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A proportion of cytogenetic abnormalities in myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) may escape detection by high-resolution genomic technologies, but can be identified by conventional cytogenetic and molecular analysis. Here, we report the detection of a reciprocal translocation t(7;21)(p22;q22) in the marrow of two adults with MDS and AML, using conventional cytogenetic analysis and fluorescence- in situ-hybridization (FISH). Reverse-transcription polymerase chain reaction (RT-PCR) and sequence analysis identified a fusion between RUNX1 and the gene encoding ubiquitin specific peptidase-42 ( USP42), with splice-variants and variable break-points within RUNX1. Combined cytomorphology and FISH studies in MDS marrow revealed abnormal RUNX1 signals within megakaryocytes, suggesting that the acquisition of t(7;21)(p22;q22) does not confer complete differentiation arrest and may represent an early genetic event in leukaemogenesis. Single nucleotide polymorphism-arrays failed to detect additional sub-microscopic genomic changes predisposing to or associated with t(7;21). Molecular analysis of 100 MDS and AML marrow specimens by RT-PCR did not reveal new cases with the RUNX1-USP42 fusion. Thus, our studies have identified t(7;21)(p22;q22) as a rare but recurrent abnormality in MDS/AML, with the existence of alternative spliced forms of the RUNX1-USP42 transcript in different patients. Further studies are required to identify the potential contribution of these splice-variants to disease heterogeneity. [ABSTRACT FROM AUTHOR]

Objective: Minimal trauma fracture (MTF) is an indication of osteoporosis and risk of future fracture. Our objective was to describe osteoporosis risk identification and secondary prevention in a regional and rural population hospitalised for an MTF. Design: A retrospective inpatient file audit and follow-up telephone interview. Setting: Patients aged 45 years and over admitted for MTF management to two regional hospitals in northern New South Wales between July 2006 and June 2007. Main outcome measures: Proportion of patients who received bone mineral densitometry (BMD) assessment and proportion commenced on osteoporosis medication post fracture. Results: There were 459 patients included in our inpatient file audit. During admission only 16% had osteoporosis risk documented, uptake of vitamin D assay or BMD were minimal and only 22% were discharged on preventive medication. Of 219 patients contacted post discharge, 36% reported discussing osteoporosis risk with their GPs, 22% reported post-discharge BMD and 32% were taking a bisphosphonate. Men were less likely to have commenced preventive medication (OR 0.42, CI, 0.19–0.91) and patients informed of their osteoporosis risk during hospitalisation were more likely to have had BMD (OR 1.93, CI, 1.03–3.61). Neither age nor history of previous MTF was predictive of preventive treatment post discharge. Conclusion: Overall, fracture risk identification and initiation of secondary prevention in this regional and rural population was low and this is consistent with findings in recent metropolitan studies. Effective regional and rural strategies are required that ensure identification and effective communication of risk to patients and their GPs. [ABSTRACT FROM AUTHOR]

