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Background: The use of proton pump inhibitors (PPIs) for the treatment of erosive esophagitis has had a major impact on the prescribing budgets of primary care organizations in the United Kingdom. Assessments of the clinical and economic effectiveness of PPIs would provide useful tools for decision-making.Objective: The goal of this study was to review the available preclinical and clinical studies comparing esomeprazole with lansoprazole in the healing and maintenance of erosive esophagitis, and to compare the budgeting impact of the 2 strategies. Comparative tolerability was also reviewed.Methods: MEDLINE (1966-September 2002) and EMBASE (1980-September 2002) were searched for abstracts and articles reporting comparative studies of esomeprazole and lansoprazole. The search terms used were gastroesophageal reflux disease, reflux esophagitis, and proton pump inhibitor; all comparisons of esomeprazole and lansoprazole at any dose were considered. The database search was supplemented based on the authors' familiarity with the literature.Results: The comparative studies that were identified fell into 4 categories: (1) intragastric acid suppression studies; (2) randomized controlled trials in the healing of erosive esophagitis; (3) randomized controlled trials in the maintenance of erosive esophagitis; and (4) health economic analyses. Based on these studies, when healing doses (esomeprazole 40 mg once daily, lansoprazole 30 mg once daily) and low doses (20 and 15 mg once daily, respectively) were compared, esomeprazole was more efficacious than lansoprazole in suppressing acid in the intragastric compartment (both comparisons, P < 0.05). More patients with erosive esophagitis experienced healing at 4 and 8 weeks with esomeprazole 40 mg once daily than with lansoprazole 30 mg once daily (P < 0.001 at 4 and 8 weeks). At 6 months, remission was maintained in more patients receiving esomeprazole 20 mg once daily than in those receiving lansoprazole 15 mg once daily (P < 0.001). No significant differences in tolerability were noted in clinical trials that directly compared the 2 PPIs. When the cost-effectiveness of esomeprazole treatment was compared with that of lansoprazole treatment in the healing and maintenance of erosive esophagitis, the greater efficacy of esomeprazole translated into potential cost savings and better outcomes.Conclusion: The currently available comparative data for esomeprazole and lansoprazole indicate clinical and cost-effectiveness advantages for esomeprazole in the healing and maintenance of erosive esophagitis compared with lansoprazole. [ABSTRACT FROM AUTHOR]

Background/Objectives : Abiraterone acetate, apalutamide, darolutamide, and enzalutamide, which make up the androgen receptor axis-targeted therapies (ARATs) drug class, are commonly used in the management of prostate cancer. Many patients on ARATs also receive oral antithrombotic therapy (i.e., anticoagulants or antiplatelets). The concomitant use of ARATs and antithrombotic therapies creates the potential for clinically relevant drug-drug interactions, but the literature regarding the actual consequences of these interactions, and guidance for co-prescribing, is limited. We assembled a multidisciplinary panel of experts and provided them with clinical information derived from a comprehensive literature review regarding the drug-drug interactions between ARATs and antithrombotic therapies. Methods : A three-stage modified electronic Delphi process was used to gather and consolidate opinions from the panel. Each stage consisted of up to three rounds of voting to achieve consensus on which ARAT/antithrombotic therapy drug pairs warrant attention, the possible clinical consequences of drug-drug interactions, and suggested actions for management. Results : The panel achieved consensus to avoid 11 ARAT/antithrombotic therapy drug pairs and modify therapy for eight pairs. Assessments relied heavily on pharmacokinetic data and extrapolation from drug-drug interaction studies of similarly metabolized drugs. Conclusions : This e-Delphi process highlights the need for further research into the clinical impact of ARAT/antithrombotic drug interactions. Nonetheless, the suggested actions aim to provide clinicians with a practical framework for therapeutic decision making.

Despite widespread adoption of tissue clearing techniques in recent years, poor access to suitable light-sheet fluorescence microscopes remains a major obstacle for biomedical end-users. Here, we present descSPIM (desktop-equipped SPIM for cleared specimens), a low-cost ($20,000-50,000), low-expertise (one-day installation by a non-expert), yet practical do-it-yourself light-sheet microscope as a solution for this bottleneck. Even the most fundamental configuration of descSPIM enables multi-color imaging of whole mouse brains and a cancer cell line-derived xenograft tumor mass for the visualization of neurocircuitry, assessment of drug distribution, and pathological examination by false-colored hematoxylin and eosin staining in a three-dimensional manner. Academically open-sourced ( https://github.com/dbsb-juntendo/descSPIM ), descSPIM allows routine three-dimensional imaging of cleared samples in minutes. Thus, the dissemination of descSPIM will accelerate biomedical discoveries driven by tissue clearing technologies., (© 2024. The Author(s).)

Background: Patients with type-2 diabetes (T2DM) are at increased risk of developing diabetic foot ulcers (DFU) and experiencing impaired wound healing related to underlying microvascular disease., Purpose: To evaluate the sensitivity of intra-voxel incoherent motion (IVIM) and blood oxygen level dependent (BOLD) MRI to microvascular changes in patients with DFUs., Study Type: Case-control., Population: 20 volunteers who were age and body mass index matched, including T2DM patients with DFUs (N = 10, mean age = 57.5 years), T2DM patients with controlled glycemia and without DFUs (DC, N = 5, mean age = 57.4 years) and healthy controls (HC, N = 5, mean age = 52.8 years)., Field Strength/sequence: 3T/multi-b-value IVIM and dynamic BOLD., Assessment: Resting IVIM parameters were obtained using a multi-b-value diffusion-weighted imaging sequence and two IVIM models were fit to obtain diffusion coefficient (D), pseudo-diffusion coefficient (D*), perfusion fraction (f) and microvascular volume fraction (MVF) parameters. Microvascular reactivity was evaluated by inducing an ischemic state in the foot with a blood pressure cuff during dynamic BOLD imaging. Perfusion indices were assessed in two regions of the foot: the medial plantar (MP) and lateral plantar (LP) regions., Statistical Tests: Effect sizes of group mean differences were assessed using Hedge's g adjusted for small sample sizes., Results: DFU participants exhibited elevated D*, f, and MVF values in both regions (g ≥ 1.10) and increased D (g = 1.07) in the MP region compared to DC participants. DC participants showed reduced f and MVF compared to HC participants in the MP region (g ≥ 1.06). Finally, the DFU group showed reduced tolerance for ischemia in the LP region (g = -1.51) and blunted reperfusion response in both regions (g < -2.32) compared to the DC group during the cuff-occlusion challenge., Data Conclusion: The combined use of IVIM and BOLD MRI shows promise in differentiating perfusion abnormalities in the feet of diabetic patients and suggests hyperperfusion in DFU patients., Level of Evidence: 1 TECHNICAL EFFICACY: Stage 1., (© 2023 International Society for Magnetic Resonance in Medicine.)

Background: This study examined perceptions of coercion, pressures and procedural injustice and how such perceptions influenced psychological well-being in those who experienced a UK COVID-19 lockdown, with a view to preparing for the possibility of future lockdowns., Methods: 40 individuals categorised as perceiving the lockdown(s) as either highly or lowly coercive took part in one of six asynchronous virtual focus groups (AVFGs)., Results: Using thematic analysis, the following key themes were identified in participants' discussions: (1) Choice, control and freedom; (2) threats; (3) fairness; (4) circumstantial factors; and (5) psychological factors., Conclusions: As the first qualitative study to investigate the psychological construct of perceived coercion in relation to COVID-19 lockdowns, its findings suggest that the extent to which individuals perceived pandemic-related lockdowns as coercive may have been linked to their acceptance of restrictions. Preparing for future pandemics should include consideration of perceptions of coercion and efforts to combat this, particularly in relation to differences in equity, in addition to clarity of public health messaging and public engagement., (© 2024. The Author(s).)

Sarbecoviruses such as SARS and SARS-CoV-2 have been responsible for two major outbreaks in humans, the latter resulting in a global pandemic. While sarbecoviruses primarily cause an acute respiratory infection, they have been shown to infect the nervous system. However, mechanisms of sarbecovirus neuroinvasion and neuropathogenesis remain unclear. In this study, we examined the infectivity and trans-synaptic transmission potential of the sarbecoviruses SARS and SARS-CoV-2 in human stem cell-derived neural model systems. We demonstrated limited ability of sarbecoviruses to infect and replicate in human stem cell-derived neurons. Furthermore, we demonstrated an inability of sarbecoviruses to transmit between synaptically connected human stem cell-derived neurons. Finally, we determined an absence of SARS-CoV-2 infection in olfactory neurons in experimentally infected ferrets. Collectively, this study indicates that sarbecoviruses exhibit low potential to infect human stem cell-derived neurons, lack an ability to infect ferret olfactory neurons, and lack an inbuilt molecular mechanism to utilise retrograde axonal trafficking and trans-synaptic transmission to spread within the human nervous system., (© 2023. The Author(s).)

