Search

Members of the genus Hypoxylon (Ascomycota) are pleomorphic fungi mostly forming conspicuous teleomorphs, consisting of perithecia embedded into stromal tissue, and their morphology has traditionally served for species delineation. However, analysis in tandem with other phenotypic characters, such as chemical and genetic traits, proved to be a more stable predictor of interspecies and intergeneric relationships. During 2014 and 2015, a set of species identified as Hypoxylon were described from the Neotropics, exclusively relying on morphological traits. The secondary metabolite profiles of their stromata were analysed by HPLC/DAD-ESI-MS, corroborating their classification within Xylariales. Additionally, molecular data for ex-type strains of H. dussii and H. sofaiense were incorporated into an inferred molecular phylogeny of the Hypoxylaceae and allies. Furthermore, a freshly collected specimen from North Carolina was selected as epitype of Sphaeria perforata Schweinitz (syn. Hypoxylon perforatum), as its morphological/chemotaxonomic characters matched those of the holotype. Our findings demonstrate that the secondary metabolism of Hypoxylon closely correlates with both morphological features and molecular data, serving as a complement for species identification.

Building on the success of initiatives put forth during the COVID-19 pandemic response, US health officials are expanding wastewater surveillance programs to track other target pathogens and diseases of public health interest. The Houston Health Department in Houston, Texas, USA, conducted a hypothesis-generating study whereby infectious disease subject matter experts suggested potential targets. This study addressed 2 criteria recommended by the National Academies of Sciences, Engineering, and Medicine for selecting wastewater targets. Results can be used as a basis of a questionnaire for a future population-based study to recommend targets of highest priority to include for expanded wastewater sampling.

Abstract Tiled amplicon sequencing has served as an essential tool for tracking the spread and evolution of pathogens. Over 15 million complete SARS-CoV-2 genomes are now publicly available, most sequenced and assembled via tiled amplicon sequencing. While computational tools for tiled amplicon design exist, they require downstream manual optimization both computationally and experimentally, which is slow and costly. Here we present Olivar, a first step towards a fully automated, variant-aware design of tiled amplicons for pathogen genomes. Olivar converts each nucleotide of the target genome into a numeric risk score, capturing undesired sequence features that should be avoided. In a direct comparison with PrimalScheme, we show that Olivar has fewer mismatches overlapping with primers and predicted PCR byproducts. We also compare Olivar head-to-head with ARTIC v4.1, the most widely used primer set for SARS-CoV-2 sequencing, and show Olivar yields similar read mapping rates (~90%) and better coverage to the manually designed ARTIC v4.1 amplicons. We also evaluate Olivar on real wastewater samples and found that Olivar has up to 3-fold higher mapping rates while retaining similar coverage. In summary, Olivar automates and accelerates the generation of tiled amplicons, even in situations of high mutation frequency and/or density. Olivar is available online as a web application at https://olivar.rice.edu and can be installed locally as a command line tool with Bioconda. Source code, installation guide, and usage are available at https://github.com/treangenlab/Olivar .

Abstract The debates over the requirement of the International Code of Nomenclature for algae, fungi, and plants (ICNafp) for a viable specimen to represent the name-bearing type material for a species or infraspecific taxon have a long history. Taxonomy of fungi commonly studied as living cultures exemplified by yeasts and moulds, strongly depend on viable reference material. The availability of viable cultures is also particularly useful for several groups of filamentous and dimorphic fungi. While the preservation of metabolically inactive cultures is permitted and recommended by the ICNafp, there is room for improvement. Below, we review the history and current status of cultures as the name-bearing type material under the Code. We also present a roadmap with tasks to be achieved in order to establish a stable nomenclatural system that properly manages taxa typified by viable specimens. Furthermore, we propose setting up rules and defining the nomenclatural status of ex-type cultures under Chapter F, the section of the ICNafp that includes provisions specific to names of fungi.

