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HDAC3 inhibition has been shown to improve memory and reduce amyloid‐β (Aβ) in Alzheimer's disease (AD) models, but the underlying mechanisms are unclear. We investigated the molecular effects of HDAC3 inhibition on AD pathology, using in vitro and ex vivo models of AD, based on our finding that HDAC3 expression is increased in AD brains. For this purpose, N2a mouse neuroblastoma cells as well as organotypic brain cultures (OBCSs) of 5XFAD and wild‐type mice were incubated with various concentrations of the HDAC3 selective inhibitor RGFP966 (0.1–10 μM) for 24 h. Treatment with RGFP966 or HDAC3 knockdown in N2a cells was associated with an increase on amyloid precursor protein (APP) and mRNA expressions, without alterations in Aβ42 secretion. In vitro chromatin immunoprecipitation analysis revealed enriched HDAC3 binding at APP promoter regions. The increase in APP expression was also detected in OBCSs from 5XFAD mice incubated with 1 μM RGFP966, without changes in Aβ. In addition, HDAC3 inhibition resulted in a reduction of activated Iba‐1‐positive microglia and astrocytes in 5XFAD slices, which was not observed in OBCSs from wild‐type mice. mRNA sequencing analysis revealed that HDAC3 inhibition modulated neuronal regenerative pathways related to neurogenesis, differentiation, axonogenesis, and dendritic spine density in OBCSs. Our findings highlight the complexity and diversity of the effects of HDAC3 inhibition on AD models and suggest that HDAC3 may have multiple roles in the regulation of APP expression and processing, as well as in the modulation of neuroinflammatory and neuroprotective genes. [ABSTRACT FROM AUTHOR]

Volatile anesthetic agents are increasingly widely used for critical care sedation. There are concerns that sevoflurane presents a risk of renal injury when used in this role. RCTs comparing the use of critical care sevoflurane sedation with any control in humans were systematically identified using MEDLINE, Cochrane CENTRAL, web of Science, and CINAHL (until May 2022), if they presented comparative data on renal function or serum inorganic fluoride levels. Pooled SMDs (95% CI) were calculated where possible after assessment of quality with GRADE and risk of bias with ROB-2. Eight studies analyzing 793 patients were included. The median duration of use of critical care sevoflurane sedation was 4.8 [IQR 3.5–9.2] hours; however, most trials also included a period of prior intraoperative use. No significant difference was found in serum creatinine at 1 day (SMD 0.05, 95% CI − 0.12 to 0.21), 48 h (SMD = − 0.04; 95% Cl − 0.25 to 0.17), 72 h (SMD = − 0.15; 95% CI − 0.45 to 0.15), and at discharge (SMD = − 0.1; 95% CI − 0.3 to 0.13) between the sevoflurane group and the control groups. Creatinine clearance was measured in two studies at 48 h with no significant difference (SMD = − 0.13; 95% Cl − 0.38 to 0.11). Levels of serum inorganic fluoride were significantly elevated in patients where sevoflurane was used. Sevoflurane was not associated with renal failure when used for critical care sedation of fewer than 72-h duration, despite the elevation of serum fluoride. Longer-term studies are currently inadequate, including in patients with compromised renal function, to further evaluate the role of sevoflurane in this setting. Trial registration PROSPERO (CRD42022333099) [ABSTRACT FROM AUTHOR]

An impact evaluation of a pro-poor market system development programme, 'Making Markets Work for the Poor' (M4P), poses several methodological issues for evaluators. M4P interventions intend to change the contextual conditions in which stakeholders take business decisions so that it triggers change processes in the wider social system and ultimately benefits poor people. An impact evaluation design for such a programme thus needs to be robust enough to adequately capture these systemic outcomes, acknowledging dynamic changes in intervention delivery as well as in market conditions over time. Theory-based evaluation can provide learning and accountability when it incorporates methods that allow a critical reflection on the key causal steps in an intervention's theory of change. We present our learnings about indicators and methods to reflect on the importance of the contributions to market system change of a large M4P programme in Ethiopia. [ABSTRACT FROM AUTHOR]