Background: Atopic dermatitis is a chronic relapsing inflammatory skin condition. One of the most common skin disorders in children, atopic dermatitis typically manifests before the age of 5 years, but it can develop at any age. Atopic dermatitis is characterised by dry, inflamed skin accompanied by intense itchiness (pruritus)., Objectives: To appraise the clinical and cost effectiveness of abrocitinib, tralokinumab and upadacitinib within their marketing authorisations as alternative therapies for treating moderate-to-severe atopic dermatitis compared to systemic immunosuppressants (first-line ciclosporin A or second-line dupilumab and baricitinib)., Data Sources: Studies were identified from an existing systematic review (search date 2019) and update searches of electronic databases (MEDLINE, EMBASE, CENTRAL) to November 2021, from bibliographies of retrieved studies, clinical trial registers and evidence provided by the sponsoring companies of the treatments under review., Methods: A systematic review of the clinical effectiveness literature was carried out and a network meta-analysis undertaken for adults and adolescents at different steps of the treatment pathway. The primary outcome of interest was a combined response of Eczema Area and Severity Index 50 + Dermatology Life Quality Index ≥ 4; where this was consistently unavailable for a step in the pathway, an analysis of Eczema Area and Severity Index 75 was conducted. A de novo economic model was developed to assess cost effectiveness from the perspective of the National Health Service in England. The model structure was informed through systematic review of the economic literature and by consulting clinical experts. Effectiveness data were obtained from the network meta-analysis. Costs and utilities were obtained from the evidence provided by sponsoring companies and standard UK sources., Results: Network meta-analyses indicate that abrocitinib 200 mg and upadacitinib 30 mg may be more effective, and tralokinumab may be less effective than dupilumab and baricitinib as second-line systemic therapies. Abrocitinib 100 mg and upadacitinib 15 mg have a more similar effectiveness to dupilumab. Upadacitinib 30 and 15 mg are likely to be more effective than ciclosporin A as a first-line therapy. Upadacitinib 15 mg, abrocitinib 200 and 100 mg may be more effective than dupilumab in adolescents. The cost effectiveness of abrocitinib and upadacitinib for both doses is dependent on the subgroup of interest. Tralokinumab can be considered cost-effective as a second-line systemic therapy owing to greater cost savings per quality-adjusted life-year lost., Conclusions: The primary strength of the analysis of the three new drugs compared with current practice for each of the subpopulations is the consistent approach to the assessment of clinical and cost effectiveness. However, the conclusions are limited by the high uncertainty around the clinical effectiveness and lack of data for the primary outcome for comparisons with baricitinib and for the adolescent and adult first-line populations., Future Work and Limitations: The most significant limitation that Eczema Area and Severity Index 50 + Dermatology Life Quality Index ≥ 4 could not be obtained for the adolescent and adult first-line systemic treatment populations is due to a paucity of data for dupilumab and ciclosporin A. A comparison of the new drugs against one another in addition to current practice would be beneficial to provide a robust view on which treatments are the most cost-effective., Study Registration: This study is registered as PROSPERO CRD42021266219., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: 135138) and is published in full in Health Technology Assessment ; Vol. 28, No. 4. See the NIHR Funding and Awards website for further award information.

Henipaviruses are zoonotic viruses, including some highly pathogenic and capable of serious disease and high fatality rates in both animals and humans. Hendra virus and Nipah virus are the most notable henipaviruses, resulting in significant outbreaks across South Asia, South-East Asia, and Australia. Pteropid fruit bats have been identified as key zoonotic reservoirs; however, the increased discovery of henipaviruses outside the geographic distribution of Pteropid fruit bats and the detection of novel henipa-like viruses in other species such as the shrew, rat, and opossum suggest that Pteropid bats are not the sole reservoir for henipaviruses. In this review, we provide an update on henipavirus spillover events and describe the recent detection of novel unclassified henipaviruses, with a strong focus on the shrew and its emerging role as a key host of henipaviruses.

Conducting research during disease outbreaks can be ethically challenging as evidenced in the 2014-2016 Ebola outbreak in West Africa and COVID-19 pandemic. Yet, there has been little empirical research conducted for understanding the views and perspectives of different stakeholders regarding ethical issues in conducting research during disease outbreaks. This preliminary study was conducted to empirically explore African public health research stakeholders' views about research ethics issues during infectious disease outbreaks in Africa. We conducted an online survey of 330 participants attending the International Conference on Re-emerging and Emerging Infectious Disease (ICREID) meeting that took place from 13-15 March 2019 in Addis Ababa, Ethiopia to elicit their views on various research ethics complexities experienced in the 2014 Ebola outbreak. Study results revealed some divergent views on several ethical themes including: ethics of using unregistered interventions in outbreaks; acceptable study design; ethics review processes; risks-benefit assessment ; exclusion of pregnant women and children ; and biological sample and data sharing . Majority (76.3%) of respondents felt that in the absence of available standard treatments or prevention modalities, the use of investigational interventions can be ethically justifiable if there is a strong scientific rationale and favorable risk-benefit ratio. Regarding conventional placebo-controlled trials during outbreaks with high case fatality rates, respondents that considered this unethical were more than three times those that felt such design were ethically justifiable. We were somewhat surprised that a majority (almost 60%) of respondents were satisfied with the exclusion of pregnant women and children in clinical trials during outbreaks. All respondents concurred with the prioritization of informed consent for research during an outbreak. Based on our findings, research ethics guidance is needed to equip research stakeholders in dealing with ethical complexities arising in the conduct of research during emerging disease outbreaks-especially regarding using experimental interventions; placebo trial design; inclusion or justified exclusion of pregnant women and children; and biological sample/data sharing. The findings will be used in ongoing efforts of developing a consultative and coherent African-centric framework to support ethical conduct of research for future emerging infectious disease outbreaks in Africa., (Copyright © 2023, the Author(s).)

Hendra virus (HeV) and Nipah virus (NiV) are henipaviruses that can cause fatal encephalitis in humans. Many animal models have been used to study henipavirus pathogenesis. In the mouse, HeV infection has previously shown that intranasal challenge can lead to neurological infection, however mice similarly challenged with NiV show no evidence of virus infecting the brain. We generated recombinant HeV (rHeV) and NiV (rNiV) where selected proteins were switched to examine their role in neuroinvasion in the mouse. These viruses displayed similar growth kinetics when compared to wildtype in vitro. In the mouse, infection outcomes with recombinant virus did not differ to infection outcomes of wildtype viruses. Virus was detected in the brain of 5/30 rHeV-challenged mice, but not rNiV-challenged mice. To confirm the permissiveness of mouse neurons to these viruses, primary mouse neurons were successfully infected in vitro, suggesting that other pathobiological factors contribute to the differences in disease outcomes in mice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Through sustainable development goals 3 and 8 and other policies, countries have committed to protect and promote workers' health by reducing the work-related burden of disease. To monitor progress on these commitments, indicators that capture the work-related burden of disease should be available for monitoring workers' health and sustainable development. The World Health Organization and the International Labour Organization estimate that only 363 283 (19%) of 1 879 890 work-related deaths globally in 2016 were due to injuries, whereas 1 516 607 (81%) deaths were due to diseases. Most monitoring systems focusing on workers' health or sustainable development, such as the global indicator framework for the sustainable development goals, include an indicator on the burden of occupational injuries. Few such systems, however, have an indicator on the burden of work-related diseases. To address this gap, we present a new global indicator: mortality rate from diseases attributable to selected occupational risk factors, by disease, risk factor, sex and age group. We outline the policy rationale of the indicator, describe its data sources and methods of calculation, and report and analyse the official indicator for 183 countries. We also provide examples of the use of the indicator in national workers' health monitoring systems and highlight the indicator's strengths and limitations. We conclude that integrating the new indicator into monitoring systems will provide more comprehensive and accurate surveillance of workers' health, and allow harmonization across global, regional and national monitoring systems. Inequalities in workers' health can be analysed and the evidence base can be improved towards more effective policy and systems on workers' health., ((c) 2023 The authors; licensee World Health Organization.)

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible disease characterized by collagen deposition within the interstitium of the lung. This impairs gas exchange and results in eventual respiratory failure. Clinical studies show a correlation between elevated neutrophil numbers and IPF disease progression; however, the mechanistic roles neutrophils play in this disease are not well described. In the present study, we describe alterations to the trafficking and function of neutrophils after the development of fibrosis. We observed increased numbers of total and aged neutrophils in peripheral tissues of fibrotic mice. This appeared to be driven by an upregulation of neutrophil chemokine Cxcl2 by lung cells. In addition, neutrophil recruitment back to the bone marrow for clearance appeared to be impaired, because we saw decreased aged neutrophils in the bone marrow of fibrotic mice. Neutrophils in fibrosis were activated, because ex vivo assays showed increased elastase and extracellular trap release by neutrophils from fibrotic mice. This likely mediated disease exacerbation, because mice exhibiting a progressive disease phenotype with greater weight loss and mortality had more activated neutrophils and increased levels of extracellular DNA present in their lungs than did mice with a nonprogressive disease phenotype. These findings further our understanding of the dynamics of neutrophil populations and their trafficking in progressive fibrotic lung disease and may help inform treatments targeting neutrophil function for patients with IPF experiencing disease exacerbation in the future., (Copyright © 2022 The Authors.)

Cocoa flavanols have been shown to improve muscle function and may offer a novel approach to protect against muscle atrophy. Hippuric acid (HA) is a colonic metabolite of (-)-epicatechin (EPI), the primary bioactive compound of cocoa, and may be responsible for the associations between cocoa supplementation and muscle metabolic alterations. Accordingly, we investigated the effects of EPI and HA upon skeletal muscle morphology and metabolism within an in vitro model of muscle atrophy. Under atrophy-like conditions (24h 100μM dexamethasone (DEX)), C2C12 myotube diameter was significantly greater following co-incubation with either 25μM HA (11.19±0.39μm) or 25μM EPI (11.01±0.21μm) compared to the vehicle control (VC; 7.61±0.16μm, both P < .001). In basal and leucine-stimulated states, there was a significant reduction in myotube protein synthesis (MPS) rates following DEX treatment in VC (P = .024). Interestingly, co-incubation with EPI or HA abrogated the DEX-induced reductions in MPS rates, whereas no significant differences versus control treated myotubes (CTL) were noted. Furthermore, co-incubation with EPI or HA partially attenuated the increase in proteolysis seen in DEX-treated cells, preserving LC3 α/β II:I and caspase-3 protein expression in atrophy-like conditions. The protein content of PGC1α, ACC, and TFAM (regulators of mitochondrial function) were significantly lower in DEX-treated versus. CTL cells (all P < .050). However, co-incubation with EPI or HA was unable to prevent these DEX-induced alterations. For the first time we demonstrate that EPI and HA exert anti-atrophic effects on C2C12 myotubes, providing novel insight into the association between flavanol supplementation and favourable effects on muscle health., Competing Interests: Declarations of competing interest None, (Copyright © 2022. Published by Elsevier Inc.)

