Safety and Efficacy of NVX-CoV2373 Covid-19 Vaccine.

BACKGROUND: Early clinical data from studies of the NVX-CoV2373 vaccine (Novavax), a recombinant nanoparticle vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that contains the full-length spike glycoprotein of the prototype strain plus Matrix-M adjuvant, showed that the vaccine was safe and associated with a robust immune response in healthy adult participants. Additional data were needed regarding the efficacy, immunogenicity, and safety of this vaccine in a larger population. METHODS: In this phase 3, randomized, observer-blinded, placebo-controlled trial conducted at 33 sites in the United Kingdom, we assigned adults between the ages of 18 and 84 years in a 1:1 ratio to receive two intramuscular 5-µg doses of NVX-CoV2373 or placebo administered 21 days apart. The primary efficacy end point was virologically confirmed mild, moderate, or severe SARS-CoV-2 infection with an onset at least 7 days after the second injection in participants who were serologically negative at baseline. RESULTS: A total of 15,187 participants underwent randomization, and 14,039 were included in the per-protocol efficacy population. Of the participants, 27.9% were 65 years of age or older, and 44.6% had coexisting illnesses. Infections were reported in 10 participants in the vaccine group and in 96 in the placebo group, with a symptom onset of at least 7 days after the second injection, for a vaccine efficacy of 89.7% (95% confidence interval [CI], 80.2 to 94.6). No hospitalizations or deaths were reported among the 10 cases in the vaccine group. Five cases of severe infection were reported, all of which were in the placebo group. A post hoc analysis showed an efficacy of 86.3% (95% CI, 71.3 to 93.5) against the B.1.1.7 (or alpha) variant and 96.4% (95% CI, 73.8 to 99.5) against non-B.1.1.7 variants. Reactogenicity was generally mild and transient. The incidence of serious adverse events was low and similar in the two groups. CONCLUSIONS: A two-dose regimen of the NVX-CoV2373 vaccine administered to adult participants conferred 89.7% protection against SARS-CoV-2 infection and showed high efficacy against the B.1.1.7 variant. (Funded by Novavax; EudraCT number, 2020-004123-16.).

The predictive role of symptoms in COVID-19 diagnostic models: A longitudinal insight.

To investigate the symptoms of SARS-CoV-2 infection, their dynamics and their discriminatory power for the disease using longitudinally, prospectively collected information reported at the time of their occurrence. We have analysed data from a large phase 3 clinical UK COVID-19 vaccine trial. The alpha variant was the predominant strain. Participants were assessed for SARS-CoV-2 infection via nasal/throat PCR at recruitment, vaccination appointments, and when symptomatic. Statistical techniques were implemented to infer estimates representative of the UK population, accounting for multiple symptomatic episodes associated with one individual. An optimal diagnostic model for SARS-CoV-2 infection was derived. The 4-month prevalence of SARS-CoV-2 was 2.1%; increasing to 19.4% (16.0%-22.7%) in participants reporting loss of appetite and 31.9% (27.1%-36.8%) in those with anosmia/ageusia. The model identified anosmia and/or ageusia, fever, congestion, and cough to be significantly associated with SARS-CoV-2 infection. Symptoms' dynamics were vastly different in the two groups; after a slow start peaking later and lasting longer in PCR+ participants, whilst exhibiting a consistent decline in PCR- participants, with, on average, fewer than 3 days of symptoms reported. Anosmia/ageusia peaked late in confirmed SARS-CoV-2 infection (day 12), indicating a low discrimination power for early disease diagnosis.

Safety and Efficacy of the NVX-CoV2373 Coronavirus Disease 2019 Vaccine at Completion of the Placebo-Controlled Phase of a Randomized Controlled Trial.

