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Abstract Background Non-inferiority trials are recommended by the World Health Organization (WHO) to demonstrate that health products show comparable efficacy to that of existing standard of care. As part of the WHO Global Malaria Programme (GMP) process of assessment of malaria vector control products, a second-in-class insecticide-treated net (ITN) must be shown to be non-inferior to a first-in-class product based on mosquito mortality. The public health impact of the first-in-class pyrethroid-piperonyl butoxide (PBO) ITN, Olyset® Plus, has been demonstrated in epidemiological trials in areas with insecticide-resistant mosquitoes, but there is a need to determine the efficacy of other pyrethroid-PBO nets to ensure timely market availability of nets in order to increase access to ITNs. The non-inferiority of a deltamethrin-PBO ITN Yorkool® G3 was evaluated entomologically against Olyset® Plus in experimental huts in Tanzania, following WHO guidelines for non-inferiority trials. Methods The trial of the two pyrethroid-PBO ITNs was conducted in experimental huts in Lupiro, Tanzania, using a randomized 7 × 7 Latin square block design. The study ran for 49 nights in 14 huts assessing the mosquito mortality and blood-feeding of wild, free-flying, pyrethroid-resistant Anopheles arabiensis. Using the non-inferiority approach, the comparative efficacy (primary endpoint was mosquito mortality at 24 h and secondary endpoint was blood-feeding) of unwashed and 20 times field-washed pyrethroid-PBO Yorkool® G3 ITNs, were compared with the first-in-class product Olyset® Plus and against a pyrethroid-only ITN, PermaNet® 2.0 ITNs, as a standard comparator. Results The experimental hut trial demonstrated non-inferiority and superiority of Yorkool® G3 to Olyset® Plus based on mosquito mortality [51% vs. 39%, OR 1.68 (95% CI 1.50–1.88)], given that lower 95% CI exceeded 0.74 (delta of 39%) and the margin of no difference (1). Blood-feeding inhibition was high for all treated ITNs (> 90%) and Yorkool® G3 was non-inferior to Olyset® Plus [4% vs. 2%, OR 1.81 (95% CI 1.46–2.39)], given that upper 95% CI was less than 4.85 (delta of 4%). The pyrethroid-PBO ITNs were superior to the pyrethroid-only net, PermaNet® 2.0, as determined by both the proportion of mortality and blood-feeding of mosquitoes (p-value

Abstract Background and Objective Acute myelogenous leukemia (AML) is a common blood cancer marked by heterogeneity in disease and diverse genetic abnormalities. Additional therapies are needed as the 5-year survival remains below 30%. Trametinib is a mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor that is widely used in solid tumors and also in tumors with activating RAS mutations. A subset of patients with AML carry activating RAS mutations; however, a small-scale clinical trial with trametinib showed little efficacy. Here, we sought to identify transcriptomic determinants of trametinib sensitivity in AML. Methods We tested the activity of trametinib against a panel of tumor cells from patients with AML ex vivo and compared this with RNA sequencing (RNA-Seq) data from untreated blasts from the same patient samples. We then used a correlation analysis between gene expression and trametinib sensitivity to identify potential biomarkers predictive of drug response. Results We found that a subset of AML tumor cells were sensitive to trametinib ex vivo, only a fraction of which (3/10) carried RAS mutations. On the basis of our RNA-Seq analysis we found that markers of trametinib sensitivity are associated with a myeloid differentiation profile that includes high expression of CD14 and CLEC7A (Dectin-1), similar to the gene expression profile of monocytes. Further characterization confirmed that trametinib-sensitive samples display features of monocytic differentiation with high CD14 surface expression and were enriched for the M4 subtypes of the FAB classification. Conclusions Our study identifies additional molecular markers that can be used with molecular features including RAS status to identify patients with AML that may benefit from trametinib treatment.