The solution structure of 1.0 M Uranyl Chloride has been determined by the EPSR modelling of a combination of neutron scattering and EXAFS data. The experimental data show an equilibrium in solution between [UO 2 (H 2 O) 5 ] 2+ and [UO 2 Cl(H 2 O) 4 ] + with a stability constant of 0.23 ± 0.03 mol -1 dm -3 . A much smaller fraction of the neutral [UO 2 Cl 2 (H 2 O) 3 ] ion is also observed. The data also show, for the first time in solution, that the uranyl ion is a very poor hydrogen bond acceptor, but the coordinated waters show enhanced hydrogen bond ability compared to the bulk water.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease characterized by collagen deposition within the lung interstitium. Bacterial infection is associated with increased morbidity and more rapid mortality in IPF patient populations, and pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) are commonly isolated from the lungs of hospitalized patients with IPF. Despite this, the effects of fibrotic lung injury on critical immune responses to infection remain unknown. In the present study, we show that, like humans with IPF, fibrotic mice infected with MRSA exhibit increased morbidity and mortality compared with uninfected fibrotic mice. We determine that fibrosis conferred a defect in MRSA clearance compared with nonfibrotic mice, resulting from blunted innate immune responses. We show that fibrosis inhibited neutrophil intracellular killing of MRSA through impaired neutrophil elastase release and oxidative radical production. Additionally, we demonstrate that lung macrophages from fibrotic mice have impaired phagocytosis of MRSA. Our study describes potentially novel impairments of antimicrobial responses upon pulmonary fibrosis development, and our findings suggest a possible mechanism for why patients with IPF are at greater risk of morbidity and mortality related to infection.

How does the information in the genome program the functions of the wide variety of cells in the body? While the development of biological organisms appears to follow an explicit set of genomic instructions to generate the same outcome each time, many biological mechanisms harness molecular noise to produce variable outcomes. Non-deterministic variation is frequently observed in the diversification of cell surface molecules that give cells their functional properties, and is observed across eukaryotic clades, from single-celled protozoans to mammals. This is particularly evident in immune systems, where random recombination produces millions of antibodies from only a few genes; in nervous systems, where stochastic mechanisms vary the sensory receptors and synaptic matching molecules produced by different neurons; and in microbial antigenic variation. These systems employ overlapping molecular strategies including allelic exclusion, gene silencing by constitutive heterochromatin, targeted double-strand breaks, and competition for limiting enhancers. Here, we describe and compare five stochastic molecular mechanisms that produce variety in pathogen coat proteins and in the cell surface receptors of animal immune and neuronal cells, with an emphasis on the utility of non-deterministic variation., Competing Interests: The 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 © 2022 Williams, Sikora, Hammer, Amin, Brinjikji, Brumley, Burrows, Carrillo, Cromer, Edwards, Emri, Fergle, Jenkins, Kaushik, Maydan, Woodard and Clowney.)

Mitochondria are critical to skeletal muscle contractile function and metabolic health. Short-term periods of step reduction (SR) are associated with alterations in muscle protein turnover and mass. However, the effects of SR on mitochondrial metabolism/muscle oxidative metabolism and insulin-mediated signaling are unclear. We tested the hypothesis that the total and/or phosphorylated protein content of key skeletal muscle markers of mitochondrial/oxidative metabolism, and insulin-mediated signaling would be altered over 7 days of SR in young healthy males. Eleven, healthy, recreationally active males (means ± SE, age: 22 ± 1 yr, BMI: 23.4 ± 0.7 kg·m 2 ) underwent a 7-day period of SR. Immediately before and following SR, fasted-state muscle biopsy samples were acquired and analyzed for the assessment of total and phosphorylated protein content of key markers of mitochondrial/oxidative metabolism and insulin-mediated signaling. Daily step count was significantly reduced during the SR intervention (13,054 ± 833 to 1,192 ± 99 steps·day -1 , P < 0.001). Following SR, there was a significant decline in maximal citrate synthase activity (fold change: 0.94 ± 0.08, P < 0.05) and a significant increase in the protein content of p-glycogen synthase (P-GS S641 ; fold change: 1.47 ± 0.14, P < 0.05). No significant differences were observed in the total or phosphorylated protein content of other key markers of insulin-mediated signaling, oxidative metabolism, mitochondrial function, or mitochondrial dynamics (all P > 0.05). These results suggest that short-term SR reduces the maximal activity of citrate synthase, a marker of mitochondrial content, without altering the total or phosphorylated protein content of key markers of skeletal muscle mitochondrial metabolism and insulin signaling in young healthy males. NEW & NOTEWORTHY Short-term (7 day) step reduction reduces the activity of citrate synthase without altering the total or phosphorylated protein content of key markers of skeletal muscle mitochondrial metabolism and insulin signaling in young healthy males.

Henipaviruses, Hendra (HeV) and Nipah (NiV), are highly pathogenic zoonotic agents that pose a serious health risk to human life, and as such are restricted to physical containment 4 (PC4) laboratories. For further analysis of virus-infected biological specimens, it is necessary to ensure absolute inactivation of any infectious virus present before removal from the PC4 laboratory. To evaluate the inactivation of HeV and NiV within infected samples, two chemical inactivation methods were assessed. Henipavirus-infected cell monolayers treated with 4 % paraformaldehyde (PFA) showed the complete inactivation of infectious virus, with an inactivation period of 15 min resulting in more than 8-log decrease in infectious titre. NiV-infected tissue samples treated with 10 % neutral-buffered formalin (NBF) showed a complete reduction of infectious virus in 7/8 ferret organs incubated for 24 h, with the remaining tissue demonstrating complete virus inactivation after 48 h. The chemical inactivation methods described herein evaluated two simple methods of henipavirus inactivation, resulting in the complete inactivation of infectious virus - an essential requirement for the safe removal and handling of biological samples from the PC4 laboratory., (Copyright © 2021. Published by Elsevier B.V.)

Modulation of the immune system is known to be important for successful pregnancy but how immune function might differ between the lymph nodes draining the reproductive tract and peripheral lymph nodes is not well understood. Additionally, if immune system changes in response to the presence of an embryo during early pregnancy, and if this response differs in local versus peripheral immune tissue, has not been well characterized. To address these questions, we examined expression of genes important for immune function using NanoString technology in the ampulla and isthmus of the oviduct, endometrium, lymph nodes draining the reproductive tract (lumbo-aortic and medial iliac) as well as a peripheral lymph node (axillary), the spleen, and circulating immune cells from ewes on day 5 of the estrous cycle or pregnancy. Concentrations of estradiol and progesterone in plasma were also determined. Principal component analysis revealed separation of the local from the peripheral lymph nodes (MANOVA P = 3.245e-08, R2 = 0.3) as well as separation of tissues from pregnant and nonpregnant animals [lymph nodes (MANOVA P = 2.337e-09, R2 = 0.5), reproductive tissues (MANOVA P = 2.417e-14, R2 = 0.47)]. Nine genes were differentially (FDR < 0.10) expressed between lymph node types, with clear difference in expression of these genes between the lumbo-aortic and axillary lymph nodes. Expression of these genes in the medial iliac lymph node was not consistently different to either the axillary or the lumbo-aortic lymph node. Expression of IL10RB was increased (FDR < 0.05) by 24% in the reproductive tissue of the pregnant animals compared to nonpregnant animals. Analysis of gene categories revealed that expression of genes of the T-cell receptor pathway in reproductive tract tissues was associated (P < 0.05) with pregnancy status. In conclusion, assessment of gene expression of reproductive and immune tissue provides evidence for a specialization of the local immune system around the reproductive tract potentially important for successful establishment of pregnancy. Additionally, differences in gene expression patterns in reproductive tissue from pregnant and nonpregnant animals could be discerned as early as day 5 of pregnancy. This was found to be associated with expression of genes important for T-cell function and thus highlights the important role of these cells in early pregnancy., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society of Animal Science.)

Background: There is much debate regarding the source/quality of dietary proteins in supporting indices of skeletal muscle anabolism., Objective: We performed a systematic review and meta-analysis to determine the effect of protein source/quality on acute muscle protein synthesis (MPS) and changes in lean body mass (LBM) and strength, when combined with resistance exercise (RE)., Methods: A systematic search of the literature was conducted to identify studies that compared the effects of ≥2 dose-matched, predominantly isolated protein sources of varying "quality." Three separate models were employed as follows: 1) protein feeding alone on MPS, 2) protein feeding combined with a bout of RE on MPS, and 3) protein feeding combined with longer-term resistance exercise training (RET) on LBM and strength. Further subgroup analyses were performed to compare the effects of protein source/quality between young and older adults. A total of 27 studies in young (18-35 y) and older (≥60 y) adults were included., Results: Analysis revealed an effect favoring higher-quality protein for postprandial MPS at rest [mean difference (MD): 0.014%/h; 95% CI: 0.006, 0.021; P < 0.001] and following RE (MD: 0.022%/h; 95% CI: 0.014, 0.030; P < 0.00001) in young (model 1: 0.016%/h; 95% CI: -0.004, 0.036; P = 0.12; model 2: 0.030%/h; 95% CI: 0.015, 0.045; P < 0.0001) and older (model 1: 0.012%/h; 95% CI: 0.006, 0.018; P < 0.001; model 2: 0.014%/h; 95% CI: 0.007, 0.021; P < 0.001) adults. However, although higher protein quality was associated with superior strength gains with RET [standardized mean difference (SMD): 0.24 kg; 95% CI: 0.02, 0.45; P = 0.03)], no effect was observed on changes to LBM (SMD: 0.05 kg; 95% CI: -0.16, 0.25; P = 0.65)., Conclusions: The current review suggests that protein quality may provide a small but significant impact on indices of muscle protein anabolism in young and older adults. However, further research is warranted to elucidate the importance of protein source/quality on musculoskeletal aging, particularly in situations of low protein intake., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