BACKGROUND: The recombinant protein-based vaccine, NVX-CoV2373, demonstrated 89.7% efficacy against coronavirus disease 2019 (COVID-19) in a phase 3, randomized, observer-blinded, placebo-controlled trial in the United Kingdom. The protocol was amended to include a blinded crossover. Data to the end of the placebo-controlled phase are reported. METHODS: Adults aged 18-84 years received 2 doses of NVX-CoV2373 or placebo (1:1) and were monitored for virologically confirmed mild, moderate, or severe COVID-19 (onset from 7 days after second vaccination). Participants who developed immunoglobulin G (IgG) against nucleocapsid protein but did not show symptomatic COVID-19 were considered asymptomatic. Secondary outcomes included anti-spike (S) IgG responses, wild-type virus neutralization, and T-cell responses. RESULTS: Of 15 185 participants, 13 989 remained in the per-protocol efficacy population (6989 NVX-CoV2373, 7000 placebo). At a maximum of 7.5 months (median, 4.5) postvaccination, there were 24 cases of COVID-19 among NVX-CoV2373 recipients and 134 cases among placebo recipients, a vaccine efficacy of 82.7% (95% confidence interval [CI], 73.3%-88.8%). Vaccine efficacy was 100% (95% CI, 17.9%-100.0%) against severe disease and 76.3% (95% CI, 57.4%-86.8%) against asymptomatic disease. High anti-S and neutralization responses to vaccination were evident, together with S-protein-specific induction of interferon-γ secretion in peripheral blood T cells. Incidence of serious adverse events and adverse events of special interest were similar between groups. CONCLUSIONS: A 2-dose regimen of NVX-CoV2373 conferred a high level of ongoing protection against asymptomatic, symptomatic, and severe COVID-19 through >6 months postvaccination. A gradual decrease of protection suggests that a booster may be indicated. CLINICAL TRIALS REGISTRATION: EudraCT, 2020-004123-16.

COVID-19 infection in people living with HIV.

BACKGROUND: Coronavirus disease 2019 (COVID-19) and human immunodeficiency virus (HIV) are intersecting pandemics, with implications for care at an individual and global scale. SOURCES OF DATA: PubMed search with relevant articles and their references reviewed. AREAS OF AGREEMENT: COVID-19 has changed the delivery of care to people living with HIV (PLWH). Vaccines are efficacious and safe for PLWH; patient care for symptomatic COVID-19 is similar to that of people without HIV. AREAS OF CONTROVERSY: It remains unclear whether PLWH experience increased COVID-19-specific mortality. Treatments to reduce severity in early COVID-19 infection lack evidence in PLWH. GROWING POINTS: The effects of the COVID-19 pandemic on HIV-related morbidity and mortality are yet to be seen. COVID-19 epidemiology among PLWH is complicated by changes to the severe acute respiratory syndrome coronavirus 2, population behaviours and vaccine availability. AREAS TIMELY FOR DEVELOPING RESEARCH: Global trends in HIV-related morbidity and mortality should be monitored to appreciate the effects of the COVID-19 pandemic. The benefits of early antiviral and/or neutralizing monoclonal antibody (nMAb) treatment for PLWH and nMAb prophylaxis require investigation.

Separating N2O production and consumption in intact agricultural soil cores at different moisture contents and depths.

Agricultural soils are a major source of the potent greenhouse gas and ozone depleting substance, N2O. To implement management practices that minimize microbial N2O production and maximize its consumption (i.e., complete denitrification), we must understand the interplay between simultaneously occurring biological and physical processes, especially how this changes with soil depth. Meaningfully disentangling of these processes is challenging and typical N2O flux measurement techniques provide little insight into subsurface mechanisms. In addition, denitrification studies are often conducted on sieved soil in altered O2 environments which relate poorly to in situ field conditions. Here, we developed a novel incubation system with headspaces both above and below the soil cores and field-relevant O2 concentrations to better represent in situ conditions. We incubated intact sandy clay loam textured agricultural topsoil (0-10 cm) and subsoil (50-60 cm) cores for 3-4 days at 50% and 70% water-filled pore space, respectively. 15N-N2O pool dilution and an SF6 tracer were injected below the cores to determine the relative diffusivity and the net N2O emission and gross N2O emission and consumption fluxes. The relationship between calculated fluxes from the below and above soil core headspaces confirmed that the system performed well. Relative diffusivity did not vary with depth, likely due to the preservation of preferential flow pathways in the intact cores. Gross N2O emission and uptake also did not differ with depth but were higher in the drier cores, contrary to expectation. We speculate this was due to aerobic denitrification being the primary N2O consuming process and simultaneously occurring denitrification and nitrification both producing N2O in the drier cores. We provide further evidence of substantial N2O consumption in drier soil but without net negative N2O emissions. The results from this study are important for the future application of the 15N-N2O pool dilution method and N budgeting and modelling, as required for improving management to minimize N2O losses.