Abstract Purpose Reaction databases are a key resource for a wide variety of applications in computational chemistry and biochemistry, including Computer-aided Synthesis Planning (CASP) and the large-scale analysis of metabolic networks. The full potential of these resources can only be realized if datasets are accurate and complete. Missing co-reactants and co-products, i.e., unbalanced reactions, however, are the rule rather than the exception. The curation and correction of such incomplete entries is thus an urgent need. Methods The SynRBL framework addresses this issue with a dual-strategy: a rule-based method for non-carbon compounds, using atomic symbols and counts for prediction, alongside a Maximum Common Subgraph (MCS)-based technique for carbon compounds, aimed at aligning reactants and products to infer missing entities. Results The rule-based method exceeded 99% accuracy, while MCS-based accuracy varied from 81.19 to 99.33%, depending on reaction properties. Furthermore, an applicability domain and a machine learning scoring function were devised to quantify prediction confidence. The overall efficacy of this framework was delineated through its success rate and accuracy metrics, which spanned from 89.83 to 99.75% and 90.85 to 99.05%, respectively. Conclusion The SynRBL framework offers a novel solution for recalibrating chemical reactions, significantly enhancing reaction completeness. With rigorous validation, it achieved groundbreaking accuracy in reaction rebalancing. This sets the stage for future improvement in particular of atom-atom mapping techniques as well as of downstream tasks such as automated synthesis planning. Scientific Contribution SynRBL features a novel computational approach to correcting unbalanced entries in chemical reaction databases. By combining heuristic rules for inferring non-carbon compounds and common subgraph searches to address carbon unbalance, SynRBL successfully addresses most instances of this problem, which affects the majority of data in most large-scale resources. Compared to alternative solutions, SynRBL achieves a dramatic increase in both success rate and accurary, and provides the first freely available open source solution for this problem.

Abstract Hepatitis C virus (HCV) is a plus-stranded RNA virus that often chronically infects liver hepatocytes and causes liver cirrhosis and cancer. These viruses replicate their genomes employing error-prone replicases. Thereby, they routinely generate a large ‘cloud’ of RNA genomes (quasispecies) which—by trial and error—comprehensively explore the sequence space available for functional RNA genomes that maintain the ability for efficient replication and immune escape. In this context, it is important to identify which RNA secondary structures in the sequence space of the HCV genome are conserved, likely due to functional requirements. Here, we provide the first genome-wide multiple sequence alignment (MSA) with the prediction of RNA secondary structures throughout all representative full-length HCV genomes. We selected 57 representative genomes by clustering all complete HCV genomes from the BV-BRC database based on k-mer distributions and dimension reduction and adding RefSeq sequences. We include annotations of previously recognized features for easy comparison to other studies. Our results indicate that mainly the core coding region, the C-terminal NS5A region, and the NS5B region contain secondary structure elements that are conserved beyond coding sequence requirements, indicating functionality on the RNA level. In contrast, the genome regions in between contain less highly conserved structures. The results provide a complete description of all conserved RNA secondary structures and make clear that functionally important RNA secondary structures are present in certain HCV genome regions but are largely absent from other regions. Full-genome alignments of all branches of Hepacivirus C are provided in the supplement.

Abstract Circulating tumor DNA (ctDNA) is the cornerstone of liquid biopsy diagnostics, revealing clinically relevant genomic aberrations from blood of cancer patients. Genomic analysis of single circulating tumor cells (CTCs) could provide additional insights into intra-patient heterogeneity, but it requires whole-genome amplification (WGA) of DNA, which might introduce bias. Here, we describe a novel approach based on mass spectrometry for mutation detection from individual CTCs not requiring WGA and complex bioinformatics pipelines. After establishment of our protocol on tumor cell line-derived single cells, it was validated on CTCs of 33 metastatic melanoma patients and the mutations were compared to those obtained from tumor tissue and ctDNA. Although concordance with tumor tissue was superior for ctDNA over CTC analysis, a larger number of mutations were found within CTCs compared to ctDNA (p = 0.039), including mutations in melanoma driver genes, or those associated with resistance to therapy or metastasis. Thus, our results demonstrate proof-of-principle data that CTC analysis can provide clinically relevant genomic information that is not redundant to tumor tissue or ctDNA analysis.

Abstract Background Micro- and macrovascular diseases are common in patients with type 2 diabetes mellitus (T2D) and may be partly caused by nocturnal hypoxemia. The study aimed to characterize the composition of nocturnal hypoxemic burden and to assess its association with micro- and macrovascular disease in patients with T2D. Methods This cross-sectional analysis includes overnight oximetry from 1247 patients with T2D enrolled in the DIACORE (DIAbetes COhoRtE) study. Night-time spent below a peripheral oxygen saturation of 90% (T90) as well as T90 associated with non-specific drifts in oxygen saturation (T90non − specific), T90 associated with acute oxygen desaturation (T90desaturation) and desaturation depths were assessed. Binary logistic regression analyses adjusted for known risk factors (age, sex, smoking status, waist-hip ratio, duration of T2D, HbA1c, pulse pressure, low-density lipoprotein, use of statins, and use of renin-angiotensin-aldosterone system inhibitors) were used to assess the associations of such parameters of hypoxemic burden with chronic kidney disease (CKD) as a manifestation of microvascular disease and a composite of cardiovascular diseases (CVD) reflecting macrovascular disease. Results Patients with long T90 were significantly more often affected by CKD and CVD than patients with a lower hypoxemic burden (CKD 38% vs. 28%, p