In vitro models of muscle aging are useful for understanding mechanisms of age-related muscle loss and aiding the development of targeted therapies. To investigate mechanisms of age-related muscle loss in vitro utilizing ex vivo human serum, fasted blood samples were obtained from four old (72 ± 1 yr) and four young (26 ± 3 yr) men. Older individuals had elevated levels of plasma CRP, IL-6, HOMA-IR, and lower concentric peak torque and work-per-repetition compared with young participants ( P < 0.05). C2C12 myotubes were serum and amino acid starved for 1 h and conditioned with human serum (10%) for 4 h or 24 h. After 4 h, C2C12 cells were treated with 5 mM leucine for 30 min. Muscle protein synthesis (MPS) was determined through the surface sensing of translation (SUnSET) technique and regulatory signaling pathways were measured via Western blot. Myotube diameter was significantly reduced in myotubes treated with serum from old, in comparison to young donors (84%, P < 0.001). MPS was reduced in myotubes treated with old donor serum, compared with young serum before leucine treatment (32%, P < 0.01). MPS and the phosphorylation of Akt, p70S6K, and eEF2 were increased in myotubes treated with young serum in response to leucine treatment, with a blunted response identified in cells treated with old serum ( P < 0.05). Muscle protein breakdown signaling pathways did not differ between groups. In summary, we show that myotubes conditioned with serum from older individuals had decreased myotube diameter and MPS compared with younger individuals, potentially driven by low-grade systemic inflammation.

Competing Interests: We declare no competing interests.

Background: Crohn's disease is a lifelong condition that can affect any segment of the gastrointestinal tract. Some people with Crohn's disease may be at higher risk of following a severe course of disease than others and being able to identify the level of risk a patient has could lead to personalised management., Objective: To assess the prognostic test accuracy, clinical impact and cost-effectiveness of two tools for the stratification of people with a diagnosis of Crohn's disease by risk of following a severe course of disease., Data Sources: The data sources MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews and the Cochrane Central Register of Controlled Trials were searched to inform the systematic reviews on prognostic accuracy, clinical impact of the prognostic tools, and economic evaluations. Additional data sources to inform the review of economic evaluations were NHS Economic Evaluation Database, Database of Abstracts of Reviews of Effects and the Health Technology Assessment Database., Review Methods: Systematic reviews of electronic databases were carried out from inception to June 2019 for studies assessing the prognostic accuracy and clinical impact of the IBDX ® (Crohn's disease Prognosis Test; Glycominds Ltd, Lod, Israel) biomarker stratification tool and the PredictSURE-IBD™ (PredictImmune Ltd, Cambridge, UK) tool. Systematic reviews of studies reporting on the cost-effectiveness of treatments for Crohn's disease were run from inception to July 2019. Two reviewers independently agreed on studies for inclusion, assessed the quality of included studies and validated the data extracted from studies. Clinical and methodological heterogeneity across studies precluded the synthesis of data for prognostic accuracy. A de novo economic model was developed to compare the costs and consequences of two treatment approaches - the 'top-down' and 'step-up' strategies, with step-up considered standard care - in people at high risk of following a severe course of Crohn's disease. The model comprised a decision tree and a Markov cohort model., Results: Sixteen publications, including eight original studies ( n  = 1478), were deemed relevant to the review of prognostic accuracy. Documents supplied by the companies marketing the prognostic tools were also reviewed. No study meeting the eligibility criteria reported on the sensitivity or specificity of the IBDX biomarker stratification tool, whereas one study provided estimates of sensitivity, specificity and negative predictive value for the PredictSURE-IBD tool. All identified studies were observational and were considered to provide weak evidence on the effectiveness of the tools. Owing to the paucity of data on the two tools, in the base-case analysis the accuracy of PredictSURE-IBD was assumed to be 100%. Accuracy of IBDX was assumed to be 100% in a scenario analysis, with the cost of the tests being the only difference between the analyses. The incremental analysis of cost-effectiveness demonstrated that top-down (via the use of PredictSURE-IBD in the model) is more expensive and generates fewer quality-adjusted life-years than step-up (via the standard care arm of the model)., Limitations: Despite extensive systematic searches of the literature, no robust evidence was identified of the prognostic accuracy of the biomarker stratification tools IBDX and PredictSURE-IBD., Conclusions: Although the model indicates that standard care dominates the tests, the lack of evidence of prognostic accuracy of the two tests and the uncertainty around the benefits of the top-down and step-up treatment approaches mean that the results should be interpreted as indicative rather than definitive., Study Registration: This study is registered as PROSPERO CRD42019138737., Funding: This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in Health Technology Assessment ; Vol. 25, No. 23. See the NIHR Journals Library website for further project information.

The dorsal cochlear nucleus (DCN) is a region of particular interest for auditory and tinnitus research. However, lack of useful genetic markers for in vivo manipulations hinders elucidation of the DCN contribution to tinnitus pathophysiology. This work assesses whether adeno-associated viral vectors (AAV) containing the calcium/calmodulin-dependent protein kinase 2α (CaMKIIα) promoter and a mouse line of nicotinic acetylcholine receptor α2 subunit (Chrna2)-Cre can target specific DCN populations. We found that CaMKIIα cannot be used to target excitatory fusiform DCN neurons as labeled cells showed diverse morphology indicating they belong to different classes of DCN neurons. Light stimulation after driving Channelrhodopsin2 (ChR2) by the CaMKIIα promoter generated spikes in some units but firing rate decreased when light stimulation coincided with sound. Expression and activation of CaMKIIα-eArchaerhodopsin3.0 in the DCN produced inhibition in some units but sound-driven spikes were delayed by concomitant light stimulation. We explored the existence of Cre+ cells in the DCN of Chrna2-Cre mice by hydrogel embedding technique (CLARITY). There were almost no Cre+ cell bodies in the DCN; however, we identified profuse projections arising from the ventral cochlear nucleus (VCN). Anterograde labeling in the VCN revealed projections to the ipsilateral superior olive and contralateral medial nucleus of the trapezoid body (MNTB; bushy cells), and a second bundle terminating in the DCN, suggesting the latter to be excitatory Chrna2+ T-stellate cells. Exciting Chrna2+ cells increased DCN firing. This work shows that cortical molecular tools may be useful for manipulating the DCN especially for tinnitus studies., (Copyright © 2021 Malfatti et al.)

Background: Poor recovery from periods of disuse accelerates age-related muscle loss, predisposing individuals to the development of secondary adverse health outcomes. Exercise prior to disuse (prehabilitation) may prevent muscle deterioration during subsequent unloading. The present study aimed to investigate the effect of short-term resistance exercise training (RET) prehabilitation on muscle morphology and regulatory mechanisms during 5 days of bed rest in older men., Methods: Ten healthy older men aged 65-80 years underwent four bouts of high-volume unilateral leg RET over 7 days prior to 5 days of inpatient bed rest. Physical activity and step-count were monitored over the course of RET prehabilitation and bed rest, whilst dietary intake was recorded throughout. Prior to and following bed rest, quadriceps cross-sectional area (CSA), and hormone/lipid profiles were determined. Serial muscle biopsies and dual-stable isotope tracers were used to determine integrated myofibrillar protein synthesis (iMyoPS) over RET prehabilitation and bed rest phases, and acute postabsorptive and postprandial myofibrillar protein synthesis (aMyoPS) rates at the end of bed rest., Results: During bed rest, daily step-count and light and moderate physical activity time decreased, whilst sedentary time increased when compared with habitual levels (P < 0.001 for all). Dietary protein and fibre intake during bed rest were lower than habitual values (P < 0.01 for both). iMyoPS rates were significantly greater in the exercised leg (EX) compared with the non-exercised control leg (CTL) over prehabilitation (1.76 ± 0.37%/day vs. 1.36 ± 0.18%/day, respectively; P = 0.007). iMyoPS rates decreased similarly in EX and CTL during bed rest (CTL, 1.07 ± 0.22%/day; EX, 1.30 ± 0.38%/day; P = 0.037 and 0.002, respectively). Postprandial aMyoPS rates increased above postabsorptive values in EX only (P = 0.018), with no difference in delta postprandial aMyoPS stimulation between legs. Quadriceps CSA at 40%, 60%, and 80% of muscle length decreased significantly in EX and CTL over bed rest (0.69%, 3.5%, and 2.8%, respectively; P < 0.01 for all), with no differences between legs. No differences in fibre-type CSA were observed between legs or with bed rest. Plasma insulin and serum lipids did not change with bed rest., Conclusions: Short-term resistance exercise prehabilitation augmented iMyoPS rates in older men but did not offset the relative decline in iMyoPS and muscle mass during bed rest., (© 2020 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.)