COVID-19 mortality among people with diagnosed HIV compared to those without during the first wave of the COVID-19 pandemic in England.

OBJECTIVES: We describe COVID-19 mortality among people with and without HIV during the first wave of the pandemic in England. METHODS: National surveillance data on adults (aged ≥ 15 years) with diagnosed HIV resident in England were linked to national COVID-19 mortality surveillance data (2 March 2020-16 June 2020); HIV clinicians verified linked cases and provided information on the circumstances of death. We present COVID-19 mortality rates by HIV status, using negative binomial regression to assess the association between HIV and mortality, adjusting for gender, age and ethnicity. RESULTS: Overall, 99 people with HIV, including 61 of black ethnicity, died of/with COVID-19 (107/100 000) compared with 49 483 people without HIV (109/100 000). Compared to people without HIV, higher COVID-19 mortality rates were observed in people with HIV of black (188 vs. 122/100 000) and Asian (131 vs. 77.0/100 000) ethnicity, and in both younger (15-59 years: 58.3 vs. 10.2/100 000) and older (≥ 60 years: 434 vs. 355/100 000) people. After adjustment for demographic factors, people with HIV had a higher COVID-19 mortality risk than those without (2.18; 95% CI: 1.76-2.70). Most people with HIV who died of/with COVID-19 had suppressed HIV viraemia (91%) and at least one comorbidity reported to be associated with poor COVID-19 outcomes (87%). CONCLUSIONS: In the first wave of the pandemic in England, COVID-19 mortality among people with HIV was low, but was higher than in those without HIV, after controlling for demographic factors. This supports the strategy of prioritizing COVID-19 vaccination for people with HIV and strongly encouraging its uptake, especially in those of black and Asian ethnicity.

Responsible agriculture must adapt to the wetland character of mid-latitude peatlands.

Drained, lowland agricultural peatlands are greenhouse gas (GHG) emission hotspots and a large but vulnerable store of irrecoverable carbon. They exhibit soil loss rates of ~2.0 cm yr-1 and are estimated to account for 32% of global cropland emissions while producing only 1.1% of crop kilocalories. Carbon dioxide emissions account for >80% of their terrestrial GHG emissions and are largely controlled by water table depth. Reducing drainage depths is, therefore, essential for responsible peatland management. Peatland restoration can substantially reduce emissions. However, this may conflict with societal needs to maintain productive use, to protect food security and livelihoods. Wetland agriculture strategies will, therefore, be required to adapt agriculture to the wetland character of peatlands, and balance GHG mitigation against productivity, where halting emissions is not immediately possible. Paludiculture may substantially reduce GHG emissions but will not always be viable in the current economic landscape. Reduced drainage intensity systems may deliver partial reductions in the rate of emissions, with smaller modifications to existing systems. These compromise systems may face fewer hurdles to adoption and minimize environmental harm until societal conditions favour strategies that can halt emissions. Wetland agriculture will face agronomic, socio-economic and water management challenges, and careful implementation will be required. Diversity of values and priorities among stakeholders creates the potential for conflict. Successful implementation will require participatory research approaches and co-creation of workable solutions. Policymakers, private sector funders and researchers have key roles to play but adoption risks would fall predominantly on land managers. Development of a robust wetland agriculture paradigm is essential to deliver resilient production systems and wider environmental benefits. The challenge of responsible use presents an opportunity to rethink peatland management and create thriving, innovative and green wetland landscapes for everyone's future benefit, while making a vital contribution to global climate change mitigation.