The ovine critical-sized defect model provides a robust preclinical model for testing tissue-engineered constructs for use in the treatment of non-union bone fractures and severe trauma. A critical question in cell-based therapies is understanding the optimal therapeutic cell dose. Key to defining the dose and ensuring successful outcomes is understanding the fate of implanted cells, e.g., viability, bio-distribution and exogenous infiltration post-implantation. This study evaluates such parameters in an ovine critical-sized defect model 2 and 7 days post-implantation. The fate of cell dose and behaviour post-implantation when combined with nanomedicine approaches for multi-model tracking and remote control using external magnetic fields is also addressed. Autologous STRO-4 selected mesenchymal stromal cells (MSCs) were labelled with a fluorescent lipophilic dye (CM-Dil), functionalised magnetic nanoparticles (MNPs) and delivered to the site within a naturally derived bone extracellular matrix (ECM) gel. Encapsulated cells were implanted within a critical-sized defect in an ovine medial femoral condyle and exposed to dynamic gradients of external magnetic fields for 1 h per day. Sheep were sacrificed at 2 and 7 days post-initial surgery where ECM was harvested. STRO-4-positive (STRO-4+) stromal cells expressed osteocalcin and survived within the harvested gels at day 2 and day 7 with a 50% loss at day 2 and a further 45% loss at 7 days. CD45-positive leucocytes were also observed in addition to endogenous stromal cells. No elevation in serum C-reactive protein (CRP) or non-haem iron levels was observed following implantation in groups containing MNPs with or without magnetic field gradients. The current study demonstrates how numbers of therapeutic cells reduce substantially after implantation in the repair site. Cell death is accompanied by enhanced leucocyte invasion, but not by inflammatory blood marker levels. Crucially, a proportion of implanted STRO-4+ stromal cells expressed osteocalcin, which is indicative of osteogenic differentiation. Furthermore, MNP labelling did not alter cell number or result in a further deleterious impact on stromal cells following implantation. [ABSTRACT FROM AUTHOR]

Background: Digital adherence technologies (DATs) are recommended to support patient-centred, differentiated care to improve tuberculosis (TB) treatment outcomes, but evidence that such technologies improve adherence is limited. We aim to implement and evaluate the effectiveness of smart pillboxes and medication labels linked to an adherence data platform, to create a differentiated care response to patient adherence and improve TB care among adult pulmonary TB participants. Our study is part of the Adherence Support Coalition to End TB (ASCENT) project in Ethiopia.Methods/design: We will conduct a pragmatic three-arm cluster-randomised trial with 78 health facilities in two regions in Ethiopia. Facilities are randomised (1:1:1) to either of the two intervention arms or standard of care. Adults aged ≥ 18 years with drug-sensitive (DS) pulmonary TB are enrolled over 12 months and followed-up for 12 months after treatment initiation. Participants in facilities randomised to either of the two intervention arms are offered a DAT linked to the web-based ASCENT adherence platform for daily adherence monitoring and differentiated response to patient adherence for those who have missed doses. Participants at standard of care facilities receive routine care. For those that had bacteriologically confirmed TB at treatment initiation and can produce sputum without induction, sputum culture will be performed approximately 6 months after the end of treatment to measure disease recurrence. The primary endpoint is a composite unfavourable outcome measured over 12 months from TB treatment initiation defined as either poor end of treatment outcome (lost to follow-up, death, or treatment failure) or treatment recurrence measured 6 months after the scheduled end of treatment. This study will also evaluate the effectiveness, feasibility, and cost-effectiveness of DAT systems for DS-TB patients.Discussion: This trial will evaluate the impact and contextual factors of medication label and smart pillbox with a differentiated response to patient care, among adult pulmonary DS-TB participants in Ethiopia. If successful, this evaluation will generate valuable evidence via a shared evaluation framework for optimal use and scale-up.Trial Registration: Pan African Clinical Trials Registry PACTR202008776694999, https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=12241 , registered on August 11, 2020. [ABSTRACT FROM AUTHOR]

Aim: Research on mesophotic coral ecosystems (MCEs) has increased exponentially in recent decades, and the significance of this ecosystem has been recognised both in terms of biodiversity and distribution. However, this research has mostly focussed on corals and is globally sporadic, with the Indian Ocean remaining largely unexplored and overall MCEs under protected. Hence, baseline data on MCE benthic communities is lacking, but nonetheless essential for developing adequate management strategies. Here, we assess the variation in diversity and community structure of MCEs along the depth gradient and among sites in the Indian Ocean and the environmental parameters that are potentially driving these differences. Location: Egmont Atoll, Chagos Archipelago, central Indian Ocean. Time Period: Present. Major Taxa Studied: Marine benthic invertebrates, plants. Methods: Using a remotely operated vehicle, we collected video transects between 15 and 160 m. We analysed the diversity and composition of benthic communities and used DistLM analysis to determine the environmental drivers of the community structure over the depth gradient and between sites. Results: We observed distinct benthic communities along the depth gradient, with a strong community break observed at ~60 m. We also identified a clear zonation of the benthic taxa with depth. This zonation was primarily driven by downward irradiance and temperature, with additional environmental processes playing a minor role in structuring the benthic communities. Main Conclusions: We show that MCEs in the Chagos Archipelago are distinct communities, and their distribution is driven primarily by irradiance and temperature. Our results highlight the variability in benthic community structure of MCEs, both along the depth gradient and at local geographical scales for the study region. This study showcases the uniqueness of MCEs and will aid in predicting their distribution, potential refugia for shallow reefs, and in developing evidence‐based protection for MCEs, to maintain overall marine biodiversity. [ABSTRACT FROM AUTHOR]