BACKGROUND: Multitargeted tyrosine kinase inhibitors (TKIs) of the vascular endothelial growth factor receptor (VEGFR) pathway have activity in differentiated thyroid cancer (DTC). Lenalidomide demonstrated preliminary efficacy in DTC, but its safety and efficacy in combination with VEGFR-targeted TKIs is unknown. We sought to determine the safety and efficacy of cediranib, a VEGFR-targeted TKI, with or without lenalidomide, in the treatment of iodine 131-refractory DTC. PATIENTS AND METHODS: In this multicenter, open-label, randomized, phase II clinical trial, 110 patients were enrolled and randomized to cediranib alone or cediranib with lenalidomide. The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate, duration of response, toxicity, and overall survival (OS). Patients (≥18 years of age) with DTC who were refractory to further surgical or radioactive iodine (RAI) therapy as reviewed at a multispecialty tumor board conference, and evidence of disease progression within the previous 12 months and no more than one prior line of systemic therapy were eligible. RESULTS: Of the 110 patients, 108 started therapy and were assessable for efficacy. The median PFS was 14.8 months [95% confidence interval (CI) 8.5-23.8 months] in the cediranib arm and 11.3 months (95% CI 8.7-18.9 months) in the cediranib with lenalidomide arm (P = 0.36). The 2-year OS was 64.8% (95% CI 43.3% to 86.4%) and 75.3% (95% CI 59.4% to 91.0%), respectively (P = 0.80). The serious adverse event rate was 41% in the cediranib arm and 46% in the cediranib with lenalidomide arm. CONCLUSIONS: Single-agent therapy with cediranib showed promising efficacy in RAI-refractory DTC similar to other VEGFR-targeted TKIs, while the addition of lenalidomide did not result in clinically meaningful improvements in outcomes.

