Search

Abstract Background RTS,S/AS01 has been recommended by WHO for widespread implementation in medium to high malaria transmission settings. Previous analyses have noted lower vaccine efficacies in higher transmission settings, possibly due to the more rapid development of naturally acquired immunity in the control group. Methods To investigate a reduced immune response to vaccination as a potential mechanism behind lower efficacy in high transmission areas, we examine initial vaccine antibody (anti-CSP IgG) response and vaccine efficacy against the first case of malaria (to exclude the effect of naturally acquired immunity) using data from three study areas (Kintampo, Ghana; Lilongwe, Malawi; Lambaréné, Gabon) from the 2009–2014 phase III trial (NCT00866619). Our key exposures are parasitemia during the vaccination series and background malaria incidence. We calculate vaccine efficacy (one minus hazard ratio) using a cox-proportional hazards model and allowing for the time-varying effect of RTS,S/AS01. Results We find that antibody responses to the primary three-dose vaccination series were higher in Ghana than in Malawi and Gabon, but that neither antibody levels nor vaccine efficacy against the first case of malaria varied by background incidence or parasitemia during the primary vaccination series. Conclusions We find that vaccine efficacy is unrelated to infections during vaccination. Contributing to a conflicting literature, our results suggest that vaccine efficacy is also unrelated to infections before vaccination, meaning that control-group immunity is likely a major reason for lower efficacy in high transmission settings, not reduced immune responses to RTS,S/AS01. This may be reassuring for implementation in high transmission settings, though further studies are needed.

Abstract Quantifying sector‐resolved methane fluxes in complex emissions environments is challenging yet necessary to improve emissions inventories and guide policy. Here, we separate energy and agriculture sector emissions using a dynamic linear model analysis of methane, ethane, and ammonia data measured at a Northern Colorado site from November 2021 to January 2022. By combining these sector‐apportioned observations with spatially resolved inventories and Bayesian inverse methods, energy and agriculture methane fluxes are optimized across the study's ∼850 km2 sensitivity area. Energy sector fluxes are synthesized with previous literature to evaluate trends in energy sector methane emissions. Optimized agriculture fluxes in the study area were 3.5× larger than inventory estimates; we demonstrate this discrepancy is consistent with differences in the modeled versus real‐world spatial distribution of agricultural sources. These results highlight how sector‐apportioned methane observations can yield multi‐sector inventory optimizations in complex environments.

Abstract Background Amyloid-related imaging abnormalities (ARIA) have been identified as the most common and serious adverse events resulting from pathological changes in the cerebral vasculature during several recent anti-amyloid-β (Aβ) immunotherapy trials. However, the precise cellular and molecular mechanisms underlying how amyloid immunotherapy enhances cerebral amyloid angiopathy (CAA)-mediated alterations in vascular permeability and microhemorrhages are not currently understood. Interestingly, brain perivascular macrophages have been implicated in regulating CAA deposition and cerebrovascular function however, further investigations are required to understand how perivascular macrophages play a role in enhancing CAA-related vascular permeability and microhemorrhages associated with amyloid immunotherapy. Methods In this study, we examined immune responses induced by amyloid-targeting antibodies and CAA-induced microhemorrhages using histology and gene expression analyses in Alzheimer’s disease (AD) mouse models and primary culture systems. Results In the present study, we demonstrate that anti-Aβ (3D6) immunotherapy leads to the formation of an antibody immune complex with vascular amyloid deposits and induces the activation of CD169+ perivascular macrophages. We show that macrophages activated by antibody mediated Fc receptor signaling have increased expression of inflammatory signaling and extracellular matrix remodeling genes such as Timp1 and MMP9 in vitro and confirm these key findings in vivo. Finally, we demonstrate enhanced vascular permeability of plasma proteins and recruitment of inflammatory monocytes around vascular amyloid deposits, which are associated with hemosiderin deposits from cerebral microhemorrhages, suggesting the multidimensional roles of activated perivascular macrophages in response to Aβ immunotherapy. Conclusions In summary, our study establishes a connection between Aβ antibodies engaged at CAA deposits, the activation of perivascular macrophages, and the upregulation of genes involved in vascular permeability. However, the implications of this phenomenon on the susceptibility to microhemorrhages remain to be fully elucidated. Further investigations are warranted to determine the precise role of CD169 + perivascular macrophages in enhancing CAA-mediated vascular permeability, extravasation of plasma proteins, and infiltration of immune cells associated with microhemorrhages.