Abstract Background While women make up over 50% of students enrolled in medical school, disparities in self-efficacy of medical skills between men and women have been observed throughout medical education. This difference is significant because low self-efficacy can impact learning, achievement, and performance, and thus create gender-confidence gaps. Simulation-based training (SBT) employs assessments of self-efficacy, however, the Dunning-Kruger effect in self-assessment posits that trainees often struggle to recognize their skill level. Additionally, the impact of gender on self-efficacy during SBT has not been as widely studied. The objective of this study was to identify if the gender-confidence gap and the Dunning-Kruger effect exist in SBT for central venous catheterization (CVC) on the dynamic haptic robotic trainer (DHRT) utilizing comparisons of self-efficacy and performance. Methods 173 surgical residents (Nwomen=61, Nmen=112) underwent training on the DHRT system over two years. Before and after using the DHRT, residents completed a 14-item Central Line Self-Efficacy survey (CLSE). During training on the DHRT, CVC performance metrics of the number of insertion attempts, backwall puncture, and successful venipuncture were also collected. The pre- and post-CLSE, DHRT performance and their relationship were compared between men and women. Results General estimating equation results indicated that women residents were significantly more likely to report lower self-efficacy for 9 of the 14 CLSE items (p

Abstract Background Simulation-based training (SBT) is vital to complex medical procedures such as ultrasound guided central venous catheterization (US-IJCVC), where the experience level of the physician impacts the likelihood of incurring complications. The Dynamic Haptic Robotic Trainer (DHRT) was developed to train residents in CVC as an improvement over manikin trainers, however, the DHRT and manikin trainer both only provide training on one specific portion of CVC, needle insertion. As such, CVC SBT would benefit from more comprehensive training. An extended version of the DHRT was created, the DHRT + , to provide hands-on training and automated feedback on additional steps of CVC. The DHRT + includes a full CVC medical kit, a false vein channel, and a personalized, reactive interface. When used together, the DHRT and DHRT + systems provide comprehensive training on needle insertion and catheter placement for CVC. This study evaluates the impact of the DHRT + on resident self-efficacy and CVC skill gains as compared to training on the DHRT alone. Methods Forty-seven medical residents completed training on the DHRT and 59 residents received comprehensive training on the DHRT and the DHRT + . Each resident filled out a central line self-efficacy (CLSE) survey before and after undergoing training on the simulators. After simulation training, each resident did one full CVC on a manikin while being observed by an expert rater and graded on a US-IJCVC checklist. Results For two items on the US-IJCVC checklist, “verbalizing consent” and “aspirating blood through the catheter”, the DHRT + group performed significantly better than the DHRT only group. Both training groups showed significant improvements in self-efficacy from before to after training. However, type of training received was a significant predictor for CLSE items “using the proper equipment in the proper order”, and “securing the catheter with suture and applying dressing” with the comprehensive training group that received additional training on the DHRT + showing higher post training self-efficacy. Conclusions The integration of comprehensive training into SBT has the potential to improve US-IJCVC education for both learning gains and self-efficacy.

Abstract Background Falls are common in a range of clinical cohorts, where routine risk assessment often comprises subjective visual observation only. Typically, observational assessment involves evaluation of an individual’s gait during scripted walking protocols within a lab to identify deficits that potentially increase fall risk, but subtle deficits may not be (readily) observable. Therefore, objective approaches (e.g., inertial measurement units, IMUs) are useful for quantifying high resolution gait characteristics, enabling more informed fall risk assessment by capturing subtle deficits. However, IMU-based gait instrumentation alone is limited, failing to consider participant behaviour and details within the environment (e.g., obstacles). Video-based eye-tracking glasses may provide additional insight to fall risk, clarifying how people traverse environments based on head and eye movements. Recording head and eye movements can provide insights into how the allocation of visual attention to environmental stimuli influences successful navigation around obstacles. Yet, manual review of video data to evaluate head and eye movements is time-consuming and subjective. An automated approach is needed but none currently exists. This paper proposes a deep learning-based object detection algorithm (VARFA) to instrument vision and video data during walks, complementing instrumented gait. Method The approach automatically labels video data captured in a gait lab to assess visual attention and details of the environment. The proposed algorithm uses a YoloV8 model trained on with a novel lab-based dataset. Results VARFA achieved excellent evaluation metrics (0.93 mAP50), identifying, and localizing static objects (e.g., obstacles in the walking path) with an average accuracy of 93%. Similarly, a U-NET based track/path segmentation model achieved good metrics (IoU 0.82), suggesting that the predicted tracks (i.e., walking paths) align closely with the actual track, with an overlap of 82%. Notably, both models achieved these metrics while processing at real-time speeds, demonstrating efficiency and effectiveness for pragmatic applications. Conclusion The instrumented approach improves the efficiency and accuracy of fall risk assessment by evaluating the visual allocation of attention (i.e., information about when and where a person is attending) during navigation, improving the breadth of instrumentation in this area. Use of VARFA to instrument vision could be used to better inform fall risk assessment by providing behaviour and context data to complement instrumented e.g., IMU data during gait tasks. That may have notable (e.g., personalized) rehabilitation implications across a wide range of clinical cohorts where poor gait and increased fall risk are common.