Background: Non-adherence to tuberculosis treatment increases the risk of poor treatment outcomes. Digital adherence technologies (DATs), including the smart pillbox (EvriMED), aim to improve treatment adherence and are being widely evaluated. As part of the Adherence Support Coalition to End TB (ASCENT) project we analysed data from a cluster-randomised trial of DATs and differentiated care in Ethiopia to examine individual-factors for poor engagement with the smart pillbox. Methods: Data were obtained from a cohort of trial participants with drug-sensitive tuberculosis (DS-TB) whose treatment started between 1 December 2020 and 1 May 2022, and who were using the smart pillbox. Poor engagement with the pillbox was defined as (i) > 20% days with no digital confirmation and (ii) the count of days with no digital confirmation, and calculated over a two evaluation periods (56-days and 168-days). Logistic random effects regression was used to model > 20% days with no digital confirmation and negative binomial random effects regression to model counts of days with no digital confirmation, both accounting for clustering of individuals at the facility-level. Results: Among 1262 participants, 10.8% (133/1262) over 56-days and 15.8% (200/1262) over 168-days had > 20% days with no digital confirmation. The odds of poor engagement was less among participants in the higher stratum of socio-economic position (SEP) over 56-days. Overall, 4,689/67,315 expected doses over 56-days and 18,042/199,133 expected doses over 168-days were not digitally confirmed. Compared to participants in the poorest SEP stratum, participants in the wealthiest stratum had lower rates of days not digitally confirmed over 168-days (adjusted rate ratio [RRa]:0.79; 95% confidence interval [CI]: 0.65, 0.96). In both evaluation periods (56-days and 168-days), HIV-positive status (RRa:1.29; 95%CI: 1.02, 1.63 and RRa:1.28; 95%CI: 1.07, 1.53), single/living independent (RRa:1.31; 95%CI: 1.03, 1.67 and RRa:1.38; 95%CI: 1.16, 1.64) and separated/widowed (RRa:1.40; 95%CI: 1.04, 1.90 and RRa:1.26; 95%CI: 1.00, 1.58) had higher rates of counts of days with no digital confirmation. Conclusion: Poorest SEP stratum, HIV-positive status, single/living independent and separated/ widowed were associated with poor engagement with smart pillbox among people with DS-TB in Ethiopia. Differentiated care for these sub-groups may reduce risk of non-adherence to TB treatment. [ABSTRACT FROM AUTHOR]

Organisms exposed to environmental stressors respond by rapidly synthesising a suite of highly conserved proteins called heat shock proteins (HSPs). Environmental stress can also enhance and/or block memory formation, with long-term memory formation requiring gene activation and protein synthesis. Thermal stress in the pond snailLymnaea stagnaliscan enhance memory formation, and, in this study, the effect of thermal stress on HSP gene expression in the nervous system was investigated. Time-related expression profiles forHSP40andHSP70indicated rapid (<30 min) induction for both transcripts. ForHSP40, induction was <20 fold relative to control and expression returned to control levels within 8 h, whereasHSP70induction was >100 fold and expression did not return to control levels within 8 h. [ABSTRACT FROM PUBLISHER]