Abstract Coagulase-negative Staphylococcus (CoNS) are opportunistic pathogens implicated in many human and animal infections. The evolutionary history of CoNS remains obscure because of the historical lack of recognition for their clinical importance and poor taxonomic sampling. Here, we sequenced the genomes of 191 CoNS isolates representing 15 species sampled from diseased animals diagnosed in a veterinary diagnostic laboratory. We found that CoNS are important reservoirs of diverse phages, plasmids and mobilizable genes encoding antimicrobial resistance, heavy metal resistance, and virulence. Frequent exchange of DNA between certain donor-recipient partners suggests that specific lineages act as hubs of gene sharing. We also detected frequent recombination between CoNS regardless of their animal host species, indicating that ecological barriers to horizontal gene transfer can be surmounted in co-circulating lineages. Our findings reveal frequent but structured patterns of transfer that exist within and between CoNS species, which are driven by their overlapping ecology and geographical proximity.

Vladislav Berdunov,1 Steve Millen,2 Andrew Paramore,2 Jane Griffin,3 Sarah Reynia,2 Nina Fryer,2 Rebecca Brown,1 Louise Longworth1 1PHMR Ltd, London, UK; 2Exact Sciences, London, UK; 3Jane Griffin Associates, East Molesey, UKCorrespondence: Vladislav Berdunov, PHMR Ltd, Berkeley Works, Berkley Grove, London, NW1 8XY, UK, Tel +44 20 3432 7450, Email vlad.berdunov@phmr.comBackground: The 21-gene assay (the Oncotype DX Breast Recurrence Score® test) is a validated multigene assay which produces the Recurrence Score® result (RS) to inform decisions on the use of adjuvant chemotherapy in human epidermal growth factor receptor 2-negative (HER2-), hormone receptor positive (HR+) early invasive breast cancer. A model-based economic evaluation estimated the cost-effectiveness of the 21-gene assay against the use of clinical risk tools alone based on the latest evidence from prospective studies.Methods: The proportion of patients assigned to chemotherapy conditional on their RS result was obtained from retrospective data from the Clalit registry. The probability of distant recurrence with endocrine and chemo-endocrine therapy conditional on RS result was obtained from TAILORx and NSABP B-20 trials. The cost-effectiveness of the 21-gene assay compared to using clinical risk tools alone was estimated in terms of cost per quality-adjusted life-year (QALY) over a lifetime horizon.Results: The 21-gene assay was more effective (0.17 more quality-adjusted life years) at a lower cost (-£ 519) over a lifetime compared to clinical risk alone. The model results were sensitive to assumptions around the magnitude of benefit of chemotherapy in the high RS result subgroup. Other assumptions underpinning the model, such as the proportion of patients assigned to chemotherapy in the low and mid-range RS result subgroups and long-term distant recurrence probabilities, had a smaller impact on the results.Conclusion: The analysis showed that the cost-effectiveness of the 21-gene assay is sensitive to assumptions for chemotherapy sparing for patients with RS 0– 25 whose outcomes with endocrine therapy are no worse compared to chemotherapy-assigned patients, and a chemotherapy benefit in the RS 26– 100 group. Future studies need to incorporate a wider set of tumour profiling tests other than the 21-gene assay to allow a direct comparison of their cost-effectiveness.Keywords: cost-effectiveness, multigene assay, breast cancer, chemotherapy, the Oncotype DX test, 21-gene assay

We present results from a field study monitoring methane and volatile organic compound emissions near an unconventional oil well development in Northern Colorado from September 2019 to May 2020 using a mid-infrared dual-comb spectrometer. This instrument allowed quantification of methane, ethane, and propane in a single measurement with high time resolution and integrated path sampling. Using ethane and propane as tracer gases for methane from oil and gas activity, we observed emissions during the drilling, hydraulic fracturing, millout, and flowback phases of well development. Large emissions were seen in drilling and millout phases and emissions decreased to background levels during the flowback phase. Ethane/methane and propane/methane ratios varied widely throughout the observations.

