 1 randomised controlled trial). Results of meta-analyses of observational studies were similar. The economic analysis indicated that local anaesthetic transperineal prostate is likely to be cost-effective compared with local anaesthetic transrectal ultrasound-guided prostate (incremental cost below £20,000 per quality-adjusted life-year gained) and less costly and no less effective than general anaesthetic transperineal prostate. local anaesthetic transperineal prostate with a freehand device is likely to be the most cost-effective strategy: incremental cost versus local anaesthetic transrectal ultrasound-guided prostate of £743 per quality-adjusted life-year for people with magnetic resonance imaging Likert score of 3 or more at first biopsy. Limitations There is limited evidence for efficacy in detecting clinically significant prostate cancer. There is comparative evidence for the PrecisionPoint™ Transperineal Access System (BXTAccelyon Ltd, Burnham, UK) but limited or no evidence for the other freehand devices. Evidence for other outcomes is sparse. The cost-effectiveness results are sensitive to uncertainty over cancer detection rates, complication rates and the numbers of core samples taken with the different biopsy methods and the costs of processing them. Conclusions Transperineal prostate biopsy under local anaesthetic is equally efficient at detecting prostate cancer as transrectal ultrasound-guided prostate biopsy under local anaesthetic but it may be better with a freehand device. local anaesthetic transperineal prostate is associated with urinary retention type complications, whereas local anaesthetic transrectal ultrasound-guided prostate has a higher infection rate. local anaesthetic transperineal prostate biopsy with a freehand device appears to meet conventional levels of costeffectiveness compared with local anaesthetic transrectal ultrasound-guided prostate. Study registration This study is registered as PROSPERO CRD42021266443. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR134220) and is published in full in Health Technology Assessment Vol. 28, No. 60. See the NIHR Funding and Awards website for further award information. Plain language summary A prostate biopsy can help determine if a person has prostate cancer. The main ways of performing a prostate biopsy involve taking small samples of the prostate out through the rectum (back passage) or through the perineum – the skin area between the anus and the scrotum (testicles). Both methods use ultrasound images from a probe inserted into the rectum to help the clinician see what they are doing. Taking samples through the rectum is usually carried out under local anaesthetic, whereas taking samples through the perineum is usually carried out under general anaesthetic. We wanted to find out if taking samples through the perineum under local anaesthetic (instead of general anaesthetic) would be equally effective at detecting prostate cancer as the other biopsy methods and whether there was any improvement or change in the sorts of side effects people may have. We also wanted to know if people found the biopsy painful or not. We carried out searches of computer research databases to find relevant clinical and cost-effectiveness studies and compared the effectiveness of the different biopsy methods they used. We read and summarised the results of the studies we found in our search. Our findings showed that taking biopsy samples through the perineum under local anaesthetic had rates of detecting prostate cancer similar to those of the other biopsy methods. But if the clinician also used a freehand device that helps guide the biopsy needle as part of the procedure, then this may be a better method for detecting cancer. The studies we found agreed that performing this prostate biopsy under local anaesthetic was not too painful for most people. Our economic estimates suggest that using a freehand device for local anaesthetic perineal (through the skin of the perineum) biopsy may be a cost-effective use of National Health Service resources. Scientific summary Background Prostate cancer accounts for 30% of all cancers diagnosed in men in the UK and the incidence is rising. It is more common in men over 45 years of age. Symptoms that cannot be attributed to other health conditions include lower back or bone pain, lethargy, erectile dysfunction, haematuria, weight loss and lower urinary tract symptoms. National Institute for Health and Care Excellence (NICE) guideline NG12 advises on recognition and referral of people presenting with possible prostate cancer. A prostate-specific antigen (PSA) test and digital rectal examination should be performed. If PSA levels are raised above normal or if the prostate feels malignant, then the person should be referred for suspected cancer. NICE guideline NG131 advises on diagnosis and management. It recommends a multiparametric magnetic resonance imaging (mpMRI) test with the results reported using a five-point Likert scale to indicate how likely the presence of prostate cancer is. The Likert scale score, or alternatively the Prostate Imaging Reporting and Data System (PI-RADS score, not mentioned in the NICE guideline), is used to assess whether the person is offered a prostate biopsy. People with a score of 3 or above should be offered a multiparametric magnetic resonance imaging (mpMRI)-influenced prostate biopsy. People with a score of 1 or 2 will discuss risks and benefits with a clinician and if a prostate biopsy goes ahead, it should be a systematic biopsy. Two main options for biopsy are transrectal ultrasound prostate biopsy under local anaesthetic (LATRUS) and transperineal prostate biopsy under general anaesthetic (GATP). Biopsies can be either targeted (based on mpMRI findings) or systematic (samples are taken according to a predefined scheme) or both. Recent studies suggest that performing transperineal prostate biopsy under local anaesthetic (LATP) could better identify cancer in particular regions of the prostate and could have lower infection rates than transrectal biopsies while also being able to be carried out in an outpatient setting. Transperineal prostate biopsy is usually carried out under general anaesthetic due to pain caused by the procedure and tolerability is a key issue. Various freehand devices to assist with LATP prostate biopsy are being introduced to the market. The six specific freehand devices specified in the NICE scope for this review are: Cambridge Prostate Biopsy Device (CamPROBE) (JEB Technologies Ltd, Suffolk, UK); EZU-PA3U (Hitachi Ltd, Tokyo, Japan); PrecisionPoint™ Transperineal Access System (BXTAccelyon Ltd, Burnham, UK); SureFire Guide (LeapMed, Jiangsu, China); Trinity® Perine Grid (KOELIS®, NJ, USA); UA1232 puncture attachment (BK Medical, MA, USA). Objectives The aim of this review is to evaluate the diagnostic yield, clinical effectiveness and cost-effectiveness of LATP prostate biopsies performed with or without available specialist devices and equipment, in people with suspected prostate cancer. Two decision questions were prioritised by NICE for this assessment, with input from relevant stakeholders: Decision question 1. Do LATP prostate biopsies in patients with suspected prostate cancer represent a clinically and cost-effective use of National Health Service (NHS) resources? Decision question 2. Do freehand transperineal biopsy devices for LATP prostate biopsies in patients with suspected prostate cancer represent a clinically effective and cost-effective use of NHS resources? There are five comparisons required to address the two decision questions in the NICE scope: LATP-any (using coaxial needle or grid and stepping device or freehand device) versus LATRUS LATP-any (using coaxial needle or grid and stepping device or freehand device) versus GATP LATP-freehand (freehand device only) versus LATRUS LATP-freehand (freehand device only) versus GATP LATP-freehand (freehand device only) versus LATP-grid and stepping device. Methods Systematic review of diagnostic test evaluation and clinical effectiveness A systematic review of diagnostic and clinical effectiveness evidence was conducted following a peer-reviewed protocol. Searches were based on a comprehensive search strategy. Bibliographic databases, including MEDLINE, EMBASE, Web of Science, The Cochrane Library and the International HTA database, were searched for English-language references in July 2021, and these searches were updated at the end of October 2021. Urology conferences and freehand-device company submissions were hand-searched, and reference lists of identified systematic reviews and meta-analyses were checked. Relevant studies were sought through contact with study authors and NICE Specialist Committee members. Studies were eligible if they included people with suspected prostate cancer with an indication for prostate biopsy and reported diagnostic yield, for example, cancer detection rates, or other clinical or patient-reported outcomes. The eligible interventions were any LATP biopsy (of which LATP-freehand biopsy is a subset) and the eligible comparators were LATRUS and GATP; the LATP-grid and stepping device was an eligible comparator when compared with the LATP-freehand intervention. The Cochrane risk of bias tool (version 1) was used to assess risk of bias for the included randomised controlled trials (RCTs) and The Joanna Briggs Institute critical appraisal checklists were used to assess the included observational studies. Two reviewers carried out study selection, data extraction and critical appraisal, with any disagreements resolved through discussion and referred to a third reviewer for resolution as necessary. We conducted meta-analysis of the cancer detection rate outcomes for which sufficient comparative data