Background As many as 70% of remand prisoners have admitted to being under the influence of alcohol when committing the crime leading to their imprisonment. Providing support and advice regarding alcohol consumption can be effective in some groups of people. There is little evidence regarding this for men on remand in prison. Objective To pilot the study measures and evaluation methods to assess the feasibility of conducting a future definitive multicentre, pragmatic, parallel group, randomised controlled trial. Design A two-arm, parallel group, individually randomised pilot study of a self-efficacy-enhancing psychosocial alcohol intervention to reduce levels of alcohol consumption for males on remand in prison and on liberation. Setting Two purposively selected prisons in Scotland and England. Participants Adult men on remand in prison with an Alcohol Use Disorders Identification Test score of ≥ 8. Intervention The APPRAISE intervention delivery comprised four steps: Step 1: 1 × 40-minute face-to-face session, delivered by a trained practitioner from Change Grow Live in prison. Steps 2, 3 and 4: 20-minute sessions conducted by phone, on or as close as possible to days 3, 7 and 21 post liberation. Control: assessment, screening and referral onto further alcohol support options. Main outcome measures Recruitment and retention rates, completion of follow-ups, outcome measures at 12 months and interventions delivered. The primary outcome for the pilot study was alcohol consumed in the 28 days prior to Time Point 2, assessed using the extended Alcohol Use Disorders Identification Test-C. Results Of 182 men on remand approached across two study sites, 132 were randomised (90 in England; 42 in Scotland) with 46 randomised to intervention and 44 to care as usual in England and 22 randomised to intervention and 20 to care as usual in Scotland. A total of 53 in-prison interventions were delivered. One day-3 post-liberation intervention was delivered, no day-7 and one day-21. At 12 months, of 132 randomised, 18 (13%) were followed up, 53 (40%) were not liberated; 47 (36%) were uncontactable and 14 (11%) had been released but could not be located. Data completeness was 96% at baseline and 8% at 12 months. The process evaluation reported good acceptability of the intervention with investment in time, capacity and space to support implementation identified. The economic study produced guidance on how to assess costs associated with implementing the APPRAISE intervention which could be applied more broadly. Harms No adverse events or side effects were noted. Conclusions A future definitive trial would be possible, but only if follow-up mechanisms can be addressed as well as full access to recidivism and health data. Collaboration with the probation service in future could offer the opportunity to develop a robust process and system to optimise follow-up post liberation. Dedicated resources to support the intervention delivery both in and out of the prison setting are recommended. Limitations Coronavirus disease discovered in 2019 impacted recruitment and follow-up, with access to prisons restricted. We were unable to deliver the post-liberation element of the intervention. We did not include probation services or other agencies in the trial. Trial registration This trial is registered as Current Controlled Trials ISRCTN36066. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (NIHR award ref: 17/44/11) and is published in full in Public Health Research; Vol. 12, No. 11. See the NIHR Funding and Awards website for further award information. Plain language summary What was the question? We know many men on remand report being under the influence of alcohol at the time of their arrest. Having a short conversation providing alcohol support and advice (known as an ‘intervention’) can be effective. However, we do not know if an alcohol intervention for men on remand in prison is possible to deliver or if we can ‘test’ the benefit of it. The aim of the study was to ‘test’ an intervention named APPRAISE using a small study, for men on remand in one Scottish and one English prison. What did we do? We aimed to get 180 men in this study. Men taking part were asked to tell us about their alcohol drinking. Men reporting ‘risky’ drinking were split into two groups by chance. One group were to be given the APPRAISE intervention while in prison and once released. The other group did not receive the intervention. We then set out to measure their drinking levels after 12 months. We interviewed different people involved in the study to find out what they thought. What did we find? We successfully recruited 132 men but had to stop due to coronavirus disease discovered in 2019, as we were unable to go into the prisons. We delivered 53 out of 68 interventions in prison but not once men were released; we were only able to contact 18 out of 132 men at 12 months. People we interviewed stated that having an intervention to reduce risky drinking would be acceptable; however, this would require investment, time, space, capacity and trust. What does this mean? Before we can plan a larger study we need to identify the best way to locate men once released from prison, to deliver the whole intervention and measure its effect on drinking levels. Scientific summary The prevalence of at-risk drinking, which includes drinking at levels that harm a person’s health, is far higher amongst those in contact with the criminal justice system (73%). For those on remand in prison, the prevalence is between 62% and 68%. This compares to 35% in the general population. Alcohol brief interventions (ABIs) are a secondary prevention activity, aimed at those individuals who are drinking in a pattern that is likely to be harmful to health and/or well-being. Similarly, the theoretical validity of a self-efficacy-enhancing alcohol intervention in other settings has shown evidence of potential effect. Study aims and objectives Objective 1: to pilot the study measures and evaluation methods to assess the feasibility of conducting a future definitive multicentre, pragmatic, parallel-group randomised controlled trial. Is it feasible to conduct a future multicentre RCT of a self-efficacy-enhancing psychosocial alcohol intervention for men on remand? Can we obtain reasonable estimates of the parameters necessary to inform the design and sample size calculation for a future definitive multicentre RCT? This includes standard deviations of potential continuous primary outcomes and estimates of recruitment met across trial arms and study, retention and follow-up rates. How well do participants complete the questionnaires necessary for a future definitive RCT? Can we collect economic data needed for a future definitive RCT? Can we access recidivism data from the Police National Computer (PNC) databases for trial participants? Can we access health data from routine National Health Service (NHS) data sources for trial participants? Objective 2: to assess intervention fidelity. What proportion of the interventions are delivered as per protocol? Is there any evidence of contamination between the two conditions and/or between those workers delivering the intervention? To what extent was the intervention changing process variables consistent with the underpinning theory? Objective 3: to qualitatively explore the feasibility and acceptability of a self-efficacy-enhancing psychosocial alcohol intervention and study measures to staff and for men on remand and on liberation. How acceptable are the trial and intervention procedures (including context and any barriers and facilitators) to the following key stakeholders: men on remand in prison and on liberation; prison staff (including healthcare staff); commissioners; policy-makers and third-sector partners? Objective 4: to assess whether operational progression criteria for conducting a future definitive randomised controlled trial are met across trial arms and study sites and, if so, develop a protocol for a future definitive trial. (Operational progression criteria are based on previous research results.) Do the two prisons invited to the study agree to take part? Based on knowledge from previous data, do at least 90 eligible participants consent to take part and be randomised across the trial arms? Do at least 70% of participants who consent to the trial receive the intervention? Are at least 60% of those who received the intervention followed up at 12 months across trial arms and study sites? Objective 5: to ascertain what alcohol services are available in male remand prisons and how coronavirus disease discovered in 2019 has affected services. To ascertain what alcohol services are currently provided within male remand prisons. To explore the prison governors’ understanding of brief interventions. To understand how the coronavirus disease discovered in 2019 pandemic has impacted the services available in male remand prisons. To identify whether the impact of the COVID-19 pandemic upon services could be avoided in the future. Methods Phase 1 pilot trial Phase I was a two-arm, parallel-group, individually randomised pilot study of a self-efficacy-enhancing psychosocial alcohol intervention for men on remand in prison to provide data, including economic, recidivism and health data, on feasibility and an assessment of the likely impact of the APPRAISE intervention to inform the feasibility of a future definitive multicentre RCT. The Phase I pilot trial was undertaken in two prison settings, one in Scotland and one in England. Those eligible to participate were adult men detained on remand in either the Scottish study site or the England study site who had been in prison for 3 months or less and had an Alcohol Use Disorders Identification Test (AUDIT) screening score of 8 or more. The original recruitment target was 180 participants, 90 at each study site. The target was reached at the England study site; however, restricted access to the prison estates due to COVID-19 meant we were unable to recruit any further participants at the Scottish study site. As a result, we recruited 132 participants (90 in England and 42 in Scotland), who were randomised. In England, 46 participants were randomised to the intervention and 44 to care as usual. For participants in Scotland, 22 were randomised to the intervention and 20 to care as usual. Allocation was conducted at the level of the participants, randomised to the active or control intervention using stratified block randomisation by site, via sealed envelopes, based on a predetermined random number allocation carried out by the study Trials Unit. The APPRAISE intervention focused on enhancing self-efficacy and comprised four steps: Step 1 comprised