OBJECTIVE Medical residents learn how to perform many complex procedures in a short amount of time. Sequential learning, or learning in stages, is a method applied to complex motor skills to increase skill acquisition and retention but has not been widely applied in simulation-based training (SBT). Central venous catheterization (CVC) training could benefit from the implementation of sequential learning. CVC is typically taught with task trainers such as the dynamic haptic robotic trainer (DHRT). This study aims to determine the impact of sequential learning on skill gains and learning curves in CVC SBT by implementing a sequential learning walkthrough into the DHRT. METHODS 103 medical residents participated in CVC training in 2021 and 2022. One group ( N = 44) received training on the original DHRT system while the other group ( N = 59) received training on the DHRT sequential with interactive videos and assessment activities. All residents were quantitatively assessed on (e.g. first trial success rate, distance to vein center, overall score) the DHRT or DHRT sequential systems. RESULTS Residents in the DHRT sequential group exhibited a 3.58 times higher likelihood of successfully completing needle insertion on their first trial than those in the DHRT only group and required significantly fewer trials to reach a pre-defined mastery level of performance. The DHRT sequential group also had fewer significant learning curves compared to the DHRT only group. CONCLUSION Implementing sequential learning into the DHRT system significantly benefitted CVC training by increasing the efficiency of initial skill gain, reducing the number of trials needed to complete training, and flattening the slope of the subsequent learning curve.

Abstract Entomological evaluations of vector control tools often use human landing catches (HLCs) as a standard measure of a direct human-vector contact. However, some tools have additional characteristics, such as mortality, and HLCS are not sensitive for measuring other effects beyond landing inhibition. Therefore, additional measures may need to be considered when evaluating these tools for public health use. This study has two main aims (1) the evaluate the accuracy of HLCs as a proxy for feeding and (2) to compare the predicted reduction in vectorial capacity when we do and do not consider these additional characteristics. To achieve this, we analyse previously published semi-field data from an experiment which used HLCs and another where mosquitoes were allowed to feed in the presence of different dosages of the volatile pyrethroid spatial repellent, transfluthrin. We compare results for two mathematical models: one which only considers the reduction in feeding effect and one which also considers mortality before and after feeding (using data gathered by the aspiration of mosquitoes after the semi-field feeding/landing period and 24 h survival monitoring). These Bayesian hierarchical models are parameterised using Bayesian inference. We observe that, for susceptible mosquitoes, reduction in landing is underestimated by HLCs. For knockdown resistant mosquitoes the relationship is less clear; with HLCs sometimes appearing to overestimate this characteristic. We find HLCs tend to under-predict the relative reduction in vectorial capacity in susceptible mosquitoes while over-predicting this impact in knockdown-resistant mosquitoes. Models without secondary effects have lower predicted relative reductions in vectorial capacities. Overall, this study highlights the importance of considering additional characteristics to reduction in biting of volatile pyrethroid spatial repellents. We recommend that these are considered when evaluating novel vector control tools.

