Mercury Methylation in Oxic Sub-Polar Marine Regions Linked with Nitrification

Methylmercury (MeHg) is a neurotoxin that bioaccumulates to potentially harmful concentrations in Arctic marine wildlife and in those that consume them. Monitoring and modeling MeHg bioaccumulation and biogeochemical cycling in the ocean requires understanding of the mechanisms behind net mercury (Hg) methylation. The key functional gene for Hg methylation, hgcAB, is widely distributed throughout ocean basins and spans multiple microbial phyla. While multiple microbially-mediated anaerobic pathways for Hg methylation are known, in the ocean, the majority of hgcA homologs have been found in oxic subsurface waters, in contrast to other ecosystems. In particular, microaerophilic Nitrospina, a genera of nitrite-oxidizing bacteria containing a hgcA-like sequence, has been proposed as a potentially important Hg methylator in upper ocean waters. The objective of this work was therefore to examine the potential of nitrifiers as Hg methylators and quantify total Hg and MeHg across three Arctic Seas (the Gulf of Alaska, the Bering Sea and the Chukchi Sea) in regions where Nitrospina are likely present. In Spring 2021, samples for Hg analysis were obtained from all sites with a trace metal clean rosette. Hg methylation rates were quantified in concert with nitrification rates using on-board incubation experiments with Hg and 15NH4+ stable isotope additions. A significant correlation between Hg methylation and nitrification was observed across all sites, with the strongest correlation in the Chukchi Sea. Nitrospina-specific hgcA-like genes were detected at all sites. This study, linking Hg methylation and nitrification in oxic seawater, furthers understanding of MeHg cycling in these high latitude waters and the ocean in general. Furthermore, these studies inform predictions of how climate and human interactions could influence MeHg concentrations in the Arctic region in the future

An economic evaluation of salt reduction policies to reduce coronary heart disease in England: a policy modeling study

AbstractObjectivesDietary salt intake has been causally linked to high blood pressure and increased risk of cardiovascular events. Cardiovascular disease causes approximately 35% of total UK deaths, at an estimated annual cost of £30 billion. The World Health Organization and the National Institute for Health and Care Excellence have recommended a reduction in the intake of salt in people's diets. This study evaluated the cost-effectiveness of four population health policies to reduce dietary salt intake on an English population to prevent coronary heart disease (CHD).MethodsThe validated IMPACT CHD model was used to quantify and compare four policies: 1) Change4Life health promotion campaign, 2) front-of-pack traffic light labeling to display salt content, 3) Food Standards Agency working with the food industry to reduce salt (voluntary), and 4) mandatory reformulation to reduce salt in processed foods. The effectiveness of these policies in reducing salt intake, and hence blood pressure, was determined by systematic literature review. The model calculated the reduction in mortality associated with each policy, quantified as life-years gained over 10 years. Policy costs were calculated using evidence from published sources. Health care costs for specific CHD patient groups were estimated. Costs were compared against a “do nothing” baseline.ResultsAll policies resulted in a life-year gain over the baseline. Change4life and labeling each gained approximately 1960 life-years, voluntary reformulation 14,560 life-years, and mandatory reformulation 19,320 life-years. Each policy appeared cost saving, with mandatory reformulation offering the largest cost saving, more than £660 million.ConclusionsAll policies to reduce dietary salt intake could gain life-years and reduce health care expenditure on coronary heart disease

Are life-extending treatments for terminal illnesses a special case? Exploring choices and societal viewpoints