Systemic change is universally desirable and poorly defined. This article seeks to refine a practitioner-developed framework - Adopt-Adapt-Expand-Respond (AAER) - for conceptualising systemic change, and offers case studies to demonstrate its utility in planning for and measuring such change. To do so, the article firstly seeks to define the nature of a system and the components of change within that system. It also discusses the relevance of behaviour change among both actors and institutions in conceptualising systemic change. Finally, in exploring the utility of AAER throughout the implementation of development interventions, it examines the role of the framework in adaptive management: utilising data on observed changes to alter programme intervention tactics. [ABSTRACT FROM AUTHOR]

Planktic foraminifera census data have been used to reconstruct past temperatures through transfer functions, as well as changes in ocean ecosystems, chemistry and circulation. Here we present new multinet, plankton net and core-top census data from 20 sites in the Subpolar North Pacific. We combine these with previous data to provide an up to date compilation of North Pacific planktic foraminifera assemblage data. Our compilation is used to define 6 faunal zones: the subpolar zone; transitional zone; upwelling zone; subtropical zone; east equatorial zone; west equatorial zone; based on the distribution of 10 major species of planktic foraminifera. Two species of planktic foraminifera Neogloboquadrina pachyderma and Globigerina bulloides provide the basis for many subpolar paleo-reconstructions. Through the analysis of new multinet and CTD data we find that G. bulloides and N. pachyderma are predominantly found within 0–50 m of the water column and coincide with high food availability. N. pachyderma also shows a strong temperature control and can thrive in food poor waters where temperatures are low. Both species bloom seasonally, particularly during the spring bloom of March to June, with G. bulloides exhibiting greater seasonal variation. We suggest that percentage abundance of N. pachyderma in paleo-assemblages can be used to assess relative changes in past temperature, with G. bulloides abundance more likely to reflect changes in food availability. By comparing our core-top and multinet data, we also find a dissolution bias of G. bulloides over N. pachyderma in the North Pacific, which may enrich assemblages in the latter species. [ABSTRACT FROM AUTHOR]

The recent proliferation of point‐of‐care ultrasonography (POCUS) in the clinical practice of many medical specialties has exposed persistent barriers to education, training and standardisation. Specialist training curriculums are already overwhelming, having grossly insufficient time available for the specialist trainees and for the small number of available trainers alike to incorporate POCUS into postgraduate education. The logical solution to overcome these barriers could be to incorporate basic POCUS education and training into the undergraduate university curriculums, introducing longitudinal integration with other relevant medical sciences. The Australasian Society of Ultrasound in Medicine already has well‐established educational programmes in POCUS with standardised assessment of competency, which could potentially offer the basis for symbiosis with the Australian and New Zealand medical schools. [ABSTRACT FROM AUTHOR]

Ventricular assist devices ( VADs) have become an indispensable tool in the management of end-stage cardiac failure, both as a means of bridging to cardiac transplantation and as destination therapy for long-term quality of life improvement. Although the technology continues to advance and these devices continue to be refined, they are still associated with significant complications. This article reviews the basics of VAD function and physiology, as well as the myriad to complications that follow their implantation. This review aims to provide a systematic approach to the troubleshooting, diagnosis and management of both VAD-associated complications and the resuscitation of the decompensated VAD patient presenting to the ED. [ABSTRACT FROM AUTHOR]

A new Interplanetary electron environment model based on statistical analyses of historical datasets is presented. The model reports generates confidence limits for solar electron fluences in a similar fashion to existing Solar proton models, as well as peak event fluxes and fluences. Electrons of Jovian origin are also modeled based on simplified diffusive transport equations to provide predicted fluxes for locations within the ecliptic plane. [ABSTRACT FROM PUBLISHER]