Changes in microbial community composition drive the response of ecosystem multifunctionality to elevated ozone.

Increasing tropospheric ozone poses a potential threat to both above- and belowground components of the terrestrial biosphere. Microorganisms are the main drivers of soil ecological processes, however, the link between soil microbial communities and ecological functions under elevated ozone remains poorly understood. In this study, we assessed the responses of three crop seedlings (i.e., soybean, maize, and wheat) growth and soil microbial communities to elevated ozone (40 ppb O3 above ambient air) in a pot experiment in the solardomes. Results showed that elevated ozone adversely affected ecosystem multifunctionality by reducing crop biomass, inhibiting soil extracellular enzyme activities, and altering nutrient availability. Elevated ozone increased bacterial and fungal co-occurrence network complexity, negatively correlated with ecosystem multifunctionality. Changes in the relative abundance of some specific bacteria and fungi were associated with multiple ecosystem functioning. In addition, elevated ozone significantly affected fungal community composition but not bacterial community composition and microbial alpha-diversity. Crop type played a key role in determining bacterial alpha-diversity and microbial community composition. In conclusion, our findings suggest that short-term elevated ozone could lead to a decrease in ecosystem multifunctionality associated with changes in the complexity of microbial networks in soils.

Development of a LoRaWAN IoT Node with Ion-Selective Electrode Soil Nitrate Sensors for Precision Agriculture.

Crop productivity is highly dependent on the availability of soluble nitrogen (N), e.g. nitrate, in soil. When N levels are low, fertilisers are applied to replenish the soil's reserves. Typically the timing of these applications is based on paper-based guidance and sensor-based measurements of canopy greenness, which provides an indirect measure of soil N status. However this approach often means that N fertiliser is applied inappropriately or too late, resulting in excess N being lost to the environment, or too little N to meet crop demand. To promote greater N use efficiency and improve agricultural sustainability, we developed an Internet of Things (IoT) approach for the real-time measurement of soil nitrate levels using ion-selective membrane sensors in combination with digital soil moisture probes. The node incorporates state-of-the-art IoT connectivity using a LoRaWAN transceiver. The sensing platform can transfer real-time data via a cloud-connected gateway for processing and storage. In summary, we present a validated soil sensor system for real-time monitoring of soil nitrate concentrations, which can support fertiliser management decisions, improve N use efficiency and reduce N losses to the environment.

Comparison of nitrogen losses from different manure treatment and application management systems in China.

There is a worldwide focus on reducing the environmental impacts of livestock manure management. In China, there are different manure treatment and application modes, including complete treatment to remove nitrogen (N) for direct discharge into watercourses. But we lack a systematic quantitative comparison of the environmental losses that occur from different management modes. We used an example farm of 10,000 finisher pigs to quantitatively analyze the annual N losses from land application (LA) and treatment to remove N from manure to the level of discharge consent (DS) under 24 sub-modes. This is an important study to unravel the effect of choice of different manure management systems on subsequent N losses. The results showed that the N losses from the LA mode (52.6% of total N excretion) were significantly lower than that from the DS mode (75.9%). Compared with other sub-modes, N emission from whole slurry injection was the smallest, accounting for 43.2% of total N excretion. NH3-N was the main source of N loss which accounted for 72.9% and 50.2% in LA and DS mode, respectively. The lowest N emission of LA mode with mitigation options, including slurry store covers, composting with bio-filter deodorization and injection application, was 28.8% of total N excretion, which is only 42.2% of N emission from DS mode with mitigation options. Insights from this systematic study of different manure management modes in China show the imperative of control ammonia emission for China, and provide guidance to the sustainable manure management in rapidly developing countries.

Spatial co-localisation of extreme weather events: a clear and present danger.