Criteria used by the National Institute for Health and Care Excellence (NICE) to assess life-extending, end-of-life (EoL) treatments imply that health gains from such treatments are valued more than other health gains. Despite claims that the policy is supported by societal values, evidence from preference elicitation studies is mixed and in-depth research has shown there are different societal viewpoints. Few studies elicit preferences for policies directly or combine different approaches to understand preferences.Survey questions were designed to investigate support for NICE EoL guidance at national and regional levels. These ‘Decision Rule’ and ‘Treatment Choice’ questions were administered to an online sample of 1496 UK respondents in May 2014. The same respondents answered questions designed to elicit their agreement with three viewpoints (previously identified and described) in relation to provision of EoL treatments for terminally ill patients. We report the findings of these choice questions and examine how they relate to each other and respondents' viewpoints.The Decision Rule questions described three policies: DA – a standard ‘value for money’ test, applied to all health technologies; DB – giving special consideration to all treatments for terminal illnesses; and DC – giving special consideration to specific categories of treatments for terminal illnesses e.g. life extension (as in NICE EoL guidance) or those that improve quality-of-life (QoL). Three Treatment Choices were presented: TA – improving QoL for patients with a non-terminal illness; TB – extending life for EoL patients; and TC – improving QoL at the EoL.DC received most support (45%) with most respondents giving special consideration to EoL only when treatments improved QoL. The most commonly preferred treatment choices were TA (51%) and TC (43%). Overall, this study challenges claims about public support for NICE's EoL guidance and the focus on life extension at EoL and substantiates existing evidence of plurality in societal values

Assessment of the relative performance of the EQ-5D-3L, ICIQ UI SF and POP-SS using data from the OPAL trial

Conducting economic evaluations alongside randomised controlled trials (RCTs) is an efficient way to collect cost-effectiveness data. Generic preference-based measures, such as EQ-5D, are often used alongside clinical data measures in RCTs. However, in the case of female urinary incontinence (UI), evidence of the relative performance of EQ-5D with condition-specific measures such as the International Consultation on Incontinence Questionnaire Urinary Incontinence Short Form (ICIQ-UI SF), measuring severity of UI, and Pelvic Organ Prolapse Symptom Score (POP-SS), measuring severity of prolapse symptoms, is limited. This study employed secondary analysis of outcome measures data collected during the Optimal Pelvic floor muscle training for Adherence Long-term (OPAL) RCT, which compared biofeedback-mediated pelvic floor muscle training to basic pelvic floor muscle training for women with UI. The relative performance of EQ-5D-3L and ICIQ-UI SF, and EQ-5D-3L and POP-SS was assessed for concurrent validity and known-groups validity. Data for 577 women (mean age 48) were available for EQ-5D-3L/ICIQ-UI SF, and 555 women (mean age 47) for EQ-5D-3L/POP-SS. Overall, EQ-5D-3L exhibited very weak association with the ICIQ-UI SF total score, or any subscale. EQ-5D-3L and POP-SS were found to be weakly correlated. EQ-5D-3L was able to distinguish between groups with known differences in severity of UI and also between types of UI. These findings provide useful information to guide researchers in selecting appropriate outcome measures for use in future clinical trials

Extending life for people with a terminal illness: a moral right and an expensive death? Exploring societal perspectives

BACKGROUND: Many publicly-funded health systems apply cost-benefit frameworks in response to the moral dilemma of how best to allocate scarce healthcare resources. However, implementation of recommendations based on costs and benefit calculations and subsequent challenges have led to ‘special cases’ with certain types of health benefits considered more valuable than others. Recent debate and research has focused on the relative value of life extensions for people with terminal illnesses. This research investigates societal perspectives in relation to this issue, in the UK. METHODS: Q methodology was used to elicit societal perspectives from a purposively selected sample of data-rich respondents. Participants ranked 49 statements of opinion (developed for this study), onto a grid, according to level of agreement. These ‘Q sorts’ were followed by brief interviews. Factor analysis was used to identify shared points of view (patterns of similarity between individuals’ Q sorts). RESULTS: Analysis produced a three factor solution. These rich, shared accounts can be broadly summarised as: i) ‘A population perspective – value for money, no special cases’, ii) ‘Life is precious – valuing life-extension and patient choice’, iii) ‘Valuing wider benefits and opportunity cost - the quality of life and death’. From the factor descriptions it is clear that the main philosophical positions that have long dominated debates on the just allocation of resources have a basis in public opinion. CONCLUSIONS: The existence of certain moral positions in the views of society does not ethically imply, and pragmatically cannot mean, that all are translated into policy. Our findings highlight normative tensions and the importance of critically engaging with these normative issues (in addition to the current focus on a procedural justice approach to health policy). Future research should focus on i) the extent to which these perspectives are supported in society, ii) how respondents' perspectives relate to specific resource allocation questions, and iii) the characteristics of respondents associated with each perspective