Changes in agriculture and rural livelihoods in Africa are often attributed to the HIV epidemic. While acknowledging that the epidemic has devastated many families and communities because of excess morbidity and mortality, this review explores other causes of change in agriculture practices and production in southern Uganda. Over the past 20 years labour shortages, because of labour migration and changing aspirations (as well as HIV), crop and livestock pests and diseases, declining soil fertility, changes in commodity markets and a growing off-farm sector have contributed to the changes seen in rural southern Uganda. Policy interventions outside agriculture and health have also had an impact on households. The HIV epidemic has not happened in isolation. The perceived impacts of the epidemic cannot be addressed in isolation from these other drivers of change. [ABSTRACT FROM AUTHOR]

The Giove-A spacecraft carries two radiation monitors, CEDEX, built by the University of Surrey and Merlin, built by QinetiQ, to study the radiation environment encountered in the Galileo orbit. The two monitors have been functioning since the beginning of the mission and have measured protons, heavy ions and electrons. The electron environment has been found to be highly variable and driven by solar interactions. Comparisons with AE-8 indicate that the electron energy spectrum for the period measured was somewhat harder than that expected from the model. A series of large solar proton events were detected in December 2006, registering as enhanced fluxes of protons, heavy ions and also triggering a large enhancement in the outer electron belt. Comparisons with POLE and INTEGRAL/IREM show an improved spectral match over AE-8. [ABSTRACT FROM PUBLISHER]

Objectives: To evaluate the effectiveness of an integrated and dynamic electronic decision support system for management of acute asthma in the ED. Methods: A randomized trial was conducted comparing clinician performance using this electronic interface compared with paper documentation in a simulation scenario. The outcomes were documentation of asthma-related information and consultation times. Results: Use of this electronic interface was associated with significantly higher rates of documentation in 7 out of 10 variables, including provision of written short-term asthma management plans. After adjustment for participant seniority, there was no significant difference in consultation times. Conclusion: In a simulation trial, use of this electronic interface was associated with improvements in clinical and discharge documentation. Further studies are required to test this prototype in clinical practice. [ABSTRACT FROM AUTHOR]

The need to improve fuel economy and reduce the emission of CO2 and other harmful pollution from internal-combustion-engine vehicles has led to engine downsizing. However, downsized turbocharged engines exhibit a relatively low torque capability at low engine speeds. To overcome this problem, an electrical torque boost may be employed while accelerating and changing gear and to facilitate energy recovery during regenerative braking. This paper describes the operational requirements of a supercapacitor-based torque-boost system, outlines the design and sizing of the electrical drive-train components, and presents experimental characterization of a demonstrator system. [ABSTRACT FROM AUTHOR]

The radiation monitors on board the Galileo Giove-A satellite, CEDEX and Merlin, and their data are presented. The instruments include energetic proton and ion detectors, an internal charging monitor, RADFETs and experimental dose-rate photodiodes. A comparison of the data with existing monitors and models is presented. [ABSTRACT FROM AUTHOR]

Abstract Self-harm has become one of the great taboos of our time. In men it is even less acknowledged, accepted and understood than it is in women. This report looks at the almost invisible population of men who self-harm. Using interviews with men who self-harm, it explores their experiences and their perspectives on the support and services to which they have access. It draws on these perspectives to identify what professionals, service providers and commissioners can learn from men who self-harm and proposes ways forward to better meet their needs. [ABSTRACT FROM AUTHOR]

In spite of a growth in sociological and cultural analyses of food practices, little attention has been paid to food writing and cookery books. This article will seek to rectify this by analysing the work of Elizabeth David and Jane Grigson. We argue that their work not only belongs to a predominantly male tradition of gastronomic writing, but that it also seeks to salvage certain forms of female domesticity. While this represents a break with tradition, the particular force of David and Grigson's work lies in its appeal to culinary authenticity. If the techniques of modern food production threaten the unique flavours of authentic foods, then David and Grigson turn initially to forms of continental cuisine, and then eventually to the traditions of English cuisine, as an antidote to the drive of modernity. We conclude that their response to the processes of modernity is thus an ambivalent one, and one which provides some useful insights into contemporary food concerns. [ABSTRACT FROM AUTHOR]

Information is provided on the conference on well-being and safety in Europe and North America from 1750 through 2000, organized by Mike Esbester of the University of Portsmouth and Tom Crook of Oxford Brookes University, held at Oxford Brookes University, Oxford, England from September 9-11, 2013. Topics, including accident prevention, road safety, industrial safety and managing risk, are discussed.