were available. Pairwise meta-analysis was conducted for the above comparisons, with randomised and non-randomised studies analysed separately. Network meta-analysis was conducted for the two decision questions specified in the NICE scope. We synthesised the data for other outcomes narratively, as evidence was too sparse for meta-analysis. Review of economic evaluations We conducted a systematic review of the cost-effectiveness of the prostate biopsy methods in scope. The search strategies were based on an early version of the clinical effectiveness searches with the addition of an economics search filter. Included studies were full economic evaluations that assessed both costs and consequences for the different prostate biopsy methods. Outcomes included measures of resource use and costs and health outcomes: life-years or quality-adjusted life-years (QALYs) gained. Economic evaluations not meeting the inclusion criteria and studies that reported on resource use and costs, and health-related quality of life (utilities) were assessed as potential sources of information for the economic model. External Assessment Group independent economic assessment We developed a decision model to estimate the cost-effectiveness of alternative biopsy methods for people referred for biopsy with suspected prostate cancer. The model includes a decision tree to estimate diagnostic outcomes and biopsy-related complications, and a Markov model that predicts the long-term costs and consequences of false-negative biopsy results. We assessed cost-effectiveness for four subgroups at different prior levels of risk, based on previous mpMRI results (Likert 1 or 2; or Likert 3 or more) and history of prostate biopsy (none; previous negative biopsy). The decision tree used published results from the economic evaluation of the Prostate MR imaging study (PROMIS) to estimate baseline prevalence in the subgroups of interest, and diagnostic yield of LATRUS biopsy. Cancer detection rates were adjusted for the other biopsy methods using relative risks (RRs) from our network meta-analyses, and evidence from the literature on biopsy complication rates and the probability of repeat biopsy. Costs of the biopsy methods were estimated in a microcosting analysis, as well as from submitted evidence and published sources. The Markov model was a replicated version of a model developed for the 2019 update of the NICE guideline (NG131). Model parameters were based on those in the NG131 model, with some adjustments to costs and utilities from more recent published sources. Results Systematic review of diagnostic test evaluation and clinical effectiveness The literature searches identified a total of 1969 references of which 111 references were subjected to full-text screening. Twenty-seven publications reported 23 studies meeting the inclusion criteria for this review: 19 comparative studies of which 6 were RCTs and 13 were observational studies (1 of which is unpublished); and 4 single-arm studies for LATP-freehand devices where no comparative evidence was identified. There were no statistically significant differences in cancer detection rates for LATP (any method) compared to LATRUS with RR = 1.00 [95% confidence interval (CI) 0.85 to 1.18] (n = 5 RCTs). A single randomised trial estimated a non-significant difference in cancer detection rates in favour of LATP using a freehand device (PrecisionPoint) compared to LATRUS RR = 1.40, 95% CI 0.96 to 2.04. This finding was supported by meta-analysis of observational comparative studies RR = 1.21 (95% CI 1.08 to 1.34) (n = 4 studies). There were no statistically significant differences in cancer detection rates in meta-analyses comparing other biopsy methods. Evidence from the systematic review for other clinical outcomes, biopsy-related complications and patient-reported outcomes was sparse. Review of economic evaluations One economic evaluation was eligible for inclusion in the economic review out of 725 results from the original and update searches. This study evaluated the CamPROBE (LATP-freehand) device versus LATRUS for use in diagnosing prostate cancer from the perspective of the UK NHS. It used a decision-tree model with a Markov model at the terminal nodes and was informed by a prospective case series for the CamPROBE device and data from the PROMIS study. The study suggested that compared with LATRUS, LATP using the CamPROBE freehand device would be cost saving at a device price below £41 per procedure, or more cost-effective at the £20,000 per QALY threshold with a price below £81 per procedure. These calculations assume a zero rate of infection for LATP and equal diagnostic accuracy for LATP using CamPROBE and LATRUS. We considered 13 excluded economic studies as sources to inform our model structure and inputs, including the cost-effectiveness analysis for the PROMIS study and the analysis for the update of the NICE guideline on prostate cancer published in May 2019 (NG131). Evidence from the BXTAccelyon company submission included a cost minimisation study developed in 2020 by the York Health Consortium that compared the costs of LATP (with the PrecisionPoint freehand device) with different combinations of LATRUS and GATP for UK NHS Trusts. The study suggests that LATP using the PrecisionPoint freehand device is cost saving, assuming equal diagnostic yield of the different biopsy methods. Independent economic assessment The base-case economic analysis comparing LATP (all methods) with LATRUS and GATP indicated that LATP is likely to be the most cost-effective option in all four subgroups, with incremental cost-effectiveness ratio (ICER) estimates for LATP compared with LATRUS below £20,000 per QALY gained, and GATP estimated as more expensive and less effective than LATP. These conclusions were supported by probabilistic sensitivity analysis and a wide range of scenario analyses, although the results for LATP compared with LATRUS were sensitive to some alternative sources of cancer detection rates, rates of biopsy-related hospital admissions, numbers of core samples and histopathology costs. The economic analysis including LATP-freehand compared with other LATP methods, as well as LATRUS and GATP, indicated that LATP with a freehand device was the most cost-effective strategy, with an ICER of £743 per QALY for the highest-risk subgroup with MRI Likert score of 3 or more at first biopsy, and £4595 per QALY for the subgroup with a MRI Likert score 1 or 2 at first biopsy. For the subgroups with a previous negative biopsy, the ICER remained below £20,000 per QALY. Again, probabilistic sensitivity analysis supported these results, but scenario analysis highlighted uncertainty related to the cost of the devices, the number of core samples and costs of processing them, and the use of other sources of evidence for cancer detection and biopsy-related complication rates. The more favourable cost-effectiveness estimates for LATP with a freehand device are mostly driven by the cancer detection rates, which rest on a single RCT for LATP with a freehand device (PrecisionPoint). In the scenario based on observational evidence of cancer detection rates, the ICERs for LATP with a freehand device were less favourable, although still well below £20,000 per QALY. Increasing the cost of LATP with a freehand device by assuming the cost of the most expensive device, the ICER remained below £20,000 per QALY for the highest-risk subgroup but not for the other subgroups. Conclusions Transperineal prostate biopsy under local anaesthetic is equally efficient at detecting prostate cancer as transrectal ultrasound-guided prostate biopsy under local anaesthetic but evidence from one RCT, supported by observational studies, suggests that it might be better when using a freehand device. Local anaesthetic transperineal prostate biopsy is associated with urinary retention-type complications, whereas local anaesthetic transrectal ultrasound-guided prostate biopsy has a higher infection rate. Economic evaluation suggests that LATP with a freehand device is likely to be cost-effective compared with LATP with other methods, LATRUS and GATP for patients with no previous biopsy at high risk of having prostate cancer indicated by previous MRI results. This result is sensitive to the estimated cost of the freehand device, the number of and cost of core samples taken, and the sources for biopsy complication rates. Recommendations for research Evidence for freehand devices. There was no comparative evidence for several of the freehand devices in the NICE scope. The TRANSLATE study is expected to help address this question, as it is evaluating the PrecisionPoint, UA1232 and ‘any ultrasound probe-mounted needle guidance device’. Outcomes not covered in included available evidence. We suggest that incidence of defined complications (standardised for grading of severity and length of follow-up), health-related quality of life and longer-term clinical outcomes could be defined in a core outcome set. LATP versus GATP. Evidence for this comparison is sparse (we identified one RCT reporting cancer detection rates). Repeat biopsy population. There is a need for separate reporting of results for this subgroup, or a separate prospective RCT. UK NHS setting. The three UK studies included in our review were single-centre observational studies with a limited set of outcomes. The TRANSLATE study is expected to remedy this; it is a multicentre randomised study across nine NHS Trusts in England. Study registration This study is registered as PROSPERO CRD42021266443. Funding This awardproject was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR134220) and is published in full in Health Technology Assessment Vol. 28, No. 60. See the NIHR Funding and Awards website for further award information.