a 1 × 40-minute face-to-face session in which the nine elements were delivered by an interventionist in the prison setting. Steps 2, 3 and 4 were 20-minute booster sessions to be delivered by phone, on or as close as possible to days 3, 7 and 21 post liberation. Interventions were delivered by Change Grow Live practitioners who had received prior training in intervention delivery. Care as usual across both sites comprised an alcohol assessment and referral onto further alcohol support options if requested. Due to COVID-19 restrictions, access to both study sites for the research assistants (RAs) and research team was halted, resulting in liberation data not being accessible. There was limited capacity of the interventionists to follow up on liberation data of those in the intervention group or deliver post-liberation intervention. Data were collected at TP0 before randomisation (baseline), TP1 (6 months) and TP2 (12 months). Follow-up assessments were attempted where participants had been (a) not liberated, (b) liberated and in the community or (c) liberated and then re-incarcerated, and were conducted by phone; hard copies of the follow-up questionnaire were sent by post with an accompanying letter to be completed and returned to the study team via a pre-paid envelope, or via hard copy in prison. As a result, modifications were made to the follow-up method to also include contact via text message, WhatsApp, Facebook and an electronic Qualtrics link to the survey sent by phone or e-mail. The case report forms (CRFs) were adapted to facilitate self-completion. The primary outcome was alcohol consumed in the 28 days prior to TP2 (12-month follow-up), assessed using the extended AUDIT-C. The following secondary outcome measures were used across the three time points: Warwick-Edinburgh Mental Well-being Scale (WEMWBS); Drinking Refusal Self-efficacy Questionnaire – revised (DRSEQ-R); Negative Alcohol Expectancy Questionnaire (NAEQ); EuroQol-5 Dimensions, five-level version; Readiness to Change Ruler; Economic Form 90. Results Of 182 men on remand approached across two study sites, 132 were randomised (90 in England; 42 in Scotland) with 46 randomised to intervention and 44 to care as usual in England, and 22 randomised to intervention and 20 to care as usual in Scotland. A total of 53 in-prison interventions were delivered. One day-3 post-liberation intervention was delivered, no day-7 post-liberation intervention was delivered and one day-21 post-liberation intervention was delivered. At 12 months out of all 132 randomised, 18 were followed up, 53 (40%) were not liberated, 47 (36%) were uncontactable and 14 (11%) had been released but could not be located. Data completeness was 96% at baseline and 8% at 12 months. Mindful of the very small sample sizes and that as such caution should be applied, provisional indications suggest that self-efficacy may be a determinant of alcohol consumption and further exploration of interventions targeting self-efficacy should be considered. We were able to develop a micro-costing methodology protocol and collect provisional scoping of routine data sources to support future cost-effectiveness analyses. We were unable to access both PNC and NHS data for participants in either study prison. Phase II process evaluation and survey In Phase II, the aim of the process evaluation was threefold: first, to assess how the intervention was implemented, second, to undertake some preliminary exploration of change mechanisms underpinning the intervention, and third, to assess the acceptability and context within which the intervention was delivered through interviews with study participants and key stakeholders involved in supporting the trial. A survey of prisons in Scotland and England was conducted to ascertain what alcohol services were available for men on remand in prisons and how COVID-19 had affected these services. Study records and semistructured interviews provided the data for the process evaluation. Purposive sampling was used for interviews. Due to COVID-19, the target of 40 interviews was not attainable. Thematic analyses using a NPT lens to support thematic identification. All interviews were digitally recorded and transcribed verbatim ahead of analysis. High levels of practitioner behaviour change skills were identified from the Behaviour Change Counselling Index (BECCI) scores of the four intervention delivery sessions recorded at the Scotland site. Differences in median dose delivered between study sites were noted. CGL intervention training evaluation was positive. From the data available evidence of contamination was limited. Fifteen semistructured interviews were conducted with three participant groups [remand participants, Change Grow Live (CGL) team and wider stakeholders] from across the two study sites. The themes generated suggested a strong acceptability of the intervention with investment in time, capacity and space identified to support implementation, as well as the buy-in from all stakeholders, development of trust and relationships as key facilitators to supporting behaviour change. From 59 prisons in Scotland and England, successful e-mails were sent to 55 prison governors. Seventeen (31%) were completed. The findings confirmed that the COVID-19 pandemic had undoubtedly impacted upon alcohol and wider prison services available to men on remand. Strengths of the study The APPRAISE study is, to the best of our knowledge, the first pilot trial of an alcohol-focused self-efficacy-enhancing intervention for men on remand. The study provides significant insight into the feasibility and acceptability of pilot trials for this particular population. The ethical approval process for the prison setting across devolved countries provided useful insights into how to navigate the submission and approvals process across a range of ethics committees. The study provided good evidence of the feasibility of recruitment, training interventionists and subsequent in-prison delivery of the APPRAISE intervention to 73% of men on remand, randomised to the intervention, within a highly complex prison setting. The economic findings provide valuable insights, as we believe this to be the first of its kind for this type of intervention in this setting. Useful insight was gained regarding the access to PNC and NHS Service Use Data. The process evaluation provided insights into the perspectives of the remand participants, the intervention delivery team and wider stakeholders on the acceptability and feasibility of intervention implementation. Our patient and public involvement (PPI) colleague, a co-applicant on the study, provided unique insights and guidance throughout the study. Limitations of the study Protracted multiple ethical approvals across devolved countries and processes meant a significant delay in recruitment commencing, particularly for the Scotland site. We were unable to deliver the post-liberation elements of the intervention. The onset of the COVID-19 pandemic resulted in prison restrictions and no access to the prison site, meaning we were unable to identify if participants had been released or not at 6 months, with no access at the England site at 12 months and very limited access at the Scotland site at 12 months. Although the COVID-19 pandemic was undoubtedly a factor in the low percentage followed up, only 13% (18/132) of those who received the intervention were followed up at 12 months. Changes to the study protocol to include self-completion of follow-up data may have made it difficult for participants to complete the survey, resulting in larger proportions of missing data as compared to RA survey completion at baseline, where missing data were minimal. We did not include probation services in the trial, which on reflection would have strengthened our post-liberation follow-up process. Recommendations regarding a definitive randomised trial From the study progression criteria for a full RCT, we have identified the following recommendations: Buy-in for a research trial of this nature in prison requires significant pre-study trust and relationship development, buy-in from the prison estate, governor, prison officers, peer mentors and embedded third-sector services. Recruitment and randomisation of men on remand to a future APPRAISE RCT are possible, with trust in the research team an important factor. Training team members of existing alcohol services to deliver APPRAISE as per protocol is possible. Delivery of the in-prison APPRAISE intervention is possible and would require appropriate space, time and team member capacity. Economic evaluation is possible. Post-liberation intervention delivery and follow-up would only be possible if there was a robust follow-up process identified and in place. Further exploration of the inclusion of and collaboration with the probation service in the service delivery and implementation of the APPRAISE intervention, and that of voluntary groups and agencies at local community levels engaged specifically in post-discharge support services, may offer higher success rates of post-liberation intervention delivery and a more robust follow-up process. PPI membership should be strengthened to reflect the complexity of the prison setting and the range of stakeholders within the criminal justice system. Conclusion Addressing alcohol harm in prisons, at what can be considered a ‘teachable moment’, can provide men with an opportunity for reflection on their risky drinking and their current position. Many men on remand do not have the opportunity to access mainstream prison health or public health services. An intervention such as APPRAISE offers an opportunity to provide an extended behavioural-based alcohol intervention to men on remand. The APPRAISE study has identified that despite the complexities of ethical approval and the time taken to build relationships and trust, it is possible to undertake key elements of a future RCT, but not all, namely follow-up. Further focused research needs to be undertaken to explore, identify and develop a robust process and system to optimise follow-up post liberation. The evidence base to meet the needs of men on remand in relation to risky drinking remains weak. However, there are opportunities to build on the work of APPRAISE to ensure equal access to interventions that have the potential to positively impact their relationship with and use of alcohol. Trial registration This trial is registered as Current Controlled Trials ISRCTN36066. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (NIHR award ref. 17/44/11) and is published in full in Public Health Research; Vol. 12, No. 11. See the NIHR Funding and Awards website for further award information.