The reproductive performance of a sheep flock is dependent on a multitude of complex interacting factors. Attaining optimal flock performance requires information about how the reproductive steps are linked and relate to readily available measurements of the state of the flock. The goal was to use data from nine commercial flocks (greater than 300,000 records) to investigate and model the key reproductive steps affecting flock reproductive performance. We also developed a maximum-likelihood based methodology to predict flock ovulation rate based on measurements of the number of fetuses at mid-pregnancy (detected by ultrasound-scanning). The model was used to determine how changes in premating liveweight, age, predicted ovulation rate, number of fetuses at mid-pregnancy, lamb survival and lamb growth rate affect the total lamb liveweight at weaning per ewe exposed to the ram in each flock. The data from the commercial flocks were also used to investigate the role of ewe age and premating liveweight on each reproductive step. Sensitivity analyses were conducted to identify the key reproductive steps affecting flock reproductive performance, with a focus on understanding how these steps vary between flocks. The elasticity for embryo survival was 60% of that for lamb survival for these flocks and the elasticities for ovulation rate were highly variable between flocks (0.16 to 0.50 for mature ewes). This indicates that ovulation rate was near-optimal for some flocks, whereas there was potential to significantly improve flock performance in suboptimal flocks. The elasticity for ewe premating liveweight was highly variable between flocks (-0.03 to 0.84 for mature ewes and -0.18 to 1.39 for ewe lambs), indicating that premating liveweight ranged from optimal to suboptimal between flocks. For these suboptimal farms, the opportunity exists to increase flock performance through improved management of ewe premating liveweight. Reproductive loss was significantly greater in ewe lambs than mature ewes, although the difference is dependent on the stage of reproduction and flock. Predicted ovulation rate was 25% lower for ewe lambs and there was a 30% relative decrease in the predicted embryo survival probability from ovulation to scanning for ewe lambs. There was a 10% relative decrease in lamb survival probability from birth to weaning for ewe lambs and lamb growth rate was 25% lower for ewe lambs., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society of Animal Science.)

Background: Unavoidable periods of disuse lead to muscle atrophy and functional decline. Preventing such declines can reduce the risk of re-injury and improve recovery of normal physiological functioning., Objectives: We aimed to determine the effectiveness of high-dose leucine supplementation on muscle morphology and strength during 7 d of unilateral lower-limb immobilization, and the role of myofibrillar (MyoPS) and mitochondrial (MitoPS) protein synthesis in disuse atrophy., Methods: Sixteen healthy males (mean ± SEM age: 23 ± 1 y) underwent 7 d of unilateral lower-limb immobilization, with thrice-daily leucine (LEU; n = 8) or placebo (PLA; n = 8) supplementation (15 g/d). Before and after immobilization, muscle strength and compartmental tissue composition were assessed. A primed continuous infusion of l-[ring-13C6]-phenylalanine with serial muscle biopsies was used to determine postabsorptive and postprandial (20 g milk protein) MyoPS and MitoPS, fiber morphology, markers of protein turnover, and mitochondrial function between the control leg (CTL) and the immobilized leg (IMB)., Results: Leg fat-free mass was reduced in IMB (mean ± SEM: -3.6% ± 0.5%; P = 0.030) but not CTL with no difference between supplementation groups. Isometric knee extensor strength declined to a greater extent in IMB (-27.9% ± 4.4%) than in CTL (-14.3% ± 4.4%; P = 0.043) with no difference between groups. In response to 20 g milk protein, postprandial MyoPS rates were significantly lower in IMB than in CTL (-22% ± 4%; P < 0.01) in both LEU and PLA. Postabsorptive MyoPS rates did not differ between legs or groups. Postabsorptive MitoPS rates were significantly lower in IMB than in CTL (-14% ± 5%; P < 0.01) and postprandial MitoPS rates significantly declined in response to 20 g milk protein ingestion (CTL: -10% ± 8%; IMB: -15% ± 10%; P = 0.039), with no differences between legs or groups. There were no significant differences in measures of mitochondrial respiration between legs, but peroxisome proliferator-activated receptor γ coactivator 1-α and oxidative phosphorylation complex II and III were significantly lower in IMB than in CTL (P < 0.05), with no differences between groups., Conclusions: High-dose leucine supplementation (15 g/d) does not appear to attenuate any functional declines associated with 7 d of limb immobilization in young, healthy males.This trial was registered at clinicaltrials.gov as NCT03762278., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

Three-dimensional cell cultures are able to better mimic the physiology and cellular environments found in tissues in vivo compared to cells grown in two dimensions. In order to study the structure and function of cells in 3-D cultures, light microscopy is frequently used. The preparation of 3-D cell cultures for light microscopy is often destructive, including physical sectioning of the samples, which can result in the loss of 3-D information. In order to probe the structure of 3-D cell cultures at high resolution, we have explored the use of expansion microscopy and compared it to a simple immersion clearing protocol. We provide a practical method for the study of spheroids, organoids and tumor-infiltrating immune cells at high resolution without the loss of spatial organization. Expanded samples are highly transparent, enabling high-resolution imaging over extended volumes by significantly reducing light scatter and absorption. In addition, the hydrogel-like nature of expanded samples enables homogenous antibody labeling of dense epitopes throughout the sample volume. The improved labeling and image quality achieved in expanded samples revealed details in the center of the organoid which were previously only observable following serial sectioning. In comparison to chemically cleared spheroids, the improved signal-to-background ratio of expanded samples greatly improved subsequent methods for image segmentation and analysis., (Copyright © 2020 Edwards, Carannante, Kuhnigk, Ring, Tararuk, Hallböök, Blom, Önfelt and Brismar.)

It was hypothesized that values for fertility variables would vary with number of rams ewes mated with in a group mating management system. In Experiment 1, for adult ewes (n = 872) joined with rams for 35-38 days, 19.0 ± 2.2 %, 19.2 ± 3.5 %, 34.4 ± 1.3 % and 27.4 ± 3.3 % were marked by zero, one, two or three rams during the first 17 days, respectively. In general, as number of rams with which ewes mated increased, number of lambs born (NLB) increased, however, ovulation rate (OR) did not. In mated ewes, embryo survival (ES) increased (P < 0.05) as number of rams with which ewes mated increased. In Experiment 2, ewes that mated with zero or one ram had lesser concentrations of estradiol than ewes that mated with two or three rams when evaluated 30 h after initiation of the follicular phase. Following breeding on the subsequent estrus, number of fetuses at mid-gestation was less in ewes that had mated, in the previous estrus, with zero or one ram compared to two or three rams. In summary, ewes mating with a larger number of rams had greater values for the fertility variables that were evaluated compared with those mating with fewer rams. When ewes mated with fewer rams during the estrous period there were lesser concentrations of estradiol, potentially associated with the decreased ES., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The reproductive performance of a sheep flock is dependent on a multitude of complex interacting factors. Achieving optimal flock performance requires knowledge of the reproductive steps and how these are linked and related to available measurements of the state and performance of the flock. The goal was to use previously collected data from a research flock that had undergone selection for fecundity (11,369 lambing records), to model the key reproductive steps affecting flock reproductive performance. The model was used to investigate how changes in liveweight, age, ovulation rate, number of fetuses at midpregnancy, number of lambs born, and birthweight affect the number of lambs weaned and the weaning weight of each lamb in this flock. The data available from the research flock were used to parameterize models of each reproductive step and assess the role of ewe age and premating liveweight on each reproductive step. These models were then linked together as a simulation tool to assess the role of different parameters on flock reproductive performance, which was defined as the total weight of lambs weaned per ewe exposed to the ram. Flock elasticities were calculated that characterize the relative importance of the effect of average premating ewe liveweight (0.81), average ovulation rate (0.33), variance in ovulation rate (-0.095), embryo survival (0.72), lamb survival (1.03), conception failure (0.35), and average ewe age (0.056) on the total kilograms of lamb liveweight at weaning per ewe exposed to the ram. The largest elasticity for lamb survival indicated that a 1% increase in lamb survival is expected to have a 1.03% increase in the total kilograms of lamb liveweight at weaning per ewe exposed to the ram in this flock. Assuming similar costs, interventions to increase lamb survival for this flock will provide the largest increase in the total kilograms of lamb liveweight at weaning per ewe exposed to the ram, which is a key metric of flock performance., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Dietary fiber provides a variety of microbiota-mediated benefits ranging from anti-inflammatory metabolites to pathogen colonization resistance. A healthy gut microbiota protects against Clostridioides difficile colonization. Manipulation of these microbes through diet may increase colonization resistance to improve clinical outcomes. The primary objective of this study was to identify how the dietary fiber xanthan gum affects the microbiota and C. difficile colonization. We added 5% xanthan gum to the diet of C57BL/6 mice and examined its effect on the microbiota through 16S rRNA gene amplicon sequencing and short-chain fatty acid analysis. Following either cefoperazone or an antibiotic cocktail administration, we challenged mice with C. difficile and measured colonization by monitoring the CFU. Xanthan gum administration is associated with increases in fiber-degrading taxa and short-chain fatty acid concentrations. However, by maintaining both the diversity and absolute abundance of the microbiota during antibiotic treatment, the protective effects of xanthan gum administration on the microbiota were more prominent than the enrichment of these fiber-degrading taxa. As a result, mice that were on the xanthan gum diet experienced limited to no C. difficile colonization. Xanthan gum administration alters mouse susceptibility to C. difficile colonization by maintaining the microbiota during antibiotic treatment. While antibiotic-xanthan gum interactions are not well understood, xanthan gum has previously been used to bind drugs and alter their pharmacokinetics. Thus, xanthan gum may alter the activity of the oral antibiotics used to make the microbiota susceptible. Future research should further characterize how this and other common dietary fibers interact with drugs. IMPORTANCE A healthy gut bacterial community benefits the host by breaking down dietary nutrients and protecting against pathogens. Clostridioides difficile capitalizes on the absence of this community to cause diarrhea and inflammation. Thus, a major clinical goal is to find ways to increase resistance to C. difficile colonization by either supplementing with bacteria that promote resistance or a diet to enrich for those already present in the gut. In this study, we describe an interaction between xanthan gum, a human dietary additive, and the microbiota resulting in an altered gut environment that is protective against C. difficile colonization., (Copyright © 2020 Schnizlein et al.)