Abstract Background Residual disease following cytoreductive surgery in patients with ovarian cancer has been associated with poorer survival outcomes compared with no residual disease. We performed a meta-analysis to assess the impact of varying levels of residual disease status on survival outcomes in patients with ovarian cancer who have undergone primary cytoreductive surgery or interval cytoreductive surgery in the setting of new therapies for this disease. Methods Medline, Embase, and Cochrane databases (January 2011 – July 2020) and grey literature, bibliographic and key conference proceedings, were searched for eligible studies. Fixed and random-effects meta-analyses compared progression and survival by residual disease level across studies. Heterogeneity between comparisons was explored via type of surgery, disease stage, and type of adjuvant chemotherapy. Results Of 2832 database and 16 supplementary search articles screened, 50 studies were selected; most were observational studies. The meta-analysis showed that median progression-free survival and overall survival decreased progressively with increasing residual disease (residual disease categories of 0 cm, > 0–1 cm and > 1 cm). Compared with no residual disease, hazard ratios (HR) for disease progression increased with increasing residual disease category (1.75 [95% confidence interval: 1.42, 2.16] for residual disease > 0–1 cm and 2.14 [1.34, 3.39] for residual disease > 1 cm), and also for reduced survival (HR versus no residual disease, 1.75 [ 1.62, 1.90] for residual disease > 0–1 cm and 2.32 [1.97, 2.72] for residual disease > 1 cm). All comparisons were significant (p