Background and purpose: Stereotactic ablative body radiotherapy (SABR) is an effective treatment for localized renal cell carcinoma (RCC). However, the role of primary site SABR for locally recurrent or metastatic RCC is unclear. Here, we report outcomes of primary SABR across a diverse cohort of localized, recurrent, and metastatic RCC patients treated at our institution. Materials and methods: RCC patients treated with SABR to lesions of the kidney or nephrectomy bed at our institution with at least 6 months of follow-up were included for analysis. Local control, overall survival, and freedom from distant failure were estimated using the Kaplan-Meier method. Estimated glomerular filtration rate (eGFR) was assessed at baseline and following SABR. Results: Fifty-three patients received primary site SABR. Thirty-seven (70 %) patients had localized RCC, and 16 (30 %) had metastatic RCC. Seven (13 %) had locally recurrent RCC after prior surgery or ablation. The median tumor size was 4.5 cm (IQR 3.7–6.3). At a median follow-up of 23 months (IQR 12–35), 2-year local control was 100 %, and 3-year local control was 94.4 % (95 % CI 84.4 %–100 %). Among patients with initially localized disease, the 2-year freedom from distant failure was 94.6 % (95 % CI 87.6 %–100 %), and the 2-year overall survival was 66.5 % (95 % CI 51.9 %–85.2 %). Twelve (23 %) patients experienced acute grade 1–2 treatment-related toxicity (nausea, vomiting, or small bowel). There were no acute grade 3–4 toxicities. Two (3.8 %) patients developed late grade 3 gastrointestinal toxicity. The median baseline eGFR was 51 mL/min/1.73 m2 (IQR 38–77). At 1-year post-SABR, the median eGFR decline was 5 mL/min/1.73 m2 (IQR −3 to 9). One patient required dialysis following SABR. Conclusion: This analysis demonstrates excellent local control rates across patients with localized, recurrent, and metastatic RCC treated with SABR. Treatment was associated with minimal eGFR decline.