Abstract Wearable inertial measurement units (IMUs) are being used to quantify gait characteristics that are associated with increased fall risk, but the current limitation is the lack of contextual information that would clarify IMU data. Use of wearable video-based cameras would provide a comprehensive understanding of an individual’s habitual fall risk, adding context to clarify abnormal IMU data. Generally, there is taboo when suggesting the use of wearable cameras to capture real-world video, clinical and patient apprehension due to ethical and privacy concerns. This perspective proposes that routine use of wearable cameras could be realized within digital medicine through AI-based computer vision models to obfuscate/blur/shade sensitive information while preserving helpful contextual information for a comprehensive patient assessment. Specifically, no person sees the raw video data to understand context, rather AI interprets the raw video data first to blur sensitive objects and uphold privacy. That may be more routinely achieved than one imagines as contemporary resources exist. Here, to showcase/display the potential an exemplar model is suggested via off-the-shelf methods to detect and blur sensitive objects (e.g., people) with an accuracy of 88%. Here, the benefit of the proposed approach includes a more comprehensive understanding of an individual’s free-living fall risk (from free-living IMU-based gait) without compromising privacy. More generally, the video and AI approach could be used beyond fall risk to better inform habitual experiences and challenges across a range of clinical cohorts. Medicine is becoming more receptive to wearables as a helpful toolbox, camera-based devices should be plausible instruments.

Falls are a major concern for people with Parkinson’s disease (PwPD), but accurately assessing real-world fall risk beyond the clinic is challenging. Contemporary technologies could enable the capture of objective and high-resolution data to better inform fall risk through measurement of everyday factors (e.g., obstacles) that contribute to falls. Wearable inertial measurement units (IMUs) capture objective high-resolution walking/gait data in all environments but are limited by not providing absolute clarity on contextual information (i.e., obstacles) that could greatly influence how gait is interpreted. Video-based data could compliment IMU-based data for a comprehensive free-living fall risk assessment. The objective of this study was twofold. First, pilot work was conducted to propose a novel artificial intelligence (AI) algorithm for use with wearable video-based eye-tracking glasses to compliment IMU gait data in order to better inform free-living fall risk in PwPD. The suggested approach (based on a fine-tuned You Only Look Once version 8 (YOLOv8) object detection algorithm) can accurately detect and contextualize objects (mAP50 = 0.81) in the environment while also providing insights into where the PwPD is looking, which could better inform fall risk. Second, we investigated the perceptions of PwPD via a focus group discussion regarding the adoption of video technologies and AI during their everyday lives to better inform their own fall risk. This second aspect of the study is important as, traditionally, there may be clinical and patient apprehension due to ethical and privacy concerns on the use of wearable cameras to capture real-world video. Thematic content analysis was used to analyse transcripts and develop core themes and categories. Here, PwPD agreed on ergonomically designed wearable video-based glasses as an optimal mode of video data capture, ensuring discreteness and negating any public stigma on the use of research-style equipment. PwPD also emphasized the need for control in AI-assisted data processing to uphold privacy, which could overcome concerns with the adoption of video to better inform IMU-based gait and free-living fall risk. Contemporary technologies (wearable video glasses and AI) can provide a holistic approach to fall risk that PwPD recognise as helpful and safe to use.

Background and aimsWith the rapid growth of artificial intelligence (AI) applications in various fields, understanding its impact on liver cancer research is paramount. This scientometrics project aims to investigate publication trends and topics in AI-related publications in liver cancer.Materials and MethodsWe employed a search strategy to identify AI-related publications in liver cancer using Scopus database. We analyzed the number of publications, author affiliations, and journals that publish AI-related publications in liver cancer. Finally, the publications were grouped based on intended application.ResultsWe identified 3950 eligible publications (2695 articles, 366 reviews, and 889 other document types) from 1968 to August 3, 2023. There was a 12.7-fold increase in AI-related publications from 2013 to 2022. By comparison, the number of total publications on liver cancer increased by 1.7-fold. Our analysis revealed a significant shift in trends of AI-related publications on liver cancer in 2019. We also found a statistically significant consistent increase in numbers of AI-related publications over time (tau = 0.756, p < 0.0001). Eight (53%) of the top 15 journals with the most publications were radiology journals. The largest number of publications were from China (n=1156), the US (n=719), and Germany (n=236). The three most common publication categories were “medical image analysis for diagnosis” (37%), “diagnostic or prognostic biomarkers modeling & bioinformatics” (19%), and “genomic or molecular analysis” (18%).ConclusionOur study reveals increasing interest in AI for liver cancer research, evidenced by a 12.7-fold growth in related publications over the past decade. A common application of AI is in medical imaging analysis for various purposes. China, the US, and Germany are leading contributors.