Background: Inorganic polyphosphates (polyPs) are linear chains of phosphates that accelerate blood clotting. Targeting polyP in vivo has been shown to reduce thrombosis. Objectives: To identify and characterize anti-polyP monoclonal antibodies that could be used as analytical tools and as antithrombotic agents. Methods: Hybridomas were prepared from spleen cells from autoimmune NZBWF1/J female mice and screened for anti-polyP antibodies. Antibodies that bound polyP using enzyme-linked immunosorbent assay and pull-down assays were further characterized with plate binding, surface plasmon resonance, and plasma-based clotting assays. Antithrombotic potential was evaluated in a murine ferric chloride–induced carotid artery thrombosis model. Results: Of 4 antibodies that bound polyP in our pull-down assay, 2 (PP2069 and PP2099) were available for further characterization. While analyzing these anti-polyP antibodies, we found secretory leukocyte peptidase inhibitor (SLPI) to be a common contaminant of these antibodies and that SLPI binds polyP. We removed SLPI quantitatively from our purified immunoglobulin G. Both PP2069 and PP2099 immunoglobulin G displayed high affinity for polyP but also bound to other polyanions such as DNA, heparin, and certain other glycosaminoglycans, indicating limited specificity. Both antibodies inhibited polyP-initiated plasma clotting in vitro. When tested in vivo in a mouse thrombosis model, however, neither PP2069 nor PP2099 exhibited a significant antithrombotic effect. Conclusion: Autoimmune mice spontaneously produce antibodies against polyP. The 2 examples of anti-polyP monoclonal antibodies studied here not only bound to polyP with high affinity but also cross-reacted with DNA and heparin. Neither antibody protected against thrombosis in a mouse model, but they might have some utility for in vitro studies of polyP.