Extreme weather events have become a dominant feature of the narrative surrounding changes in global climate with large impacts on ecosystem stability, functioning and resilience; however, understanding of their risk of co-occurrence at the regional scale is lacking. Based on the UK Met Office's long-term temperature and rainfall records, we present the first evidence demonstrating significant increases in the magnitude, direction of change and spatial co-localisation of extreme weather events since 1961. Combining this new understanding with land-use data sets allowed us to assess the likely consequences on future agricultural production and conservation priority areas. All land-uses are impacted by the increasing risk of at least one extreme event and conservation areas were identified as the hotspots of risk for the co-occurrence of multiple event types. Our findings provide a basis to regionally guide land-use optimisation, land management practices and regulatory actions preserving ecosystem services against multiple climate threats.

Meta-analysis of global livestock urine-derived nitrous oxide emissions from agricultural soils.

Nitrous oxide (N2 O) is an air pollutant of major environmental concern, with agriculture representing 60% of anthropogenic global N2 O emissions. Much of the N2 O emissions from livestock production systems result from transformation of N deposited to soil within animal excreta. There exists a substantial body of literature on urine patch N2 O dynamics, we aimed to identify key controlling factors influencing N2 O emissions and to aid understanding of knowledge gaps to improve GHG reporting and prioritize future research. We conducted an extensive literature review and random effect meta-analysis (using REML) of results to identify key relationships between multiple potential independent factors and global N2 O emissions factors (EFs) from urine patches. Mean air temperature, soil pH and ruminant animal species (sheep or cow) were significant factors influencing the EFs reviewed. However, several factors that are known to influence N2 O emissions, such as animal diet and urine composition, could not be considered due to the lack of reported data. The review highlighted a widespread tendency for inadequate metadata and uncertainty reporting in the published studies, as well as the limited geographical extent of investigations, which are more often conducted in temperate regions thus far. Therefore, here we give recommendations for factors that are likely to affect the EFs and should be included in all future studies, these include the following: soil pH and texture; experimental set-up; direct measurement of soil moisture and temperature during the study period; amount and composition of urine applied; animal type and diet; N2 O emissions with a measure of uncertainty; data from a control with zero-N application and meteorological data.

Adherence to guidelines across different specialties to prevent infections in patients undergoing immunosuppressive therapies.

BACKGROUND: Substantial numbers of patients are now receiving either immunosuppressive therapies or chemotherapy. There are significant risks in such patients of developing opportunistic infections or re-activation of latent infections, with higher associated morbidity and mortality. The aim of this quality improvement project was to determine how effective 5 different specialties were in assessing and mitigating risks of developing opportunistic infections or re-activation of latent infections in patients undergoing immunosuppressive therapies. METHODS: This was a single centre audit where records of patients attending clinics providing immunosuppressive therapies were reviewed for the following: evidence of screening for blood-borne virus [BBV] infections, varicella and measles immunity, latent/active TB or hypogammaglobulinaemia, and whether appropriate vaccines had been advised or various infection risks discussed. These assessments were audited against both national and international guidelines, or a cross-specialty consensus guideline where specific recommendations were lacking. Two sub-populations were also analysed separately: patients receiving more potent immunosuppression and black and minority ethnic [BME] patients,. RESULTS: For the 204 patients fulfilling the inclusion criteria, BBV, varicella/measles and latent TB screening was inconsistent, as was advice for vaccinations, with few areas complying with specialty or consensus guidelines. Less than 10% of patients in one specialty were tested for HIV. In BME patients screening for HIV [60%], measles [0%] and varicella [40%] immunity and latent [30%] or active [20%] TB was low. Only 38% of patients receiving potent immunosuppression received Pneumocystis prophylaxis, with 3 of 4 specialties providing less than 15% of patients in this category with prophylaxis. CONCLUSIONS: Compliance with guidelines to mitigate risks of infection from immunosuppressive therapies was either inconsistent or poor for most specialties. New approaches to highlight such risks and assist appropriate pre-immunosuppression screening are needed.

Pyogenic brain abscess and subdural empyema: presentation, management, and factors predicting outcome.