Background: Cryptogenic stroke is a stroke for which no cause is identified after standard diagnostic tests. Long-term implantable cardiac monitors may be better at diagnosing atrial fibrillation and provide an opportunity to reduce the risk of stroke recurrence with anticoagulants., Objectives: The objectives were to assess the diagnostic test accuracy, clinical effectiveness and cost-effectiveness of three implantable monitors [BioMonitor 2-AF™ (Biotronik SE & Co. KG, Berlin, Germany), Confirm Rx™ (Abbott Laboratories, Lake Bluff, IL, USA) and Reveal LINQ™ (Medtronic plc, Minneapolis, MN, USA)] in patients who have had a cryptogenic stroke and for whom no atrial fibrillation is detected after 24 hours of external electrocardiographic monitoring., Data Sources: MEDLINE, EMBASE, The Cochrane Library, Database of Abstracts of Reviews of Effects and Health Technology Assessment databases were searched from inception until September 2018., Review Methods: A systematic review was undertaken. Two reviewers agreed on studies for inclusion and performed quality assessment using the Cochrane Risk of Bias 2.0 tool. Results were discussed narratively because there were insufficient data for synthesis. A two-stage de novo economic model was developed: (1) a short-term patient flow model to identify cryptogenic stroke patients who have had atrial fibrillation detected and been prescribed anticoagulation treatment (rather than remaining on antiplatelet treatment) and (2) a long-term Markov model that captured the lifetime costs and benefits of patients on either anticoagulation or antiplatelet treatment., Results: One randomised controlled trial, Cryptogenic Stroke and underlying Atrial Fibrillation (CRYSTAL-AF) (Sanna T, Diener HC, Passman RS, Di Lazzaro V, Bernstein RA, Morillo CA, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 2014; 370 :2478-86), was identified, and no diagnostic test accuracy study was identified. The CRYSTAL-AF trial compared the Reveal™ XT (a Reveal LINQ predecessor) (Medtronic plc) monitor with standard of care monitoring. Twenty-six single-arm observational studies for the Reveal devices were also identified. The only data for BioMonitor 2-AF or Confirm Rx were from mixed population studies supplied by the companies. Atrial fibrillation detection in the CRYSTAL-AF trial was higher with the Reveal XT than with standard monitoring at all time points. By 36 months, atrial fibrillation was detected in 19% of patients with an implantable cardiac monitor and in 2.3% of patients receiving conventional follow-up. The 26 observational studies demonstrated that, even in a cryptogenic stroke population, atrial fibrillation detection rates are highly variable and most cases are asymptomatic; therefore, they probably would not have been picked up without an implantable cardiac monitor. Device-related adverse events, such as pain and infection, were low in all studies. The de novo economic model produced incremental cost effectiveness ratios comparing implantable cardiac monitors with standard of care monitoring to detect atrial fibrillation in cryptogenic stroke patients based on data for the Reveal XT device, which can be related to Reveal LINQ. The BioMonitor 2-AF and Confirm RX were included in the analysis by making a strong assumption of equivalence with Reveal LINQ. The results indicate that implantable cardiac monitors could be considered cost-effective at a £20,000-30,000 threshold. When each device is compared incrementally, BioMonitor 2-AF dominates Reveal LINQ and Confirm RX., Limitations: The cost-effectiveness analysis for implantable cardiac monitors is based on a strong assumption of clinical equivalence and should be interpreted with caution., Conclusions: All three implantable cardiac monitors could be considered cost-effective at a £20,000-30,000 threshold, compared with standard of care monitoring, for cryptogenic stroke patients with no atrial fibrillation detected after 24 hours of external electrocardiographic monitoring; however, further clinical studies are required to confirm their efficacy in cryptogenic stroke patients., Study Registration: This study is registered as PROSPERO CRD42018109216., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 24, No. 5. See the NIHR Journals Library website for further project information., Competing Interests: No competing interests were declared.

After the success of the Toxics Release Inventory (TRI) in the United States (US), Canada created the National Pollutant Release Inventory (NPRI). Both NPRI and TRI focus on public opinion to coerce facilities to reduce quantities of emissions, through market pressure, although early reductions in Canada may be attributed to traditional command-and-control mechanisms. NPRI uses a quantity-based approach to report atmospheric and effluent releases of pollutants to air and water, but does not account for relative toxicity of releases, which could lead to harmful chemicals being overlooked. A toxicity-based approach using characterization factors from the USEtox® environmental impact assessment tool was used for this study. Releases of organic and inorganic pollutants to both air and water in Nova Scotia for 2015 were analyzed. Using an ecotoxicity analysis found that the highest priority chemicals identified using the NPRI's quantity-based approach differed markedly from those identified using the toxicity-based approach. Many of the high-priority chemicals identified using toxicity-based analysis are detrimental to ecosystem health and warrant regulatory attention. The Office of the Auditor General of Canada recently suggested that the Canadian federal government needs to improve control risks of toxic substances. Using a toxicity-based approach may help decision makers in the Canadian federal government effectively control risks of toxic substances and help to inform decision makers, regulators, and Canadians about those risks.

Studtite, [UO 2 (η 2 -O 2 )(H 2 O) 2 ]·2H 2 O, and metastudtite, [UO 2 (η 2 -O 2 )(H 2 O) 2 ], are important phase alterations of UO 2 in a spent nuclear fuel repository and have previously been shown to react with Np(v). In this work we extend the study to Am(v) on a tracer scale and show spectroscopic evidence that the Am is incorporated into the structure of studtite as Am(iii). A computational study on the possible mechanisms for the incorporation of Np and Am shows that protonation of the -yl oxygen is the favoured route and the calculated incorporation energies are large and positive. The results suggest that Am is less favoured compared to Np but energetically more favoured to incorporate both actinide ions into metastudtite rather than studtite. Finally, we have shown that once incorporated, Am readily leaches into water but spectroscopic measurements suggest subtle changes in the structure of studtite.

As part of its Single Technology Appraisal (STA) process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer (EUSA Pharma) of dinutuximab beta (Qarziba ® ) to submit evidence of its clinical and cost effectiveness for treating neuroblastoma. The BMJ Technology Assessment Group (BMJ-TAG) was commissioned to act as the Evidence Review Group (ERG), reviewing the submission from the company. The Decision Support Unit (DSU) was commissioned to review additional evidence submitted by the company and to undertake further analyses. This article presents the critical review of the company's submissions by the ERG and DSU, further analyses undertaken by the DSU, and the outcome of the NICE guidance. The clinical effectiveness for dinutuximab beta was derived from a phase III randomised controlled trial (RCT) that assessed the safety and efficacy of the addition of interleukin (IL)-2 to dinutuximab beta plus isotretinoin. This trial did not inform the relative effectiveness of dinutuximab beta versus isotretinoin alone, which was established practice in the UK for maintenance treatment. In the absence of direct evidence, the company initially conducted a naïve indirect treatment comparison against a historical control, and later performed a matching-adjusted indirect comparison (MAIC) against the isotretinoin arm of an RCT comparing dinutuximab alpha and isotretinoin. The company submitted a partitioned survival analysis model that calculated the incremental cost effectiveness of dinutuximab beta versus isotretinoin. The company's original incremental cost-effectiveness ratio (ICER) was £22,338 per quality-adjusted life-year (QALY) gained. However, the ERG were concerned that the company's ICER was not suitable for decision making, and thus carried out initial exploratory analysis as a first step to overcome the naïve estimation of treatment effectiveness in the model. The ERG's analysis estimated an ICER of £111,858 per QALY gained. In their revised analysis incorporating the MAIC and other changes as requested by the appraisal committee, the company's ICER was £24,661 per QALY gained. When the DSU incorporated longer-term isotretinoin data and made corrections to the model, the ICER increased to between £62,886 and £87,164 per QALY gained depending on the choice of survival model. A confidential Patient Access Scheme (PAS) decreased the ICERs. The ICERs with the PAS were over £40,000 per QALY gained, but the NICE committee additionally considered the patient population and its size, the disease severity, the potential for significant survival benefit and uncaptured health benefits, and recommended dinutuximab beta as a treatment option, subject to the company providing the agreed discount in the PAS.