Faith-based colleges and universities in America have historically been described as "church-related." Unfortunately, this classification is too one-dimensional, revealing virtually nothing about how faith-based identity influences the mission, rhetoric, curriculum, or policies of institutions. Although scholars have advanced sophisticated typologies of Protestant and Catholic institutions, we propose that we still need a new means of empirical analysis to determine the degree to which the faith identity of an institution influences important administrative, curricular, and co-curricular decisions. We then apply our Operationalizing Faith Identity Guide (OFIG) to Protestant institutions in the United States to demonstrate the helpfulness of its application.

Soft X-ray spectromicroscopy at the O K-edge, U N4,5-edges and Ce M4,5-edges has been performed on focused ion beam sections of spent nuclear fuel for the first time, yielding chemical information on the sub-micrometer scale. To analyze these data, a modification to non-negative matrix factorization (NMF) was developed, in which the data are no longer required to be non-negative, but the non-negativity of the spectral components and fit coefficients is largely preserved. The modified NMF method was utilized at the O K-edge to distinguish between two components, one present in the bulk of the sample similar to UO2 and one present at the interface of the sample which is a hyperstoichiometric UO2+x species. The species maps are consistent with a model of a thin layer of UO2+x over the entire sample, which is likely explained by oxidation after focused ion beam (FIB) sectioning. In addition to the uranium oxide bulk of the sample, Ce measurements were also performed to investigate the oxidation state of that fission product, which is the subject of considerable interest. Analysis of the Ce spectra shows that Ce is in a predominantly trivalent state, with a possible contribution from tetravalent Ce. Atom probe analysis was performed to provide confirmation of the presence and localization of Ce in the spent fuel.

Abstract Background Hypercholesterolemia is associated with tendon pathology, but the reasons underpinning this relationship are not well understood. Cholesterol can accumulate in the tendon non-collagenous matrix which may affect both global and local tissue mechanics. Changes to the local strain environment within tendon may have significant implications for mechanosensitive tenocytes. Here, we investigated the association between elevated blood cholesterol and presence of tendon lipids in the Achilles tendon. We expected lipids to be localised in the proteoglycan-rich inter-sub-tendon matrix (ISTM), therefore we also sought to examine the impact of this on the biomechanical and viscoelastic properties of the ISTM. Methods The Achilles tendons of 32 young wild-type (SD) and 32 apolipoprotein E knock-out rats (ApoE −/− ) were harvested at 15.6 ± 2.3 weeks of age. 32 specimens underwent histological examination to assess the distribution of lipids throughout sub-tendons and ISTM. The remaining specimens were prepared for biomechanical testing, where the ISTM between the gastrocnemius and soleus sub-tendons was subjected to shear load mechanical testing. A sub-set of tests were video recorded to enable a strain analysis. Results ApoE −/− serum cholesterol was double that of SD rats (mean 2.25 vs. 1.10 mg/ml, p