A spectrally and spatially dense sensor array consisting of 15 regenerated fiber Bragg gratings (RFBGs) over a length of 30 mm is presented for precise and fast multipoint temperature sensing up to 700°C. For the first time, it could be shown that with a dense fiber Bragg grating (FBG)-based sensor array the accuracy requirements of Class 1 thermocouples could be achieved and even exceeded. This also represents the highest spatial density of FBG-based high-temperature multipoint sensing reported so far. The mitigation of broadband losses during the regeneration process was studied, revealing the advantages of the low broadband loss characteristics of the RFBGs, especially when larger numbers of measuring points are required. Low measurement uncertainties were achieved by a new, improved calibration methodology and by an analysis of interferences of an FBG with the side lobes of spectrally neighboring FBGs as well as their suppression by a suitable arrangement of the Bragg wavelengths within the array and corresponding data processing. The capabilities of this multipoint sensor technique were demonstrated by resolving the temperature profile within the calibration volume of a calibration furnace and by resolving the temporal and spatial temperature gradients within the flame of a Bunsen burner. The results are of great importance for fiber-optic sensing of high-temperature profiles in real-world applications.

Animals have the innate ability to select optimal defensive behaviors with appropriate intensity within specific contexts. The vomeronasal organ (VNO) serves as a primary sensory channel for detecting predator cues by relaying signals to the medial hypothalamic nuclei, particularly the ventromedial hypothalamus (VMH), which directly controls defensive behavioral outputs. Here, we demonstrate that cat saliva contains predator cues that signal the imminence of predator threat and modulate the intensity of freezing behavior through the VNO in mice. Cat saliva activates VNO neurons expressing the V2R-A4 subfamily of sensory receptors, and the number of VNO neurons activated in response to saliva correlates with both the freshness of saliva and the intensity of freezing behavior. Moreover, the number of VMH neurons activated by fresh, but not old, saliva positively correlates with the intensity of freezing behavior. Detailed analyses of the spatial distribution of activated neurons, as well as their overlap within the same individual mice, revealed that fresh and old saliva predominantly activate distinct neuronal populations within the VMH. Collectively, this study suggests that there is an accessory olfactory circuit in mice that is specifically tuned to time-sensitive components of cat saliva, which optimizes their defensive behavior to maximize their chance of survival according to the imminence of threat.