Study Design: An in-vitro biomechanical study of human cadaver sacroiliac joints.Objective: Our study aimed to develop a more comprehensive understanding of the native motion of the SIJ within the context of spinal kinematics and spinal implant evaluation.Summary Of Background Data: Increasing attention has been given to the sacroiliac joint (SIJ) as a source of low back pain, despite its limited range of motion. We sought to characterize the rotational and translational motion in each axis utilizing standard pure moment flexion-extension (FE), lateral bending (LB), and axial rotation (AR) testing.Methods: Sixteen sacroiliac joints were evaluated from eight lumbosacral cadaver specimens (six females, two males) from subjects aged 28 to 57 years (mean age 46.8) with body mass index (BMI) 22 to 36 (mean BMI 30). Single leg stance was modeled by clamping the blocks on one ischium in a vise and letting the contralateral ischium hang freely. Pure moment loading was applied in FE, right/left AR, and right/left LB. Relative motions were collected with infrared markers.Results: The on-axis ratio was significantly lower in LB than in FE (P = 0.012) and in AR (P = 0.017). The rotation deviation angle measured 13.9 ± 9.1° in FE, 17.1 ± 8.7° in AR, and 35.7 ± 25.7° in LB. In LB the rotational deviation angle is significantly higher than both FE and AR (P = 0.003 and P = 0.011, respectively). In-plane translation was significantly higher (P = 0.005) in FE loading than in LB loading.Conclusion: A nontrivial amount of rotation and translation occurred out of the expected axis of motion. The largest amount of off-axis rotation was observed in lateral bending. Relative to resultant translation, in-plane translation was lowest in lateral bending. Our results indicate that rotation of the SIJ is not fully described with the in-plane metrics which are normally reported in evaluation of fusion devices. Future studies of the SIJ may need to consider including off-axis rotation measurements when describing SIJ kinematics.Level of Evidence: 5. [ABSTRACT FROM AUTHOR]

Background In 2015, the UK government established the Fleming Fund with the aim to address critical gaps in surveillance of antimicrobial resistance (AMR) in low- and middle-income countries in Asia and Africa. Among a large portfolio of grants, the Capturing Data on Antimicrobial Resistance Patterns and Trends in Use in Regions of Asia (CAPTURA) project was awarded with the specific objective of expanding the volume of historical data on AMR, consumption (AMC), and use (AMU) in the human healthcare sector across 12 countries in South and Southeast Asia. Methods Starting in early 2019, the CAPTURA consortium began working with local governments and >100 relevant data-holding facilities across the region to identify, assess for quality, prioritize, and subsequently retrieve data on AMR, AMC, and AMU. Relevant and shared data were collated and analyzed to provide local overviews for national stakeholders as well as regional context, wherever possible. Results From the vast information resource generated on current surveillance capacity and data availability, the project has highlighted gaps and areas for quality improvement and supported comprehensive capacity-building activities to optimize local data-collection and -management practices. Conclusions The project has paved the way for expansion of surveillance networks to include both the academic and private sector in several countries and has actively engaged in discussions to promote data sharing at the local, national, and regional levels. This paper describes the overarching approach to, and emerging lessons from, the CAPTURA project, and how it contributes to other ongoing efforts to strengthen national AMR surveillance in the region and globally. [ABSTRACT FROM AUTHOR]