IntroductionParalyzed and physically impaired patients face communication difficulties, even when they are mentally coherent and aware. Electroencephalographic (EEG) brain–computer interfaces (BCIs) offer a potential communication method for these people without invasive surgery or physical device controls.MethodsAlthough virtual keyboard protocols are well documented in EEG BCI paradigms, these implementations are visually taxing and fatiguing. All English words combine 44 unique phonemes, each corresponding to a unique EEG pattern. In this study, a complete phoneme-based imagined speech EEG BCI was developed and tested on 16 subjects.ResultsUsing open-source hardware and software, machine learning models, such as k-nearest neighbor (KNN), reliably achieved a mean accuracy of 97 ± 0.001%, a mean F1 of 0.55 ± 0.01, and a mean AUC-ROC of 0.68 ± 0.002 in a modified one-versus-rest configuration, resulting in an information transfer rate of 304.15 bits per minute. In line with prior literature, the distinguishing feature between phonemes was the gamma power on channels F3 and F7.DiscussionHowever, adjustments to feature selection, trial window length, and classifier algorithms may improve performance. In summary, these are iterative changes to a viable method directly deployable in current, commercially available systems and software. The development of an intuitive phoneme-based EEG BCI with open-source hardware and software demonstrates the potential ease with which the technology could be deployed in real-world applications.

Abstract Background The human landing catch (HLC) method, in which human volunteers collect mosquitoes that land on them before they can bite, is used to quantify human exposure to mosquito vectors of disease. Comparing HLCs in the presence and absence of interventions such as repellents is often used to measure protective efficacy (PE). Some repellents have multiple actions, including feeding inhibition, whereby mosquitoes may be unable to bite even if they land on a host. A comparison was made between the PE of the volatile pyrethroid spatial repellent (VPSR) transfluthrin determined using a landing method (HLC) and a biting method (allowing the mosquitoes that landed to blood-feed) to evaluate whether HLC is a suitable method for the estimation of the personal PE of a VPSR. Methods A fully balanced, two-arm crossover design study was conducted using a 6 × 6 × 2-m netted cage within a semi-field system. Hessian strips (4 m × 0.1 m) treated with a 5-, 10-, 15-, or 20-g dose of transfluthrin were evaluated against a paired negative control for three strains of laboratory-reared Anopheles and Aedes aegypti mosquitoes. Six replicates were performed per dose using either the landing or the biting method. The number of recaptured mosquitoes was analysed by negative binomial regression, and the PEs calculated using the two methods were compared by Bland–Altman plots. Results For Anopheles, fewer mosquitoes blood-fed in the biting arm than landed in the landing arm (incidence rate ratio = 0.87, 95% confidence interval 0.81–0.93, P

The study assessed the trapping efficacy of locally modified (1) Gravid Aedes Trap (GAT) lined with insecticide-treated net (ITN) as a killing agent and (2) Autocidal Gravid Ovitrap (AGO) with sticky board in the semi-field system (SFS) and field setting. Fully balanced Latin square experiments were conducted to compare GAT lined with ITN vs. AGO, both with either yeast or grass infusion. Biogent-Sentinel (BGS) with BG-Lure and no CO2 was used as a standard trap for Aedes mosquitoes. In the SFS, GAT outperformed AGO in collecting both nulliparous (65% vs. 49%, OR = 2.22, [95% CI: 1.89–2.60], p < 0.001) and gravid mosquitoes (73% vs. 64%, OR = 1.67, [95% CI: 1.41–1.97], p < 0.001). Similar differences were observed in the field. Yeast and grass infusion did not significantly differ in trapping gravid mosquitoes (OR = 0.91, [95% CI: 0.77–1.07], p = 0.250). The use of ITN improved mosquito recapture from 11% to 70% in the SFS. The same trend was observed in the field. Yeast was chosen for further evaluation in the optimized GAT due to its convenience and bifenthrin net for its resistance management properties. Mosquito density was collected when using 4× GATs relative to BGS-captured gravid mosquitoes 64 vs. 58 (IRR = 0.82, [95% CI: 0.35–1.95], p = 0.658) and showed no density dependence. Deployment of multiple yeast-baited GAT lined with bifenthrin net is cost-effective (single GAT < $8) compared to other traps such as BGS ($160).