The physiological performance of a reef-building coral is a combined outcome of both the coral host and its algal endosymbionts, Symbiodinium. While Orbicella annularis--a dominant reef-building coral in the Wider Caribbean-- is known to be a flexible host in terms of the diversity of Symbiodinium types it can associate with, it is uncertain how this diversity varies across the Caribbean, and whether spatial variability in the symbiont community is related to either O. annularis genotype or environment. Here, we target the Symbiodinium-ITS2 gene to characterize and map dominant Symbiodinium hosted by O. annularis at an unprecedented spatial scale. We reveal northwest-southeast partitioning across the Caribbean, both in terms of the dominant symbiont taxa hosted and in assemblage diversity. Multivariate regression analyses incorporating a suite of environmental and genetic factors reveal that observed spatial patterns are predominantly explained by chronic thermal stress (summer temperatures) and are unrelated to host genotype. Furthermore, we were able to associate the presence of specific Symbiodinium types with local environmental drivers (for example, Symbiodinium C7 with areas experiencing cooler summers, B1j with nutrient loading and B17 with turbidity), associations that have not previously been described. [ABSTRACT FROM AUTHOR]

New high-resolution image data obtained from the Hebrides Terrace Seamount and analysed by ourselves and Henry and Roberts (Henry, L-A., and Roberts, J. M. Recommendations for best practice in deep-sea habitat classification: Bullimore et al. as a case study. ICES Journal of Marine Science, 71: 895–898.), suggested that we may have misidentified Solenosmilia variabilis as either Lophelia pertusa or Madrepora oculata in a previously analysed dataset from the Anton Dohrn Seamount (published in Bullimore et al., 2013). Therefore, we undertook a reanalysis of our entire image data holdings from multiple sample sites and identified possible records of S. variabilis from four sites previously sampled: Anton Dohrn Seamount, Rockall Bank, George Bligh Bank and the Hatton-Rockall Basin. The reanalysis of our image data holdings together with historic data from the wider literature suggests that, in the Northeast Atlantic region, S. variabilis is distributed from 888–2803 m (mean ∼1500 m) with reef habitat present only on Anton Dohrn Seamount. In this paper we discuss the use of video and imagery as a survey and monitoring too and make recommendations of best practice in data acquisition and analysis. We highlight the need for the development of training materials for deep-sea field identification in order to achieve reliable, replicable and comparable datasets among observers, and suggest possible quality assurance procedures. [ABSTRACT FROM PUBLISHER]

Evidence of alloparental care during the incubation stage has largely been demonstrated for species that incubate their offspring externally in a nest. Alloparental care in these species generally consists of the rearing of mixed broods which contain a low proportion of "foreign" young alongside the host's own offspring. However, many animals, including sea anemones, incubate offspring either on or within their bodies. The beadlet anemone Actinia equina incubate their young internally, and as many sea anemones are capable of reproducing both sexually and asexually, the origin of these internally brooded young has been the subject of much debate. While genetically identical young are brooded internally under the juvenile stage, it is thought that those produced sexually are released as larvae into the water and must return to the gastric cavity of an adult in order for metamorphosis to occur. As the likelihood of a planula larva finding its way back to its parent is slim, this suggests that alloparental care may play a role in the survival of juveniles in this species, a hypothesis first suggested a century ago but rarely tested. Here, using highly polymorphic microsatellite markers, we find evidence of alloparental care in A. equina. Our results indicate that while a high proportion of juveniles were genetically identical to their brooding adult, the remaining juveniles showed stark genetic differences to their brooding adult. These juveniles shared far fewer alleles with their "parent" than expected under sexual reproduction, indicating that they were not the adult's offspring. Furthermore, we found variation in the genetic composition of broods, which consisted either of (a) entirely genetically identical individuals, (b) a mix of unique individuals and clonemates or (c) entirely unique individuals, that is no shared genotype. Our results thus indicate that adult A. equina tolerate the presence of non‐offspring within their gastric cavity and furthermore that they may incubate entirely "foreign" broods. [ABSTRACT FROM AUTHOR]