Objective: To compare the effectiveness and safety of treatments for advanced or metastatic renal cell carcinoma (amRCC) after treatment with vascular endothelial growth factor (VEGF)-targeted treatment., Design: Systematic review and network meta-analysis of randomised controlled trials (RCTs) and comparative observational studies. MEDLINE, EMBASE and Cochrane Library were searched up to January 2018., Participants: People with amRCC requiring treatment after VEGF-targeted treatment., Interventions: Axitinib, cabozantinib, everolimus, lenvatinib with everolimus, nivolumab, sorafenib and best supportive care (BSC)., Outcomes: Primary outcomes were overall survival (OS) and progression-free survival (PFS); secondary outcomes were objective response rate (ORR), adverse events, and health-related quality of life (HRQoL)., Results: Twelve studies were included (n=5144): five RCTs and seven observational studies. Lenvatinib with everolimus significantly increased OS and PFS over everolimus (HR 0.61, 95% Credible Interval [95%CrI]: 0.36 to 0.96 and 0.47, 95%CrI: 0.26 to 0.77, respectively) as did cabozantinib (HR 0.66, 95%CrI: 0.53 to 0.82 and 0.51, 95%CrI: 0.41 to 0.63, respectively). This remained the case when observational evidence was included. Nivolumab also significantly improved OS versus everolimus (HR 0.74, 95%CrI: 0.57 to 0.93). OS sensitivity analysis, including observational studies, indicates everolimus being more effective than axitinib and sorafenib. However, inconsistency was identified in the OS sensitivity analysis. PFS sensitivity analysis suggests axitinib is more effective than everolimus, which may be more effective than sorafenib. The results for ORR supported the OS and PFS analyses. Nivolumab is associated with fewer grade 3 or grade 4 adverse events than lenvatinib with everolimus or cabozantinib. HRQoL could not be analysed due to differences in tools used., Conclusions: Lenvatinib with everolimus, cabozantinib and nivolumab are effective in prolonging the survival for people with amRCC subsequent to VEGF-targeted treatment, but there is considerable uncertainty about how they compare to each other and how much better they are than axitinib and sorafenib., Prospero Registration Number: CRD42017071540., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Introduction: While nausea and vomiting in early pregnancy are very common, affecting approximately 80% of the pregnancies, hyperemesis gravidarum is a severe form affecting 0.3-1.0% of the pregnancies. Although hyperemesis gravidarum is rarely a source of mortality, it is a significant source of morbidity. It is one of the most common indications for hospitalization in pregnancy. Beyond the maternal and fetal consequences of malnutrition, the severity of hyperemesis symptoms causes a major psychosocial burden leading to depression, anxiety, and even pregnancy termination. The aim of this meta-analysis was to examine all randomized controlled trials of interventions specifically for hyperemesis gravidarum and evaluate them based on both subjective and objective measures of efficacy, maternal and fetal/neonatal safety, and economic costs., Material and Methods: Randomized controlled trials were identified by searching electronic databases. We included all randomized controlled trials for the treatment of hyperemesis gravidarum. The primary outcome was intervention efficacy as defined by severity, reduction, or cessation in nausea/vomiting; number of episodes of emesis; and days of hospital admission. Secondary outcomes included other measures of intervention efficacy, adverse maternal/fetal/neonatal outcomes, quality of life measures, and economic costs., Results: Twenty-five trials (2052 women) met the inclusion criteria but the majority of 18 different comparisons described in the review include data from single studies with small numbers of participants. Selected comparisons reported below: No primary outcome data were available when acupuncture was compared with placebo. There was insufficient evidence to identify clear differences between acupuncture and metoclopramide in a study with 81 participants regarding reduction/cessation in nausea or vomiting (risk ratio (RR) 1.40, 95% CI 0.79-2.49 and RR 1.51, 95% CI 0.92-2.48, respectively). Midwife-led outpatient care was associated with fewer hours of hospital admission than routine inpatient admission (mean difference (MD) - 33.20, 95% CI -46.91 to -19.49) with no difference in pregnancy-unique quantification of emesis and nausea (PUQE) score, decision to terminate the pregnancy, miscarriage, small-for-gestational age infants, or time off work when compared with routine care. Women taking vitamin B6 had a slightly longer hospital stay compared with placebo (MD 0.80 days, 95% CI 0.08-1.52). There was insufficient evidence to demonstrate a difference in other outcomes including mean number of episodes of emesis (MD 0.50, 95% CI -0.40-1.40) or side effects. A comparison between metoclopramide and ondansetron identified no clear difference in the severity of nausea or vomiting (MD 1.70, 95% CI -0.15-3.55, and MD -0.10, 95% CI -1.63-1.43; one study, 83 women, respectively). However, more women taking metoclopramide complained of drowsiness and dry mouth (RR 2.40, 95% CI 1.23-4.69, and RR 2.38, 95% CI 1.10-5.11, respectively). There were no clear differences between groups for other side effects. In a single study with 146 participants comparing metoclopramide with promethazine, more women taking promethazine reported drowsiness, dizziness, and dystonia (risk ratio (RR) 0.70, 95% CI 0.56-0.87, RR 0.48, 95% CI 0.34-0.69, and RR 0.31, 95% CI 0.11-0.90, respectively). There were no clear differences between groups for other important outcomes including quality of life and other side effects. In a single trial with 30 women, those receiving ondansetron had no difference in duration of hospital admission compared to those receiving promethazine (mean difference (MD) 0.00, 95% CI -1.39-1.39), although there was increased sedation with promethazine (RR 0.06, 95% CI 0.00-0.94). Regarding corticosteroids, in a study with 110 participants there was no difference in days of hospital admission compared to placebo (MD -0.30, 95% CI -0.70-0.10), but there was a decreased readmission rate (RR 0.69, 95% CI 0.50-0.94; 4 studies, 269 women). For hydrocortisone compared with metoclopramide, no data were available for primary outcomes and there was no difference in the readmission rate (RR 0.08, 95% CI 0.00-1.28; one study, 40 women). In a study with 80 women, compared to promethazine, those receiving prednisolone had increased nausea at 48 h (RR 2.00, 95% CI 1.08-3.72), but not at 17 days (RR 0.81, 95% CI 0.58-1.15). There was no clear difference in the number of episodes of emesis or subjective improvement in nausea/vomiting., Conclusions: While there were a wide range of interventions studied, both pharmaceutical and otherwise, there were a limited number of placebo controlled trials. In comparing the efficacy of the commonly used antiemetics, metoclopramide, ondansetron, and promethazine, the results of this review do not support the clear superiority of one over the other in symptomatic relief. Other factors such as side effect profile medication safety and healthcare costs should also be considered when selecting an intervention.

Regulation of the growth and maturation of the ovarian follicle is critical for normal reproductive function. Alterations in this growth can lead to pathological conditions, such as cystic follicles, reduced oocyte quality, or an abnormal endocrine environment leading to poor fertility. Alterations in follicular growth also influence the number of follicles ovulating and thus can change litter size. Both endocrine factors, such as follicle stimulating hormone and luteinizing hormone, as well as local factors, are known to regulate follicular growth and development. This review will focus on the role of local factors in regulation of ovarian follicular growth in ruminants, with a focus on members of the transforming growth factor superfamily. The potential role of these factors in regulating proliferation, apoptosis, steroidogenesis and responsiveness to gonadotrophins will be considered.

Inhibitory interneurons participate in mnemonic processes. However, defined roles for identified interneuron populations are scarce. A subpopulation of oriens lacunosum-moleculare (OLM) interneurons genetically defined by the expression of the nicotinic receptor α2 subunit has been shown to gate information carried by either the temporoammonic pathway or Schaffer collaterals in vitro. Here we set out to determine whether selective modulation of OLMα2 cells in the intermediate CA1 affects learning and memory in vivo. Our data show that intermediate OLMα2 cells can either enhance (upon their inhibition) or impair (upon their activation) object memory encoding in freely moving mice, thus exerting bidirectional control. Moreover, we find that OLMα2 cell activation inhibits fear-related memories and that OLMα2 cells respond differently to nicotine in the dorsoventral axis. These results suggest that intermediate OLMα2 cells are an important component in the CA1 microcircuit regulating learning and memory processes. VIDEO ABSTRACT., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Despite many potential applications, miniature mass spectrometers have had limited adoption in the field due to the tradeoff between throughput and resolution that limits their performance relative to laboratory instruments. Recently, a solution to this tradeoff has been demonstrated by using spatially coded apertures in magnetic sector mass spectrometers, enabling throughput and signal-to-background improvements of greater than an order of magnitude with no loss of resolution. This paper describes a proof of concept demonstration of a cycloidal coded aperture miniature mass spectrometer (C-CAMMS) demonstrating use of spatially coded apertures in a cycloidal sector mass analyzer for the first time. C-CAMMS also incorporates a miniature carbon nanotube (CNT) field emission electron ionization source and a capacitive transimpedance amplifier (CTIA) ion array detector. Results confirm the cycloidal mass analyzer's compatibility with aperture coding. A >10× increase in throughput was achieved without loss of resolution compared with a single slit instrument. Several areas where additional improvement can be realized are identified. Graphical Abstract ᅟ.

Background: Several therapies have recently been approved for use in the NHS for pretreated advanced or metastatic renal cell carcinoma (amRCC), but there is a lack of comparative evidence to guide decisions between them., Objective: To evaluate the clinical effectiveness and cost-effectiveness of axitinib (Inlyta ® , Pfizer Inc., NY, USA), cabozantinib (Cabometyx ® , Ipsen, Slough, UK), everolimus (Afinitor ® , Novartis, Basel, Switzerland), nivolumab (Opdivo ® , Bristol-Myers Squibb, NY, USA), sunitinib (Sutent ® , Pfizer, Inc., NY, USA) and best supportive care (BSC) for people with amRCC who were previously treated with vascular endothelial growth factor (VEGF)-targeted therapy., Data Sources: A systematic review and mixed-treatment comparison (MTC) of randomised controlled trials (RCTs) and non-RCTs. Primary outcomes were overall survival (OS) and progression-free survival (PFS). Secondary outcomes were objective response rates (ORRs), adverse events (AEs) and health-related quality of life (HRQoL). MEDLINE, EMBASE and The Cochrane Library were searched from inception to January and June 2016 for RCTs and non-RCTs, respectively. Two reviewers abstracted data and performed critical appraisals., Review Methods: A fixed-effects MTC was conducted for OS, PFS [hazard ratios (HRs)] and ORR (odds ratios), and all were presented with 95% credible intervals (CrIs). The RCT data formed the primary analyses, with non-RCTs and studies rated as being at a high risk of bias included in sensitivity analyses (SAs). HRQoL and AE data were summarised narratively. A partitioned survival model with health states for pre progression, post progression and death was developed to perform a cost-utility analysis. Survival curves were fitted to the PFS and OS results from the MTC. A systematic review of HRQoL was undertaken to identify sources of health state utility values., Results: Four RCTs ( n  = 2618) and eight non-RCTs ( n  = 1526) were included. The results show that cabozantinib has longer PFS than everolimus (HR 0.51, 95% CrI 0.41 to 0.63) and both treatments are better than BSC. Both cabozantinib (HR 0.66, 95% CrI 0.53 to 0.82) and nivolumab (HR 0.73, 95% CrI 0.60 to 0.89) have longer OS than everolimus. SAs were consistent with the primary analyses. The economic analysis, using drug list prices, shows that everolimus may be more cost-effective than BSC with an incremental cost-effectiveness ratio (ICER) of £45,000 per quality-adjusted life-year (QALY), as it is likely to be considered an end-of-life treatment. Cabozantinib has an ICER of £126,000 per QALY compared with everolimus and is unlikely to be cost-effective. Nivolumab was dominated by cabozantinib (i.e. more costly and less effective) and axitinib was dominated by everolimus., Limitations: Treatment comparisons were limited by the small number of RCTs. However, the key limitation of the analysis is the absence of the drug prices paid by the NHS, which was a limitation that could not be avoided owing to the confidentiality of discounts given to the NHS., Conclusions: The RCT evidence suggests that cabozantinib is likely to be the most effective for PFS and OS, closely followed by nivolumab. All treatments appear to delay disease progression and prolong survival compared with BSC, although the results are heterogeneous. The economic analysis shows that at list price everolimus could be recommended as the other drugs are much more expensive with insufficient incremental benefit. The applicability of these findings to the NHS is somewhat limited because existing confidential patient access schemes could not be used in the analysis. Future work using the discounted prices at which these drugs are provided to the NHS would better inform estimates of their relative cost-effectiveness., Study Registration: This study is registered as PROSPERO CRD42016042384., Funding: The National Institute for Health Research Health Technology Assessment programme.