Background: While there is widespread recognition of global health failures when it comes to infectious disease outbreaks, there is little discussion on how policy-makers and global health organizations can learn to better prepare and respond. Serious games provide an underutilized tool to promote learning and innovation around global health crises. In order to explore the potential of Serious Games as a policy learning tool, Global Affairs Canada, in collaboration with the Department of National Defense and academic partners, developed and implemented a matrix game aimed at prompting critical reflection and gender-based analysis on infectious disease outbreak preparedness and response. This commentary, written by the core development team, reflects on the process and outcomes of the gaming exercise, which we believe will be of interest to others hoping to promote innovative thinking and learning around global health policy and crisis response, as well as the application of serious games more broadly.Main Body: Participants reported, through discussions and a post-game survey, that they felt the game was reflective of real-world decision-making and priority-setting challenges during a crisis. They reflected on the challenges that emerge around global health co-operation and outbreak preparedness, particularly noting the importance of learning to work with private actors. While participants only sporadically applied gender-based analysis or considered the social determinants of health during the game, post-game discussions led to reflection on the ways in which equity concerns are put aside during a crisis scenario and on why this happens, offering critical learning opportunities.Conclusion: Matrix games provide opportunities for policy-makers and health professionals to experience the challenges of global health co-operation, test ideas and explore how biases, such as those around gender, influence policy-making and implementation. Due to their flexibility, adaptability and accessibility, serious games offer a potentially powerful learning tool for global health policy-makers and practitioners. [ABSTRACT FROM AUTHOR]

Environmental water requirements (EWRs), including past inundation regimes, provide useful information for the conservation and management of wetlands systems. However, determining past inundation regimes is difficult as very few wetlands have historical records of water level or flow to determine EWRs. Generally, two approaches have been used to reconstruct wetland inundation regimes; remote sensing or hydrological modelling. Remote sensing methods have applied spectral indices of inundation to multi-temporal archival satellite imagery and developed simple empirical models to link inundation extent to rainfall or stream flow records. Hydrological models use a water balance approach and simple relationships between volume and area based on the wetland bathymetry to derive an inundation regime. While remote sensing approaches can provide a high spatial resolution of information, the temporal resolution is limited to an image every few weeks, and the usability of each image is subject to cloud cover. Hydrological models require some data in the region of interest for calibration, and often the model is not sensitive to the inundation variables of interest when calibrating to the data available. A study is presented where this is the case, where good results are achieved by a hydrological model when compared to downstream flow data, but very different wetland inundation regimes can be simulated. Due to this limitation, the remotely-sensed inundation regime was required as another source of information to calibrate the hydrological model, constraining the parameters involved in the modelled wetland storages. The remote-sensing constrained hydrological model provided greater confidence in the representation of processes occurring in the simulated wetland storages, and hence could be considered appropriate to be applied to a validation time period and for scenario testing. The findings of this research support the combination of remotely sensed indicators of inundation and hydrological modelling to increase confidence in the spatial representation of the dynamics of inundation. Understanding wetland inundation dynamics is critical to the understanding and management of threatened wetland ecosystems. Hence, the methods outlined in paper will ultimately assist in informing better management of wetlands. [ABSTRACT FROM AUTHOR]

X-ray repair cross complementing protein 1 (XRCC1) plays an important role in base excision DNA repair (BER) as a scaffolding protein for BER enzymes. BER is one of the basic DNA repair pathways repairing greater than 20,000 endogenous lesions per cell per day. Proper functioning of XRCC1, one of the most important players in BER, was suggested to be indispensable for effective DNA repair. Despite accumulating evidence of an important role that XRCC1 plays in maintaining genomic stability, the relationship between one of its most predominant variants, R280H (rs25489), and cancer prevalence remains ambiguous. In the current study we functionally characterized the effect of the R280H variant expression on immortal non-transformed mouse mammary epithelial C127 and human breast epithelial MCF10A cells. We found that expression of R280H results in increased focus formation in mouse C127 cells and induces cellular transformation in human MCF10A cells. Cells expressing R280H showed significantly increased levels of chromosomal aberrations and accumulate double strand breaks in the G1 cell cycle phase. Our results confirm a possible link between R280H and genomic instability and suggest that individuals carrying this mutation may be at increased risk of cancer development. [ABSTRACT FROM AUTHOR]