Background: Digital adherence technologies (DATs) may provide a patient-centred approach to supporting tuberculosis (TB) medication adherence and improving treatment outcomes. We synthesised evidence addressing costs and cost-effectiveness of DATs to support TB treatment., Methods: A systematic review (PROSPERO-CRD42022313531) identified relevant literature from January 2000 to April 2023 in MEDLINE, Embase, CENTRAL, CINAHL, Web of Science along with preprints from medRxiv, Europe PMC and ClinicalTrials.gov. Studies with observational, experimental or quasi-experimental designs (minimum 20 participants) and modelling studies reporting quantitative data on the cost or cost-effectiveness of DATs for TB infection or disease treatment were included. Study characteristics, cost and cost-effectiveness outcomes were extracted., Results: Of 3619 titles identified by our systematic search, 29 studies met inclusion criteria, of which 9 addressed cost-effectiveness. DATs included short message service (SMS) reminders, phone-based technologies, digital pillboxes, ingestible sensors and video-observed therapy (VOT). VOT was the most extensively studied (16 studies) and was generally cost saving when compared with healthcare provider directly observed therapy (DOT), particularly when costs to patients were included-though findings were largely from high-income countries. Cost-effectiveness findings were highly variable, ranging from no clinical effect in one study (SMS), to greater effectiveness with concurrent cost savings (VOT) in others. Only eight studies adequately reported at least 80% of the elements required by Consolidated Health Economic Evaluation Reporting Standards, a standard reporting checklist for health economic evaluations., Conclusion: DATs may be cost saving or cost-effective compared with healthcare provider DOT, particularly in high-income settings. However, more data of higher quality are needed, notably in lower-income and middle-income countries which have the greatest TB burden., Competing Interests: Competing interests: KS reports research funding from the Canadian Institutes of Health Research. He has also served as chair of the Data Safety and Monitoring Board for a COVID-19 therapeutic investigated by Laurent Pharmaceuticals., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Digital adherence technologies (DATs), such as phone-based technologies and digital pillboxes, can provide more person-centric approaches to support tuberculosis (TB) treatment. However, there are varying estimates of their performance for measuring medication adherence., Methods: We conducted a systematic review (PROSPERO-CRD42022313526), which identified relevant published literature and preprints from January 2000 to April 2023 in five databases. Studies reporting quantitative data on the performance of DATs for measuring TB medication adherence against a reference standard, with at least 20 participants, were included. Study characteristics and performance outcomes (eg, sensitivity, specificity and predictive values) were extracted. Sensitivity was the proportion correctly classified as adherent by the DAT, among persons deemed adherent by a reference standard. Specificity was the proportion correctly classified as non-adherent by the DAT, among those deemed non-adherent by a reference standard., Results: Of 5692 studies identified by our systematic search, 13 met inclusion criteria. These studies investigated medication sleeves with phone calls (branded as '99DOTS'; N=4), digital pillboxes N=5), ingestible sensors (N=2), artificial intelligence-based video-observed therapy (N=1) and multifunctional mobile applications (N=1). All but one involved persons with TB disease. For medication sleeves with phone calls, compared with urine testing, reported sensitivity and specificity were 70%-94% and 0%-61%, respectively. For digital pillboxes, compared with pill counts, reported sensitivity and specificity were 25%-99% and 69%-100%, respectively. For ingestible sensors, the sensitivity of dose detection was ≥95% compared with direct observation. Participant selection was the most frequent potential source of bias., Conclusion: The limited number of studies available suggests suboptimal and variable performance of DATs for dose monitoring, with significant evidence gaps, notably in real-world programmatic settings. Future research should aim to improve understanding of the relationships of specific technologies, settings and user engagement with DAT performance and should measure and report performance in a more standardised manner., Competing Interests: Competing interests: KS reports research funding from the Canadian Institutes of Health Research. He has also served as chair of the Data Safety and Monitoring Board for a COVID-19 therapeutic investigated by Laurent Pharmaceuticals., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Cartilage tissue engineering aims to develop functional substitutes for treating cartilage defects and osteoarthritis. Traditional two-dimensional (2D) cell culture systems lack the complexity of native cartilage, leading to the development of 3D regenerative cartilage models. In this study, we developed a 3D model using Gelatin Methacryloyl (GelMA)-based hydrogels seeded with Y201 cells, a bone marrow mesenchymal stem cell line. The model investigated chondrogenic differentiation potential in response to Wnt3a stimulation within the GelMA scaffold and validated using known chondrogenic agonists. Y201 cells demonstrated suitability for the model, with increased proteoglycan content and upregulated chondrogenic marker expression under chondrogenic conditions. Wnt3a enhanced cell proliferation, indicating activation of the Wnt/β-catenin pathway, which plays a role in cartilage development. GelMA hydrogels provided an optimal scaffold, supporting cell viability and proliferation. The 3D model exhibited consistent responses to chondrogenic agonists, with TGF-β3 enhancing cartilage-specific extracellular matrix (ECM) production and chondrogenic differentiation. The combination of Wnt3a and TGF-β3 showed synergistic effects, promoting chondrogenic differentiation and ECM production. This study presents a 3D regenerative cartilage model with potential for investigating cartilage biology, disease mechanisms, and drug screening. The model provides insights into complex cartilage regeneration mechanisms and offers a platform for developing therapeutic approaches for cartilage repair and osteoarthritis treatment., (© 2024. The Author(s).)