Assessing water sources for drinking and irrigation along with community vulnerability, especially in developing and rural regions, is important for reducing risk posed by poor water quality and limited water availability and accessibility. We present a case study of rural mining-agricultural communities in the Lake Poopó Basin, one of the poorest regions on the Bolivian Altiplano. Here, relatively low rainfall, high evaporation, salinization and unregulated mining activity have contributed to environmental degradation and water issues, which is a situation facing many Altiplano communities. Social data from 72 households and chemical water quality data from 27 surface water and groundwater sites obtained between August 2013 and July 2014 were used to develop locally relevant vulnerability assessment methodologies and ratings with respect to water availability and quality, and Chemical Water Quality Hazard Ratings to assess water quality status. Levels of natural and mining-related contamination in many waters (CWQHR ≥ 6; 78% of assessed sites) mean that effective remediation would be challenging and require substantial investment. Although waters of fair to good chemical quality (CWQHR ≤ 5; 22% of assessed sites) do exist, treatment may still be required depending on use, and access issues remain problematic. There is a need to comply with water quality legislation, improve and maintain basic water supply and storage infrastructure, build and operate water and wastewater treatment plants, and adequately and safely contain and treat mine waste. This study serves as a framework that could be used elsewhere for assessing and mitigating water contamination and availability affecting vulnerable populations.

Background: Skin cancer is one of the most common cancers in the UK. Patients with suspicious skin lesions are assessed clinically with/without dermoscopy, and lesions still considered suspicious are then surgically removed or have the diagnosis confirmed by a punch biopsy., Aim: To evaluate the diagnostic accuracy of the in vivo VivaScope © reflective confocal microscopy (RCM) system, a noninvasive technology designed to provide a more accurate presurgical diagnosis, leading to fewer biopsies of benign lesions, or to provide greater accuracy for lesion margins., Methods: MEDLINE, EMBASE and the Cochrane Library were searched to identify studies evaluating dermoscopy plus RCM, or RCM alone, with histopathology as the reference test. Clinical experts were also contacted for information on unpublished studies., Results: Eleven studies met the inclusion criteria but were too heterogeneous to be combined by meta-analysis. Results indicated that VivaScope subsequent to dermoscopy may improve diagnostic accuracy of malignant melanomas compared with dermoscopy. For margin delineation, the data suggest that mapping using VivaScope 1500 for lentigo maligna (LM) and LM melanoma may improve accuracy in terms of complete excision of lesions compared with dermoscopically determined margins. For basal cell carcinoma, the limited data show high diagnostic accuracy with both VivaScope 1500 and VivaScope 3000. Evidence on the effectiveness of VivaScope in diagnosing cutaneous squamous cell carcinomas was very limited., Conclusion: The use of VivaScope 1500 following dermoscopy may improve patient care and management of suspicious skin lesions, although the generalizability of these results to the UK population remains unclear., (© 2017 British Association of Dermatologists.)

Martinotti cells are the most prominent distal dendrite-targeting interneurons in the cortex, but their role in controlling pyramidal cell (PC) activity is largely unknown. Here, we show that the nicotinic acetylcholine receptor α2 subunit (Chrna2) specifically marks layer 5 (L5) Martinotti cells projecting to layer 1. Furthermore, we confirm that Chrna2-expressing Martinotti cells selectively target L5 thick-tufted type A PCs but not thin-tufted type B PCs. Using optogenetic activation and inhibition, we demonstrate how Chrna2-Martinotti cells robustly reset and synchronize type A PCs via slow rhythmic burst activity and rebound excitation. Moreover, using optical feedback inhibition, in which PC spikes controlled the firing of surrounding Chrna2-Martinotti cells, we found that neighboring PC spike trains became synchronized by Martinotti cell inhibition. Together, our results show that L5 Martinotti cells participate in defined cortical circuits and can synchronize PCs in a frequency-dependent manner. These findings suggest that Martinotti cells are pivotal for coordinated PC activity, which is involved in cortical information processing and cognitive control., Competing Interests: The authors have declared that no competing interests exist.

Background: Fibrin sealants are used in different types of surgery to prevent the accumulation of post-operative fluid (seroma) or blood (haematoma) or to arrest haemorrhage (bleeding). However, there is uncertainty around the benefits and harms of fibrin sealant use., Objectives: To systematically review the evidence on the benefits and harms of fibrin sealants in non-emergency surgery in adults., Data Sources: Electronic databases [MEDLINE, EMBASE and The Cochrane Library (including the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects, the Health Technology Assessment database and the Cochrane Central Register of Controlled Trials)] were searched from inception to May 2015. The websites of regulatory bodies (the Medicines and Healthcare products Regulatory Agency, the European Medicines Agency and the Food and Drug Administration) were also searched to identify evidence of harms., Review Methods: This review included randomised controlled trials (RCTs) and observational studies using any type of fibrin sealant compared with standard care in non-emergency surgery in adults. The primary outcome was risk of developing seroma and haematoma. Only RCTs were used to inform clinical effectiveness and both RCTs and observational studies were used for the assessment of harms related to the use of fibrin sealant. Two reviewers independently screened all titles and abstracts to identify potentially relevant studies. Data extraction was undertaken by one reviewer and validated by a second. The quality of included studies was assessed independently by two reviewers using the Cochrane Collaboration risk-of-bias tool for RCTs and the Centre for Reviews and Dissemination guidance for adverse events for observational studies. A fixed-effects model was used for meta-analysis., Results: We included 186 RCTs and eight observational studies across 14 surgical specialties and five reports from the regulatory bodies. Most RCTs were judged to be at an unclear risk of bias. Adverse events were inappropriately reported in observational studies. Meta-analysis across non-emergency surgical specialties did not show a statistically significant difference in the risk of seroma for fibrin sealants versus standard care in 32 RCTs analysed [ n  = 3472, odds ratio (OR) 0.84, 95% confidence interval (CI) 0.68 to 1.04; p  = 0.13; I 2  = 12.7%], but a statistically significant benefit was found on haematoma development in 24 RCTs ( n  = 2403, OR 0.62, 95% CI 0.44 to 0.86; p  = 0.01; I 2  = 0%). Adverse events related to fibrin sealant use were reported in 10 RCTs and eight observational studies across surgical specialties, and 22 RCTs explicitly stated that there were no adverse events. One RCT reported a single death but no other study reported mortality or any serious adverse events. Five regulatory body reports noted death from air emboli associated with fibrin sprays., Limitations: It was not possible to provide a detailed evaluation of individual RCTs in their specific contexts because of the limited resources that were available for this research. In addition, the number of RCTs that were identified made it impractical to conduct independent data extraction by two reviewers in the time available., Conclusions: The effectiveness of fibrin sealants does not appear to vary according to surgical procedures with regard to reducing the risk of seroma or haematoma. Surgeons should note the potential risk of gas embolism if spray application of fibrin sealants is used and not to exceed the recommended pressure and spraying distance. Future research should be carried out in surgery specialties for which only limited data were found, including neurological, gynaecological, oral and maxillofacial, urology, colorectal and orthopaedics surgery (for any outcome); breast surgery and upper gastrointestinal (development of haematoma); and cardiothoracic heart or lung surgery (reoperation rates). In addition, studies need to use adequate sample sizes, to blind participants and outcome assessors, and to follow reporting guidelines., Study Registration: This study is registered as PROSPERO CRD42015020710., Funding: The National Institute for Health Research Health Technology Assessment programme.

Background: Randomised controlled trials (RCTs) often fail to recruit sufficient participants, despite altruism being cited as their motivation. Previous investigations of factors influencing participation decisions have been methodologically limited. This study evaluated how women weigh up different motivations after initially expressing altruism, and explored their understanding of a trial and its alternatives. The trial was the 'Quality of Life after Mastectomy and Breast Reconstruction' (QUEST) trial., Methods: Thirty-nine women participated in qualitative interviews 1 month post-surgery. Twenty-seven women (10 trial decliners and 17 acceptors) who spontaneously mentioned 'altruism' were selected for thematic analysis. Verbatim transcripts were coded independently by two researchers. Participants' motivations to accept or decline randomisation were cross-referenced with their understanding of the QUEST trials and the process of randomisation., Results: The seven emerging themes were: (1) altruism expressed by acceptors and decliners; (2) overriding personal needs in decliners; (3) pure altruism in acceptors; (4) 'hypothetical altruism' amongst acceptors; (5) weak altruism amongst acceptors; (6) conditional altruism amongst acceptors; and (7) sense of duty to participate. Poor understanding of the trial rationale and its implications was also evident., Conclusions: Altruism was a motivating factor for participation in the QUEST randomised controlled trials where the main outcomes comprised quality of life and allocated treatments comprised established surgical procedures. Women's decisions were influenced by their understanding of the trial. Both acceptors and decliners of the trial expressed 'altruism', but most acceptors lacked an obvious treatment preference, hoped for personal benefits regarding a treatment allocation, or did not articulate complete understanding of the trial., Trial Registration: QUEST A, ISRCTN38846532 ; Date assigned 6 January 2010. QUEST B, ISRCTN92581226 ; Date assigned 6 January 2010.