PURPOSE: To describe the presentation and management of bacterial brain abscess and subdural empyema in adults treated at two tertiary centers. In addition, to identify factors that may predict a poor clinical outcome. METHODS: A retrospective analysis of data obtained from clinical records was performed, followed by multivariate regression analysis of patient and treatment-related factors. RESULTS: 113 patients were included with a median age of 53 years and a male preponderance. At presentation symptoms were variable, 28% had a focal neurological deficit, and 39% had a reduced Glasgow coma scale (GCS). Brain abscesses most frequently affected the frontal, temporal, and parietal lobes while 36% had a subdural empyema. An underlying cause was identified in 76%; a contiguous ear or sinus infection (43%), recent surgery or trauma (18%) and haematogenous spread (15%). A microbiological diagnosis was confirmed in 86%, with streptococci, staphylococci, and anaerobes most frequently isolated. Treatment involved complex, prolonged antibiotic therapy (> 6 weeks in 84%) combined with neurosurgical drainage (91%) and source control surgery (34%). Mortality was 5% with 31% suffering long-term disability and 64% achieving a good clinical outcome. A reduced GCS, focal neurological deficit, and seizures at presentation were independently associated with an unfavorable clinical outcome (death or disability). CONCLUSIONS: Complex surgical and antimicrobial treatment achieves a good outcome in the majority of patients with bacterial brain abscess and subdural empyema. Factors present at diagnosis can help to predict those likely to suffer adverse outcomes. Research to determine optimal surgical and antibiotic management would be valuable.

Reduction of Methane Emission during Slurry Storage by the Addition of Effective Microorganisms and Excessive Carbon Source from Brewing Sugar.

Storing livestock manure is the primary stage of manure management where microbial processes and chemical reactions result in the release of methane (CH), nitrous oxide (NO), ammonia (NH), and carbon dioxide (CO). This study examined the reduction of CH emissions from slurry storage under two temperatures (cool [10°C] and warm [30°C]) when a glucose-rich substrate (brewing sugar) and activated effective microorganisms were applied at 10% (w/w) and 5% (v/w), respectively. Brewing sugar addition influenced microbial anaerobic respiration, resulting in a reduction of slurry pH to <5.0, through "self-acidification" caused by lactic acid production. Subsequently, CH emissions were significantly reduced by 87 and 99% in the cool and warm environments, respectively. The effective microorganism treatment did not change the chemical characteristics of the slurry but reduced CH emissions by 17 and 27% ( < 0.05) in the cool and warm environments, respectively. These results suggest that self-acidification after addition of a carbon source may be a promising alternative to slurry acidification using concentrated acids.

Seasonal persistence of faecal indicator organisms in soil following dairy slurry application to land by surface broadcasting and shallow injection.

Dairy farming generates large volumes of liquid manure (slurry), which is ultimately recycled to agricultural land as a valuable source of plant nutrients. Different methods of slurry application to land exist; some spread the slurry to the sward surface whereas others deliver the slurry under the sward and into the soil, thus helping to reduce greenhouse gas (GHG) emissions from agriculture. The aim of this study was to investigate the impact of two slurry application methods (surface broadcast versus shallow injection) on the survival of faecal indicator organisms (FIOs) delivered via dairy slurry to replicated grassland plots across contrasting seasons. A significant increase in FIO persistence (measured by the half-life of E. coli and intestinal enterococci) was observed when slurry was applied to grassland via shallow injection, and FIO decay rates were significantly higher for FIOs applied to grassland in spring relative to summer and autumn. Significant differences in the behaviour of E. coli and intestinal enterococci over time were also observed, with E. coli half-lives influenced more strongly by season of application relative to the intestinal enterococci population. While shallow injection of slurry can reduce agricultural GHG emissions to air it can also prolong the persistence of FIOs in soil, potentially increasing the risk of their subsequent transfer to water. Awareness of (and evidence for) the potential for 'pollution-swapping' is critical in order to guard against unintended environmental impacts of agricultural management decisions.

Effect of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal carriage: an observer-blind, phase 3 randomised clinical trial.