Abstract Background Mass distributions of long-lasting insecticidal nets (LLINs) have contributed to large reductions in the malaria burden. However, this success is in jeopardy due in part to the increasing pyrethroid-resistant mosquito population as well as low LLINs coverage in various areas because the lifespan of LLINs is often shorter than the interval between replenishment campaigns. New insecticide-treated nets (ITNs) containing pyrethroid and piperonyl-butoxide (PBO) have shown a greater reduction in the incidence of malaria than pyrethroid LLINs in areas with pyrethroid-resistant mosquitoes. However, the durability (attrition, bio-efficacy, physical integrity and chemical retainment) of pyrethroid-PBO ITNs under operational settings has not been fully characterized. This study will measure the durability of pyrethroid-PBO ITNs to assess whether they meet the World Health Organization (WHO) three years of operational performance criteria required to be categorized as “long-lasting”. Methods A prospective household randomized controlled trial will be conducted simultaneously in Tanzania, India and Côte d’Ivoire to estimate the field durability of three pyrethroid-PBO ITNs (Veeralin®, Tsara® Boost, and Olyset® Plus) compared to a pyrethroid LLIN: MAGNet®. Durability monitoring will be conducted up to 36 months post-distribution and median survival in months will be calculated. The proportion of ITNs: (1) lost (attrition), (2) physical integrity, (3) resistance to damage score, (4) meeting WHO bio-efficacy (≥ 95% knockdown after 1 h or ≥ 80% mortality after 24 h for WHO cone bioassay, or ≥ 90% blood-feeding inhibition or ≥ 80% mortality after 24 h for WHO Tunnel tests) criteria against laboratory-reared resistant and susceptible mosquitoes, and insecticidal persistence over time will be estimated. The non-inferiority of Veeralin® and Tsara® Boost to the first-in-class, Olyset® Plus will additionally be assessed for mortality, and the equivalence of 20 times washed ITNs compared to field aged ITNs will be assessed for mortality and blood-feeding inhibition endpoints in the Ifakara Ambient Chamber Test, Tanzania. Conclusion This will be the first large-scale prospective household randomized controlled trial of pyrethroid-PBO ITNs in three different countries in East Africa, West Africa and South Asia, simultaneously. The study will generate information on the replenishment intervals for PBO nets.

Abstract Background Long-lasting insecticidal nets (LLINs) have contributed to the reduction of malaria in sub-Saharan Africa, including Tanzania. However, they rely on daily user behaviour and high coverage which is difficult to maintain. Also, insecticide resistance among malaria vector mosquitoes is contributing to reduced efficacy of control tools. To overcome these problems, we propose to evaluate a new tool for house modification, the insecticide-treated eave nets (ITENs) in combination with insecticide-treated window screens (ITWS) incorporated with dual active ingredient (dual AI) for the control of malaria. Methods Four hundred and fifty (450) households with intact walls, open eaves without screens or nets on the windows in Chalinze district will be eligible and recruited upon written informed consent. The households will be randomly allocated into two arms: one with ITENs and ITWS installed and the other without. Malaria parasite detection using a quantitative polymerase chain reaction (qPCR) will be conducted shortly after the long rain (June/July, 2022) as the primary outcome and shortly after the short rain (January/February, 2022) as the secondary outcome. Other secondary outcomes include clinical malaria cases, and density of malaria vectors and nuisance after the short rain and long rain. In addition, surveys will be conducted in households with ITENs and ITWS to estimate the intervention’s cost during installation, adverse effects one month after installation, and presence, fabric integrity and user acceptance six and twelve months after installation. Bioefficacy and chemical content will be evaluated twelve months after installation. Discussion ITENs and ITWS have been shown in Kenya to reduce indoor mosquito density. However, it is not known if indoor mosquito density reduction translates into reduction of malaria cases. Data from the study will measure the potential public health value of an additional intervention for malaria control at the household level in areas of mosquito insecticide resistance that does not require daily adherence. Trial registration The study is registered on ClinicalTrials.gov .