Cytotoxic protein aggregation-induced impairment of cell function and homeostasis are hallmarks of age-related neurodegenerative pathologies. As proteasomal degradation represents the major clearance pathway for oxidatively damaged proteins, a detailed understanding of the molecular events underlying its stress response is critical for developing strategies to maintain cell viability and function. Although the 26S proteasome has been shown to disassemble during oxidative stress, its conformational dynamics remains unclear. To this end, we have developed a new quantitative cross-linking mass spectrometry (QXL-MS) workflow to explore the structural dynamics of proteasome complexes in response to oxidative stress. This strategy comprises SILAC-based metabolic labeling, HB tag-based affinity purification, a 2-step cross-linking reaction consisting of mild in vivo formaldehyde and on-bead DSSO cross-linking, and multi-stage tandem mass spectrometry (MSn) to identify and quantify cross-links. This integrated workflow has been successfully applied to explore the molecular events underlying oxidative stress-dependent proteasomal regulation by comparative analyses of proteasome complex topologies from treated and untreated cells. Our results show that H2O2 treatment weakens the 19S-20S interaction within the 26S proteasome, along with reorganizations within the 19S and 20S subcomplexes. Altogether, this work sheds light on the mechanistic response of the 26S to acute oxidative stress, suggesting an intermediate proteasomal state(s) before H2O2-mediated dissociation of the 26S. The QXL-MS strategy presented here can be applied to study conformational changes of other protein complexes under different physiological conditions.

Objectives: The role of community in individuals' well-being has been extensively examined in the Western context. However, little is known about how the host community is related to sojourners' well-being in a crisis in an Asian context. The current study aims at exploring international students’ sense of community in the Chinese context under the direct threat of a global health crisis. Methods: Using a cross-sectional sample of 102 international students staying in Wuhan during the 76-day lockdown at the earliest stage of the COVID-19 pandemic, the current study explored the relationship between international students’ sense of community and anxiety, and the mediating role of social contact, social support from three key sources in the host community (host university, international students, and Chinese friends). Results: Results showed that participants’ stronger sense of community indirectly reduced anxiety via the role of sources of contact and support from the host community. Conclusions: This study provided further evidence to support the nurturance of the sense of community in community resilience and provided implications on how the host community can help to enhance sojourners’ psychological well-being in a global crisis.

This study presents a digital ethnography of the Anglo-Chinese academic family community (ASAFC) amid China's transformation into the post-pandemic era. The ASAFC members are men from Anglophone countries married to Chinese women. Thus, two American male authors and one Chinese male author observed WeChat group texts shared by 64 individuals from Anglophone countries between 16 November 2022, and 31 January 2023, and in turn, triangulated their field notes to analyse the experiences of the ASAFC. By underpinning the concepts of intercultural capital and ambiguous loss within the context of in-between space, this study promoted scholarly conversations about the life stories of the ASAFC during the rapid public policy paradigm shift and the peak time of the COVID-19 infection. Overall, this study discusses China's transformation into the post-pandemic era, culminating with an overview of the most overarching challenges in recent history. [ABSTRACT FROM AUTHOR]

This cross-cultural ethnography explored the global student mobility patterns of international students from English-speaking countries in China and asked research questions about (a) their motivational factors and acculturation expectations before arrival; (b) linguistic factors influencing their acculturative stressors in the host group community's culture and its academic, social, and public systems after arrival; and (c) their reflections on intergroup ideologies with the host community after graduation, based on looking ahead. This study collected data through fieldwork by observing and interacting with approximately 80 individuals from the United Kingdom, the United States, Canada, Australia, and New Zealand in university towns in East China during the academic years from 2012 to 2023. In turn, 17 individuals who graduated before 2021 were selected as the final sample to conduct in-depth interviews. The study placed the concepts of acculturation expectations and intergroup ideologies at the nexus of linguistic hegemony, symbolic power, and social space. The overarching findings showed that despite positive motivations to visit China, language barriers led participants to express confusion, culture shock, anxiety, and perceived discrimination in their academic, social, and public domains. However, some participants who remained in China after graduation expressed their authentic voices regarding changes in attitude toward the host community culture and their heritage language. Therefore, this study focused on a different dimension of acculturation and linguistic ideology by examining how a linguistically and culturally dominant cohort faced acculturative challenges and negotiated to cope with their stressors in power dynamics. [ABSTRACT FROM AUTHOR]