BACKGROUND: Meningococcal conjugate vaccines protect individuals directly, but can also confer herd protection by interrupting carriage transmission. We assessed the effects of meningococcal quadrivalent glycoconjugate (MenACWY-CRM) or serogroup B (4CMenB) vaccination on meningococcal carriage rates in 18-24-year-olds. METHODS: In this phase 3, observer-blind, randomised controlled trial, university students aged 18-24 years from ten sites in England were randomly assigned (1:1:1, block size of three) to receive two doses 1 month apart of Japanese Encephalitis vaccine (controls), 4CMenB, or one dose of MenACWY-CRM then placebo. Participants were randomised with a validated computer-generated random allocation list. Participants and outcome-assessors were masked to the treatment group. Meningococci were isolated from oropharyngeal swabs collected before vaccination and at five scheduled intervals over 1 year. Primary outcomes were cross-sectional carriage 1 month after each vaccine course. Secondary outcomes included comparisons of carriage at any timepoint after primary analysis until study termination. Reactogenicity and adverse events were monitored throughout the study. Analysis was done on the modified intention-to-treat population, which included all enrolled participants who received a study vaccination and provided at least one assessable swab after baseline. This trial is registered with ClinicalTrials.gov, registration number NCT01214850. FINDINGS: Between Sept 21 and Dec 21, 2010, 2954 participants were randomly assigned (987 assigned to control [984 analysed], 979 assigned to 4CMenB [974 analysed], 988 assigned to MenACWY-CRM [983 analysed]); 33% of the 4CMenB group, 34% of the MenACWY-CRM group, and 31% of the control group were positive for meningococcal carriage at study entry. By 1 month, there was no significant difference in carriage between controls and 4CMenB (odds ratio 1·2, 95% CI 0·8-1·7) or MenACWY-CRM (0·9, [0·6-1·3]) groups. From 3 months after dose two, 4CMenB vaccination resulted in significantly lower carriage of any meningococcal strain (18·2% [95% CI 3·4-30·8] carriage reduction), capsular groups BCWY (26·6% [10·5-39·9] carriage reduction), capsular groups CWY (29·6% [8·1-46·0] carriage reduction), and serogroups CWY (28·5% [2·8-47·5] carriage reduction) compared with control vaccination. Significantly lower carriage rates were also noted in the MenACWY-CRM group compared with controls: 39·0% (95% CI 17·3-55·0) carriage reduction for serogroup Y and 36·2% (15·6-51·7) carriage reduction for serogroup CWY. Study vaccines were generally well tolerated, with increased rates of transient local injection pain and myalgia in the 4CMenB group. No safety concerns were identified. INTERPRETATION: Although we detected no significant difference between groups at 1 month after vaccine course, MenACWY-CRM and 4CMenB vaccines reduced meningococcal carriage rates during 12 months after vaccination and therefore might affect transmission when widely implemented. FUNDING: Novartis Vaccines.

Tenofovir is associated with increased tubular proteinuria and asymptomatic renal tubular dysfunction in Ghana.

BACKGROUND: HIV infection is associated with increased risk of renal dysfunction, including tubular dysfunction (TD) related to antiretroviral therapy (ART). Tenofovir disoproxil fumarate (TDF) is becoming available for ART in sub-Saharan Africa, although data on its long-term safety there is limited. We aimed to study the prevalence of HIV-associated renal dysfunction in Ghana and explore associations between proteinuria or TD and potential risk factors, including TDF use. METHODS: A single-centre cross-sectional observational study of patients taking ART was undertaken. Creatinine clearance (CrCl) was calculated and proteinuria detected with dipsticks. Spot urinary albumin and protein:creatinine ratios (uACR/uPCR) were measured and further evidence of TD (defined as having two or more characteristic features) sought. Logistic regression analysis identified factors associated with proteinuria or TD. RESULTS: In 330 patients, of whom 101 were taking TDF (median 20 months), the prevalence of CrCl < 60 ml/min/1.73 m(2), dipstick proteinuria and TD was 7 %, 37 % and 15 %. Factors associated with proteinuria were baseline CD4-count [aOR 0.86/100 cell increment (95 % CI, 0.74-0.99)] and TDF use [aOR 2.74 (95 % CI, 1.38-5.43)]. The only factor associated with TD was TDF use [aOR 3.43 (95 % CI, 1.10-10.69)]. In a subset with uPCR measurements, uPCRs were significantly higher in patients taking TDF than those on other drugs (10.8 vs. 5.7 mg/mmol, p < 0.001), and urinary albuin:protein ratios significantly lower (0.24 vs. 0.58, p < 0.001). CONCLUSIONS: Both proteinuria and TD are common and associated with TDF use in Ghana. Further longitudinal studies to determine whether proteinuria, TD or TDF use are linked to progressive decline in renal function or other adverse outcomes are needed in Africa.