Abstract Background Quality assurance (QA) of insecticide-treated nets (ITNs) delivered to malaria-endemic countries is conducted by measuring physiochemical parameters, but not bioefficacy against malaria mosquitoes. This study explored utility of cone bioassays for pre-delivery QA of pyrethroid ITNs to test the assumption that cone bioassays are consistent across locations, mosquito strains, and laboratories. Methods Double-blinded bioassays were conducted on twenty unused pyrethroid ITNs of 4 brands (100 nets, 5 subsamples per net) that had been delivered for mass distribution in Papua New Guinea (PNG) having passed predelivery inspections. Cone bioassays were performed on the same net pieces following World Health Organization (WHO) guidelines at the PNG Institute of Medical Research (PNGIMR) using pyrethroid susceptible Anopheles farauti sensu stricto (s.s.) and at Ifakara Health Institute (IHI), Tanzania using pyrethroid susceptible Anopheles gambiae s.s. Additionally, WHO tunnel tests were conducted at IHI on ITNs that did not meet cone bioefficacy thresholds. Results from IHI and PNGIMR were compared using Spearman’s Rank correlation, Bland–Altman (BA) analysis and analysis of agreement. Literature review on the use of cone bioassays for unused pyrethroid ITNs testing was conducted. Results In cone bioassays, 13/20 nets (65%) at IHI and 8/20 (40%) at PNGIMR met WHO bioefficacy criteria. All nets met WHO bioefficacy criteria on combined cone/tunnel tests at IHI. Results from IHI and PNGIMR correlated on 60-min knockdown (KD60) (rs = 0.6,p = 0.002,n = 20) and 24-h mortality (M24) (rs = 0.9,p 80% M24, and for all ITNs provided inherent stochastic variation and systematic bias are accounted for. The literature review confirms that WHO cone bioassay bioefficacy criteria have been previously achieved by all pyrethroid ITNs (unwashed), without the need for additional tunnel tests. The 80% M24 threshold remains the most reliable indicator of pyrethroid ITN quality using pyrethroid susceptible mosquitoes. In the absence of alternative tests, cone bioassays could be used as part of pre-delivery QA.

Abstract Background Vector mosquito biting intensity is an important measure to understand malaria transmission. Human landing catch (HLC) is an effective but labour-intensive, expensive, and potentially hazardous entomological surveillance tool. The Centres for Disease Control light trap (CDC-LT) and the human decoy trap (HDT) are exposure-free alternatives. This study compared the CDC-LT and HDT against HLC for measuring Anop heles biting in rural Tanzania and assessed their suitability as HLC proxies. Methods Indoor mosquito surveys using HLC and CDC-LT and outdoor surveys using HLC and HDT were conducted in 2017 and in 2019 in Ulanga, Tanzania in 19 villages, with one trap/house/night. Species composition, sporozoite rates and density/trap/night were compared. Aggregating the data by village and month, the Bland–Altman approach was used to assess agreement between trap types. Results Overall, 66,807 Anopheles funestus and 14,606 Anopheles arabiensis adult females were caught with 6,013 CDC-LT, 339 indoor-HLC, 136 HDT and 195 outdoor-HLC collections. Indoors, CDC-LT caught fewer An. arabiensis (Adjusted rate ratio [Adj.RR] = 0.35, 95% confidence interval [CI]: 0.27–0.46, p