Deletion of the trpc4 gene and its role in simple and complex strategic learning

The TRPC4 ion channel is expressed extensively in corticolimbic and a subpopulation of midbrain dopamine neurons. While TRPC4 knockout (KO) rats exhibit reduced sociability and social exploration, little is known about the role of TRPC4 in motivation and learning. To identify a function for TRPC4 channels in learning processes  we tested TRPC4 KO and normal wild type (WT) rats. TRPC4 KO and WT rats exhibited no differences in Y-­maze learning or simple discrimination learning. Furthermore, on a more complex serial reversal shift task designed  to assess strategic learning where the reward and non-­reward cues were repeatedly reversed between training sessions both TRPC4 KO and WT rats   performed equally well. Finally, we found no   performance differences when using a conditional reversal shift task where a tone signals the reversal of reward and non-reward cues within sessions. These data suggest that although TRPC4 channels may play a role in social interaction/anxiety  they exert a minimal role in simple and complex strategic learning

The economic contribution of third sector initiatives for older people: a systematic review and development of a framework for evaluation

An ageing population has placed strains on health and social care systems. Innovative solutions have been sought to inject capacity and capability in order to deliver services to older people more efficiently and effectively. Over the last two decades, governments have actively encouraged third sector organisations to deliver public services on the assumption that they exhibit higher levels of innovation, efficiency and responsiveness. The evidence base, particularly for whether they provide better value for money, remains poor. We present the results of a systematic literature review on the costs and outcomes of services for older people delivered by third sector organisations. We combine this evidence with a framework for analysing the benefits and costs of third sector-led initiatives, and test this out empirically with a group of initiatives delivered for older people in an urban context. We find that our method may hold considerable promise for the evaluation of third sector initiatives

Effectiveness and safety of dolutegravir and raltegravir for treating children and adolescents living with HIV: a systematic review

INTRODUCTION: Globally about 1.7 million children were living with HIV in 2020. Two integrase strand transfer inhibitors, dolutegravir and raltegravir, are increasingly used in children. We conducted a systematic review to assess the effectiveness and safety of dolutegravir and raltegravir in children and adolescents living with HIV, aged 0–19 years. METHODS: Sources included MEDLINE, Embase, the Cochrane Library, clinical trial registries, abstracts from key conferences and reference list searching. Observational studies and clinical trials published January 2009–March 2021 were eligible. Outcomes included efficacy/effectiveness (CD4 counts and viral load) and/or safety outcomes (mortality, grade 3/4 adverse events and treatment discontinuation) through 6 months or more post-treatment initiation. Risk of bias was assessed using previously published tools appropriate for the study design. Narrative syntheses were conducted. RESULTS AND DISCUSSION: In total, 3626 abstracts and 371 papers were screened. Eleven studies, including 2330 children/adolescents, reported data on dolutegravir: one randomized controlled trial (RCT; low risk of bias), one single-arm trial (unclear risk of bias) and nine cohort studies (three low risk of bias, two unclear risk and four high risk). Ten studies, including 649 children/adolescents receiving raltegravir, were identified: one RCT (low risk of bias), one single-arm trial (low risk of bias) and eight cohort studies (four low risk of bias, three unclear risk and one high risk). Viral suppression levels in children/adolescents at 12 months were high (>70%) in most studies assessing dolutegravir (mostly second- or subsequent-line, or mixed treatment lines), and varied from 42% (5/12) to 83% (44/53) at 12 months in studies assessing raltegravir (mostly second- or subsequent-line). Across all studies assessing dolutegravir or raltegravir, grade 3/4 adverse events (clinical and/or laboratory) were reported in 0–50% of subjects, few resulted in discontinuation, few were drug related and no deaths were attributed to either drug. CONCLUSIONS: These reassuring findings suggest that dolutegravir and raltegravir are effective and safe as preferred regimens in children and adolescents living with HIV. With the rollout of dolutegravir in paediatric populations already underway, it is critical that data are collected on safety and effectiveness in infants, children and adolescents, including on longer-term outcomes, such as weight and metabolic changes