Soft X-ray spectromicroscopy at the O K-edge, U N4,5-edges and Ce M4,5-edges has been performed on focused ion beam sections of spent nuclear fuel for the first time, yielding chemical information on the sub-micrometer scale. To analyze these data, a modification to non-negative matrix factorization (NMF) was developed, in which the data are no longer required to be non-negative, but the non-negativity of the spectral components and fit coefficients is largely preserved. The modified NMF method was utilized at the O K-edge to distinguish between two components, one present in the bulk of the sample similar to UO2 and one present at the interface of the sample which is a hyperstoichiometric UO2+x species. The species maps are consistent with a model of a thin layer of UO2+x over the entire sample, which is likely explained by oxidation after focused ion beam (FIB) sectioning. In addition to the uranium oxide bulk of the sample, Ce measurements were also performed to investigate the oxidation state of that fission product, which is the subject of considerable interest. Analysis of the Ce spectra shows that Ce is in a predominantly trivalent state, with a possible contribution from tetravalent Ce. Atom probe analysis was performed to provide confirmation of the presence and localization of Ce in the spent fuel.

Summary: Background: As opioid overdoses surge, medications for opioid use disorder (MOUD) remain underutilized. MOUD is rarely offered in correctional facilities although individuals involved in the criminal justice system have higher rates of OUD and mortality relative to the general population. Methods: A retrospective cohort design examined the effect of MOUD while incarcerated on 12 months post-release treatment engagement and retention, overdose mortality, and recidivism. Individuals (N = 1600) who participated in the Rhode Island Department of Corrections (RIDOC) MOUD program (the United States’ first statewide program) and were released from incarceration from December 1, 2016, to December 31, 2018, were included. The sample was 72.6% Male (27.4% female) and 80.8% White (5.8% Black, 11.4% Hispanic, 2.0% another race). Findings: 56% were prescribed methadone, 43% buprenorphine, and 1% naltrexone. During incarceration, 61% were continued on MOUD from the community, 30% were inducted onto MOUD upon incarceration, and 9% were inducted pre-release. At 30 days and 12 months post-release, 73% and 86% of participants engaged in MOUD treatment, respectively, and those newly inducted had lower post-release engagement than those who continued from the community. Reincarceration rates (52%) were similar to the general RIDOC population. Twelve overdose deaths occurred during the 12-month follow-up, with only one overdose death during the first two weeks post-release. Interpretations: Implementing MOUD in correctional facilities, with seamless linkage to community care is a needed life-saving strategy. Funding: Rhode Island General Fund, the NIH of Health HEAL Initiative, the NIGMS, and the NIDA.

Abstract Background Lateral wedge insoles (both standalone and those incorporating individualized arch support) have been frequently studied for the effects on knee joint loading and pain in people with knee osteoarthritis. It has been shown that many people who use these insoles do not obtain the intended biomechanical effect, and thus may not experience a clinical benefit. The ability to identify biomechanical responders to lateral wedge insoles before research or clinical intervention is an important objective for efficient resource use and optimizing patient outcomes. The purpose of our exploratory, hypothesis‐generating study was to provide an initial assessment of variables that are associated with the biomechanical response to lateral wedge insoles in people with knee osteoarthritis. Methods We collected a number of demographic (age, sex, body mass index, foot posture), clinical (knee pain, foot pain, radiographic disease severity), and walking‐related (speed, knee alignment, frontal plane subtalar movement, and foot rotation) outcomes from 53 individuals with painful, radiographically‐confirmed knee osteoarthritis. The walking‐related outcomes were obtained using equipment both from the research laboratory and the clinical setting. We used logistic regression to generate predictive models to determine candidate variables associated with a reduction in the knee adduction moment during walking – a surrogate for tibiofemoral load distribution, and a known biomechanical risk factor for osteoarthritis progression – with the use of standalone and arch‐supported lateral wedge insoles. Three different response thresholds (2%, 6%, and 10% reductions in the knee adduction moment) were used. Results In general, biomechanical responders were those who walked faster, were female, had less varus alignment, and had less severe radiographic severity. Findings were similar between the standalone and arch‐supported lateral wedge insoles, as well as between models using the laboratory‐derived or clinically‐available measures of walking performance. Conclusions Our hypothesis‐generating study provides valuable information that will inform future research into the efficient and effective use of lateral wedge insoles in the conservative management of knee osteoarthritis.