Background Klebsiella species, including the notable pathogen K. pneumoniae , are increasingly associated with antimicrobial resistance (AMR). Genome-based surveillance can inform interventions aimed at controlling AMR. However, its widespread implementation requires tools to streamline bioinformatic analyses and public health reporting. Methods We developed the web application Pathogenwatch, which implements analytics tailored to Klebsiella species for integration and visualization of genomic and epidemiological data. We populated Pathogenwatch with 16 537 public Klebsiella genomes to enable contextualization of user genomes. We demonstrated its features with 1636 genomes from 4 low- and middle-income countries (LMICs) participating in the NIHR Global Health Research Unit (GHRU) on AMR. Results Using Pathogenwatch, we found that GHRU genomes were dominated by a small number of epidemic drug-resistant clones of K. pneumoniae. However, differences in their distribution were observed (eg, ST258/512 dominated in Colombia, ST231 in India, ST307 in Nigeria, ST147 in the Philippines). Phylogenetic analyses including public genomes for contextualization enabled retrospective monitoring of their spread. In particular, we identified hospital outbreaks, detected introductions from abroad, and uncovered clonal expansions associated with resistance and virulence genes. Assessment of loci encoding O-antigens and capsule in K. pneumoniae , which represent possible vaccine candidates, showed that 3 O-types (O1–O3) represented 88.9% of all genomes, whereas capsule types were much more diverse. Conclusions Pathogenwatch provides a free, accessible platform for real-time analysis of Klebsiella genomes to aid surveillance at local, national, and global levels. We have improved representation of genomes from GHRU participant countries, further facilitating ongoing surveillance. [ABSTRACT FROM AUTHOR]

Purpose: Changes in tumour 3′-deoxy-3′-[F]fluorothymidine (FLT) uptake during concurrent chemo-radiotherapy in patients with non-small cell lung cancer (NSCLC) have been reported, at variable time points, in two pilot positron emission tomography (PET) studies. The aim of this study was to assess whether FLT changes occur early in response to radiotherapy (RT) without concurrent chemotherapy and whether such changes exceed test-retest variability. Methods: Sixteen patients with NSCLC, scheduled to have radical RT, underwent FLT PET once/twice at baseline to assess reproducibility and/or after 5-11 RT fractions to evaluate response. Primary and nodal malignant lesions were manually delineated on CT and volume, mean and maximum standardized uptake values (SUV and SUV) estimated. Analysis included descriptive statistics and parameter fitting to a mixed-effects model accounting for patients having different numbers of evaluable lesions. Results: In all, 35 FLT PET scans from 7 patients with a total of 18 lesions and 12 patients with a total of 30 lesions were evaluated for reproducibility and response, respectively. SUV reproducibility in primary tumours (SD 8.9 %) was better than SUV reproducibility (SD 12.6 %). In nodes, SUV and SUV reproducibilities (SD 18.0 and 17.2 %) were comparable but worse than for primary tumours. After 5-11 RT fractions, primary tumour SUV decreased significantly by 25 % ( p = 0.0001) in the absence of significant volumetric change, whereas metastatic nodes decreased in volume by 31 % ( p = 0.020) with a larger SUV decrease of 40 % ( p < 0.0001). Similar changes were found for SUV. Conclusion: Across this group of NSCLC patients, RT induced an early, significant decrease in lesion FLT uptake exceeding test-retest variability. This effect is variable between patients, appears distinct between primary and metastatic nodal lesions, and in primary tumours is lower than previously reported for concurrent chemo-RT at a similar time point. These results confirm the potential for FLT PET to report early on radiation response and to enhance the clinical development of novel drug-radiation combinations by providing an interpretable, early pharmacodynamic end point. [ABSTRACT FROM AUTHOR]