Aims: Acute heart failure (AHF) is typified by inflammatory and oxidative stress responses, which are associated with unfavorable patient outcomes. Given the anti-inflammatory and antioxidant properties of high-density lipoprotein (HDL), this study sought to examine the relationship between impaired HDL function and mortality in AHF patients. The complex interplay between various HDL-related biomarkers and clinical outcomes remains poorly understood. Methods: HDL subclass distribution was quantified by nuclear magnetic resonance spectroscopy. Lecithin–cholesterol acyltransferase (LCAT) activity, cholesterol ester transfer protein (CETP) activity, and paraoxonase (PON-1) activity were assessed using fluorometric assays. HDL-cholesterol efflux capacity (CEC) was assessed in a validated assay using [3H]-cholesterol-labeled J774 macrophages. Results: Among the study participants, 74 (23.5 %) out of 315 died within three months after hospitalization due to AHF. These patients exhibited lower activities of the anti-oxidant enzymes PON1 and LCAT, impaired CEC, and lower concentration of small HDL subclasses, which remained significant after accounting for potential confounding factors. Smaller HDL particles, particularly HDL3 and HDL4, exhibited a strong association with CEC, PON1 activity, and LCAT activity. Conclusions: In patients with AHF, impaired HDL CEC, HDL antioxidant and anti-inflammatory function, and impaired HDL metabolism are associated with increased mortality. Assessment of HDL function and subclass distribution could provide valuable clinical information and help identify patients at high risk.

Штучний інтелект (ШI) потребує мережевого мислення. Хоча сам ШI не становить проблеми, наслідки випливають з його інтеграції в процес вивчення мови. Очевидно, що ШI може спростити як домашню, так і семінарську, що змушує школи та університети замислитися над розумним регулюванням використання програм, таких як ChatGPT. Перші пропозиції вказують на поновне запровадження усних іспитів та культивування більш творчих текстів та інноваційних тестових завдань для запобігання шахрайству, яке уможливлює ШІ. У цьому дослідженні надаються певні пропозиції щодо того, як викладачі російської мови (РМ) можуть протистояти цим викликам та ефективно впроваджувати такі програми в навчальний процес. Для досягнення цієї мети чату GPT було поставлене завдання згенерувати довгий діалог підлітків, які знайомі один з одним, на побутову тему, орієнтуючись на знання мови студентами на рівні В1. У діалозі передбачалося використання розмовного мовлення, яке часто відсутнє в сучасних підручниках. Після цього було запропоновано переглянути діалог для кращого відтворення автентичної усної взаємодії молоді. Через аналіз та порівняння діалогів та відповідних монологів, це дослідження ставить за мету забезпечити вчителів рекомендаціями для ефективного розгляду загальних розмовних явищ у навчанні РМ – як з точки зору рецептивної, так і продуктивної комунікативної компетентності, а також для уникнення потенційних мовленнєвих проблем, таких як зловживання розмовними виразами.

Chronic kidney disease (CKD) is often associated with decreased activity of lecithin-cholesterol acyltransferase (LCAT), an enzyme essential for HDL maturation. This reduction in LCAT activity may potentially contribute to an increased risk of cardiovascular mortality in patients with CKD. The objective of this study was to investigate the association between LCAT activity in patients with CKD and the risk of adverse outcomes. We measured serum LCAT activity and characterized lipoprotein profiles using nuclear magnetic resonance spectroscopy in 453 non-dialysis CKD patients from the CARE FOR HOMe study. LCAT activity correlated directly with smaller HDL particle size, a type of HDL potentially linked to greater cardiovascular protection. Over a mean follow-up of 5.0 ± 2.2 years, baseline LCAT activity was inversely associated with risk of death (standardized HR 0.62, 95% CI 0.50–0.76; P

Cilia are antenna-like organelles protruding from the surface of many cell types in the human body. Defects in ciliary structure or function often lead to diseases that are collectively called ciliopathies. Cilia and flagella-associated protein 410 (CFAP410) localizes at the basal body of cilia/flagella and plays essential roles in ciliogenesis, neuronal development and DNA damage repair. It remains unknown how its specific basal body location is achieved. Multiple single amino acid mutations in CFAP410 have been identified in patients with various ciliopathies. One of the mutations, L224P, is located in the C-terminal domain (CTD) of human CFAP410 and causes severe spondylometaphyseal dysplasia, axial (SMDAX). However, the molecular mechanism for how the mutation causes the disorder remains unclear. Here, we report our structural studies on the CTD of CFAP410 from three distantly related organisms, Homo sapiens, Trypanosoma brucei and Chlamydomonas reinhardtii. The crystal structures reveal that the three proteins all adopt the same conformation as a tetrameric helical bundle. Our work further demonstrates that the tetrameric assembly of the CTD is essential for the correct localization of CFAP410 in T. brucei, as the L224P mutation that disassembles the tetramer disrupts its basal body localization. Taken together, our studies reveal that the basal body localization of CFAP410 is controlled by the CTD and provide a mechanistic explanation for how the mutation L224P in CFAP410 causes ciliopathies in humans.