Purpose The aim of this study was to assess efficacy of a virtual, double-flipped clinical rotation in ophthalmology for medical students during the coronavirus disease 2019 (COVID-19) pandemic. Methods We instituted a virtual, reverse-classroom clinical elective for eight medical students interested in ophthalmology as a career. The course included required prework, interactive case-based discussions, and follow-up quizzes (first flip) entirely prepared and delivered by the students as teachers (second flip). After completion of the course, we surveyed students on five domains: (1) Autonomy and Leadership, (2) Self-Efficacy, (3) Impact on Career Selection, (4) Quality of Educational Experience, and (5) Clear Goals and Feedback using a Likert scale of 1–5 (5 being the most positive). We also asked open-ended questions regarding the overall experience, that is, strengths, weaknesses, and future recommendations for the course. Due to the small N and exploratory nature of the study, no formal statistical inference was performed. Results Seven students responded to the survey. Aggregated mean survey scores for each domain are represented in parentheses. Responses were very positive in regard to “Autonomy and Leadership” (4.5), “Impact on Career Selection” (4.1), “Quality of Educational Experience” (5.0), and “Clear Goals and Feedback” (4.4). “Self-Efficacy,” which had an emphasis on ability to perform an eye exam and basic knowledge of ophthalmology, had a lower mean (3.4). The subjective responses were also very positive, but similarly alluded to the limitation of learning examination skills virtually. Conclusions A medical school clinical elective can be successfully executed in a virtual format with an emphasis on student-directed learning. The novel “double-flipped” approach was highly rated by our small sample size. However, there remained a glaring limitation in the ability to transfer clinical skills in the virtual format. In the context of limited in-person contact due to the COVID-19 pandemic, we believe that the double-flipped, virtual format was a viable replacement for a traditional clinical rotation.

Abstract Background RTS,S/AS01 is the first vaccine against malaria to undergo pilot implementation, beginning in 2019 and vaccinating 360,000 children per year in Malawi, Ghana, and Kenya. The four-dose vaccine is given as a primary three-dose series with a fourth dose given approximately 18 months later. The efficacy of RTS,S/AS01 was variable among the 11 sites participating in the 2009–2014 phase III trial (MALARIA-055, NCT00866619 ), possibly due to differences in transmission intensity. However, a within-site examination of environmental factors related to transmission intensity and their impact on vaccine efficacy has yet to be conducted. Methods We implemented the phase III RTS,S/AS01 trial at the Malawi site, which enrolled 1578 infants (6–12 weeks) and children (5–17 months) living in the Lilongwe District in Central Malawi and followed them for 3 years between 2009 and 2014. A global positioning system survey and an ecological questionnaire were conducted to collect participant household locations and characteristics, while additional data on background malaria prevalence were obtained from a concurrent Malaria Transmission Intensity (MTI) survey. Negative binomial regression models were used to assess whether the efficacy of the vaccine varied by estimated background malaria prevalence, household roof type, or amount of nearby vegetation. Results Vaccine efficacy did not significantly vary by estimated malaria prevalence or by roof type. However, increased vegetation cover was associated with an increase in the efficacy of the three-dose primary RTS,S/AS01 series in the 18 months before the fourth dose and a decrease in the efficacy of the primary vaccine series in the second 18 months following, if the fourth dose was not given. Vegetation cover did not alter the efficacy of the fourth dose in a statistically or practically significant manner. Conclusions Vegetation coverage in this study site might be a proxy for nearness to rivers or branching, shallow wetlands called “dambos” which could serve as breeding sites for mosquitoes. We observed statistically significant modification of the efficacy of RTS,S/AS01 by forest cover, suggesting that initial vaccine efficacy and the importance of the fourth dose varies based on ecological context. Trial registration Efficacy of GSK Biologicals’ Candidate Malaria Vaccine (257049) Against Malaria Disease Caused by P. falciparum Infection in Infants and Children in Africa. NCT00866619 prospectively registered 20 March 2009.