Introduction: Digital adherence technologies (DATs) can offer alternative approaches to support tuberculosis treatment medication adherence. Evidence on their feasibility and acceptability in high TB burden settings is limited. We conducted a cross-sectional survey among adults with drug-sensitive tuberculosis (DS-TB), participating in pragmatic cluster-randomized trials for the Adherence Support Coalition to End TB project in Ethiopia (PACTR202008776694999), the Philippines, South Africa and Tanzania (ISRCTN 17706019)., Methods: From each country we selected 10 health facilities implementing the DAT intervention (smart pillbox or medication labels, with differentiated care support), ensuring inclusion of urban/rural and public/private facilities. Adults on DS-TB regimen using a DAT were randomly selected from each facility. Feasibility of the DATs was assessed using a standardized tool. Acceptability was measured using a 5-point Likert-scale, using the Capability, Opportunity, Motivation, Behavior (COM-B) model. Mean scores of Likert-scale responses within each COM-B category were estimated, adjusted for facility-level clustering. Data were summarized by country and DAT type., Results: Participants using either the pillbox ( n = 210) or labels ( n = 169) were surveyed. Among pillbox users, phone ownership (79%), use of pillbox reminders (87%) and taking treatment without the pillbox (22%) varied by country. Among label users, phone ownership (81%), paying extra to use the labels (8%) and taking treatment without using labels (41%) varied by country. Poor network, problems with phone charging and access, not having the pillbox and forgetting to send text were reasons for not using DATs. Overall, people with TB had a favorable impression of both DATs, with mean composite scores between 4·21 to 4·42 across COM-B categories. Some disclosure concerns were reported., Conclusion: From client-perspective, pillboxes and medication labels with differentiated care support were feasible to implement and acceptable in variety of settings. However, implementation challenges related to network, phone access, stigma, additional costs to people with TB to use DATs need to be addressed., Competing Interests: TD, NM, and SC were employed by The Aurum Institute. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Tadesse, Mganga, Dube, Alacapa, van Kalmthout, Letta, Mleoh, Garfin, Maraba, Charalambous, Foster, Jerene and Fielding.)