Summary: Plasmid DNA (pDNA) transfection is advantageous for gene therapies requiring larger genetic elements, including “all-in-one” CRISPR/Cas9 plasmids, but is limited by toxicity as well as poor intracellular release and transfection efficiency in immune cell populations. Here, we developed a synthetic non-viral gene delivery platform composed of poly(ethylene glycol)-b-poly(propylene sulfide) copolymers linked to a cationic dendritic peptide (DP) via a reduceable bond, PEG-b-PPS-ss-DP (PPDP). A library of self-assembling PPDP polymers was synthesized and screened to identify optimal constructs capable of transfecting macrophages with small (pCMV-DsRed, 4.6 kb) and large (pL-CRISPR.EFS.tRFP, 11.7 kb) plasmids. The optimized PPDP construct transfected macrophages, fibroblasts, dendritic cells, and T cells more efficiently and with less toxicity than a commercial Lipo2K reagent, regardless of pDNA size and under standard culture conditions in the presence of serum. The PPDP technology described herein is a stimuli-responsive polymeric nanovector that can be leveraged to meet diverse challenges in gene delivery.

Current aptamer discovery approaches are unable to probe the complete space of possible sequences. Here, the authors use machine learning to facilitate the development of DNA aptamers with improved binding affinities, and truncate them without significantly compromising binding affinity.

Introduction HIV continues to have great impact on millions of lives. Novel methods are needed to disrupt HIV transmission networks. In the USA, public health departments routinely conduct contact tracing and partner services and interview newly HIV-diagnosed index cases to obtain information on social networks and guide prevention interventions. Sequence clustering methods able to infer HIV networks have been used to investigate and halt outbreaks. Incorporation of such methods into routine, not only outbreak-driven, contact tracing and partner services holds promise for further disruption of HIV transmissions.Methods and analysis Building on a strong academic–public health collaboration in Rhode Island, we designed and have implemented a state-wide prospective study to evaluate an intervention that incorporates real-time HIV molecular clustering information with routine contact tracing and partner services. We present the rationale and study design of our approach to integrate sequence clustering methods into routine public health interventions as well as related important ethical considerations. This prospective study addresses key questions about the benefit of incorporating a clustering analysis triggered intervention into the routine workflow of public health departments, going beyond outbreak-only circumstances. By developing an intervention triggered by, and incorporating information from, viral sequence clustering analysis, and evaluating it with a novel design that avoids randomisation while allowing for methods comparison, we are confident that this study will inform how viral sequence clustering analysis can be routinely integrated into public health to support the ending of the HIV pandemic in the USA and beyond.Ethics and dissemination The study was approved by both the Lifespan and Rhode Island Department of Health Human Subjects Research Institutional Review Boards and study results will be published in peer-reviewed journals.

Introducing Chronos...

The authors explore the strategies stated in the supplement "Lessons Learned From the Centers for Disease Control and Prevention's National Initiative to Address COVID-19 Health Disparities Among Populatoins at High-Risk and Underserved," published by the U.S. Centers for Disease Control and Prevention in partnership with the National Network for Public Health Improvement. Topics discussed include research articles that showed pitfalls of applying data-driven approaches to reducing inequities.

Natural biomolecules such as peptides and DNA can dynamically self-organize into diverse hierarchical structures. Here the authors report experiments and simulations on the dynamic network self-assembly and subsequent collapse of the synthetic homopolymer poly(propylene sulfone).

In the early days of the coronavirus outbreak, we observed mask use in public among 1,330 people across China. People in regions with a history of farming rice wore masks more often than people in wheat regions. Cultural differences persisted after taking into account objective risk factors such as local COVID cases. The differences fit with the emerging theory that rice farming's labor and irrigation demands made societies more interdependent, with tighter social norms. Cultural differences were strongest in the ambiguous, early days of the pandemic, then shrank as masks became nearly universal (94%). Separate survey and internet search data replicated this pattern. Although strong cultural differences lasted only a few days, research suggests that acting just a few days earlier can reduce deaths substantially.