Inderpal Singh,1 Priya Fernando,1 Jane Griffin,2 Chris Edwards,2 Kathryn Williamson,3 Patrick Chance2 1Department of Geriatric Medicine, Ysbyty Ystrad Fawr, Aneurin Bevan University Health Board, 2Royal Gwent Hospital, Aneurin Bevan University Board, 3Department of Old Age Psychiatry, Ysbyty Ystrad Fawr, Aneurin Bevan University Health Board, Wales, UK Background: Hospitals are currently admitting an increasing number of older people, and more than one-third could have an underlying mental health problem. The existing Older Adult Mental Health (OAMH) liaison service was increasingly unable to meet the escalating needs of older and frail patients. Therefore, the service was modernized and enhanced on an “invest-to-save” principle to provide a prompt holistic assessment for older adults with mental health problems. The objective of this study was a service evaluation to appraise clinical outcome, minimize the length of stay, and measure the predictors of adverse outcomes to streamline this enhanced service. Materials and methods: Patient demographics, social care needs, comorbidity burden (Charlson comorbidity index, CCI), and functional status (Barthel index, BI) were recorded from November 2014 to February 2015. Frailty status (frailty index, FI) was measured by an index (Rockwood index) of accumulated deficits. The outcomes were compared with the previous OAMH liaison service data over the same period a year earlier. Results: The new Rapid Assessment Interface and Discharge service assessed 339 patients compared to 179 by the previous liaison team over the 4-month period. Mean age was 82.18±8.04 years, with 60% women; preadmission BI was 14.96±4.35, and admission BI was 11.38±5.73 (P

Translational medicine requires facile experimental systems to replicate the dynamic biological systems of diseases. Drug approval continues to lag, partly due to incongruencies in the research pipeline that traditionally involve 2D models, which could be improved with 3D models. The bone marrow (BM) poses challenges to harvest as an intact organ, making it difficult to study disease processes such as breast cancer (BC) survival in BM, and to effective evaluation of drug response in BM. Furthermore, it is a challenge to develop 3D BM structures due to its weak physical properties, and complex hierarchical structure and cellular landscape. To address this, we leveraged 3D bioprinting to create a BM structure with varied methylcellulose (M): alginate (A) ratios. We selected hydrogels containing 4% (w/v) M and 2% (w/v) A, which recapitulates rheological and ultrastructural features of the BM while maintaining stability in culture. This hydrogel sustained the culture of two key primary BM microenvironmental cells found at the perivascular region, mesenchymal stem cells and endothelial cells. More importantly, the scaffold showed evidence of cell autonomous dedifferentiation of BC cells to cancer stem cell properties. This scaffold could be the platform to create BM models for various diseases and also for drug screening.

Abstract While many factors contribute to resistance and susceptibility to infectious disease, a major component is the genotype of the host and the way in which it is expressed. Johne’s disease is a chronic inflammatory bowel disease affecting ruminants and is caused by infection with Mycobacterium avium subspecies paratuberculosis (MAP). We have previously identified red deer breeds (Cervus elaphus) that are resistant; have a low rate of MAP infection and do not progress to develop Johne’s disease. In contrast, susceptible breeds have a high rate of MAP infection as seen by seroconversion and progress to develop clinical Johne’s disease. The aim of this study was to determine if immunological differences exist between animals of resistant or susceptible breeds. Macrophage cultures were derived from the monocytes of deer genotypically defined as resistant or susceptible to the development of Johne’s disease. Following in vitro infection of the cells with MAP, the expression of candidate genes was assessed by quantitative PCR as well as infection rate and cell death rate. The results indicate that macrophages from susceptible animals show a significantly higher upregulation of inflammatory genes (iNOS, IL-1α, TNF-α and IL-23p19) than the macrophages from resistant animals. Cells from resistant animals had a higher rate of apoptosis at 24 hours post infection (hpi) compared to macrophages from susceptible animals. The excessive expression of inflammatory mRNA transcripts in susceptible animals could cause inefficient clearing of the mycobacterial organism and the establishment of disease. Controlled upregulation of inflammatory pathways coupled with programmed cell death in the macrophages of resistant animals may predispose the host to a protective immune response against this mycobacterial pathogen.

ObjectiveTo assess whether late surfactant treatment in extremely low gestational age (GA) newborn infants requiring ventilation at 7-14 days, who often have surfactant deficiency and dysfunction, safely improves survival without bronchopulmonary dysplasia (BPD).Study designExtremely low GA newborn infants (GA ≤28 0/7 weeks) who required mechanical ventilation at 7-14 days were enrolled in a randomized, masked controlled trial at 25 US centers. All infants received inhaled nitric oxide and either surfactant (calfactant/Infasurf) or sham instillation every 1-3 days to a maximum of 5 doses while intubated. The primary outcome was survival at 36 weeks postmenstrual age (PMA) without BPD, as evaluated by physiological oxygen/flow reduction.ResultsA total of 511 infants were enrolled between January 2010 and September 2013. There were no differences between the treated and control groups in mean birth weight (701 ± 164 g), GA (25.2 ± 1.2 weeks), percentage born at GA