Can macrophyte harvesting from eutrophic water close the loop on nutrient loss from agricultural land?

Eutrophication is a major water pollution issue and can lead to excessive growth of aquatic plant biomass (APB). However, the assimilation of nutrients into APB provides a significant target for their recovery and reuse, and harvesting problematic APB in impacted freshwater bodies offers a complementary approach to aquatic restoration, which could potentially deliver multiple wider ecosystem benefits. This critical review provides an assessment of opportunities and risks linked to nutrient recovery from agriculturally impacted water-bodies through the harvesting of APB for recycling and reuse as fertilisers and soil amendments. By evaluating the economic, social, environmental and health-related dimensions of this resource recovery from 'waste' process we propose a research agenda for closing the loop on nutrient transfer from land to water. We identify that environmental benefits are rarely, if ever, prioritised as essential criteria for the exploitation of resources from waste and yet this is key for addressing the current imbalance that sees environmental managers routinely undervaluing the wider environmental benefits that may accrue beyond resource recovery. The approach we advocate for the recycling of 'waste' APB nutrients is to couple the remediation of eutrophic waters with the sustainable production of feed and fertiliser, whilst providing multiple downstream benefits and minimising environmental trade-offs. This integrated 'ecosystem services approach' has the potential to holistically close the loop on agricultural nutrient loss, and thus sustainably recover finite resources such as phosphorus from waste.

Pharmacogenetic associations with plasma efavirenz concentrations and clinical correlates in a retrospective cohort of Ghanaian HIV-infected patients.

OBJECTIVES: Efavirenz is widely used in first-line antiretroviral therapy in sub-Saharan Africa. However, exposure to efavirenz shows marked interindividual variability that is genetically mediated with potential for important pharmacodynamic consequences. The aims of this study were to assess the frequencies of CYP2B6, CYP2A6, UGT2B7 and CAR single nucleotide polymorphisms (SNPs) and their impact on plasma efavirenz concentration and clinical/immunological responses in Ghanaian patients. METHODS: Genomic DNA from 800 HIV-infected patients was genotyped for selected SNPs by real-time PCR-based allelic discrimination. Mid-dose plasma efavirenz concentrations were measured for 521 patients using HPLC with UV detection. Clinical outcomes in 299 patients on efavirenz were retrospectively assessed. Univariate and multivariate linear regression were performed using best subset selection. Time-to-event outcomes were analysed using a Cox proportional hazards regression model. RESULTS: The variant allele frequencies for CYP2B6 516G>T (rs3745274), CYP2B6 983T>C (rs28399499), CYP2A6 -48T>G (CYP2B6*9B; rs28399433), UGT2B7 802C>T (UGT2B7*2; rs7439366), UGT2B7 735A>G (UGT2B7*1c; rs28365062) and CAR 540C>T (rs2307424) were 48%, 4%, 3%, 23%, 15% and 7%, respectively. CYP2B6 516G>T, CYP2B6 983T>C and CYP2A6 -48T>G were associated with significantly elevated efavirenz concentrations. A trend towards association between plasma efavirenz concentration and CAR 540C>T was observed. CYP2B6 516G homozygosity was associated with immunological failure [adjusted hazards ratio compared with T homozygosity, 1.70 (1.04-2.76); P = 0.03]. CONCLUSIONS: CYP2B6 and CYP2A6 SNPs were associated with higher plasma efavirenz concentrations due to reduction in major and minor phase I routes of elimination, respectively. Further prospective studies are needed to validate the pharmacodynamic correlates of these polymorphisms in this population.