Abstract Background Between 2000 and 2019, more than 1.8 billion long-lasting insecticidal nets (LLINs) were distributed in Africa. While the insecticidal durability of LLINs is around 3 years, nets are commonly discarded 2 years post distribution. This study investigated the factors associated with the decision of users to discard LLINs. Methods A mixed-method sequential explanatory approach using a structured questionnaire followed by focus group discussions (FGDs) to collect information on experiences, views, reasons, how and when LLINs are discarded. Out of 6,526 households that responded to the questionnaire of LLINs durability trial, 160 households were randomly selected from the households in four villages in Bagamoyo Tanzania for FGDs but only 155 households participated in the FGDs. Five of the household representatives couldn’t participate due to unexpected circumstances. A total of sixteen FGDs each comprising of 8–10 adults were conducted; older women (40–60 years), older men (40–60 years), younger women (18–39 years), younger men (18–39 years). During the FGDs, participants visually inspected seven samples of LLINs that were “too-torn” based on Proportionate Hole Index recommended by the World Health Organization (WHO) guidelines on LLIN testing, the nets were brought to the discussion and participants had to determine if such LLINs were to be kept or discarded. The study assessed responses from the same participants that attended FGD and also responded to the structured questionnaire, 117 participants fulfilled the criteria, thus data from only 117 participants are analysed in this study. Results In FGDs, integrity of LLIN influenced the decision to discard or keep a net. Those of older age, women, and householders with lower income were more likely to classify a WHO “too-torn” net as “good”. The common methods used to discard LLINs were burning and burying. The findings were seen in the quantitative analysis. For every additional hole, the odds of discarding a WHO “too-torn” LLIN increased [OR = 1.05 (95%CI (1.04–1.07)), p

Abstract Neurological complications worsen outcomes in COVID-19. To define the prevalence of neurological conditions among hospitalized patients with a positive SARS-CoV-2 reverse transcription polymerase chain reaction test in geographically diverse multinational populations during early pandemic, we used electronic health records (EHR) from 338 participating hospitals across 6 countries and 3 continents (January–September 2020) for a cross-sectional analysis. We assessed the frequency of International Classification of Disease code of neurological conditions by countries, healthcare systems, time before and after admission for COVID-19 and COVID-19 severity. Among 35,177 hospitalized patients with SARS-CoV-2 infection, there was an increase in the proportion with disorders of consciousness (5.8%, 95% confidence interval [CI] 3.7–7.8%, p FDR

Abstract Background Intravenous iron is often used to treat iron deficiency anaemia in non-dialysis chronic kidney disease (ND-CKD), but the optimal dosing regimen remains unclear. We evaluated the impact of high- versus low-dose intravenous iron isomaltoside on the probability of retreatment with intravenous iron in iron-deficient ND-CKD patients. Methods This real-world, prospective, observational study collected data from 256 ND-CKD patients treated for anaemia in the UK. Following an initial course of iron isomaltoside, patients were followed for ≥12 months. Iron dose and the need for retreatment were determined at the investigators’ discretion. The primary study outcome was the need for retreatment at 52 weeks compared between patients who received >1000 mg of iron during Course 1 and those who received ≤1000 mg. Safety was evaluated through adverse drug reactions. Results The probability of retreatment at Week 52 was significantly lower in the >1000 mg iron group (n = 58) versus the ≤1000 mg group (n = 198); hazard ratio (95% confidence interval [CI]): 0.46 (0.20, 0.91); p = 0.012. Mean (95% CI) haemoglobin increased by 6.58 (4.94, 8.21) g/L in the ≤1000 mg group and by 10.59 (7.52, 13.66) g/L in the >1000 mg group (p = 0.024). Changes in other blood and iron parameters were not significantly different between the two groups. Administering >1000 mg of iron isomaltoside saved 8.6 appointments per 100 patients compared to ≤1000 mg. No serious adverse drug reactions were reported. Of the patients who received ≤1000 mg of iron in this study, 82.3% were eligible for a dose >1000 mg. Conclusions The >1000 mg iron isomaltoside regimen reduced the probability of retreatment, achieved a greater haemoglobin response irrespective of erythropoiesis-stimulating agent treatment, and reduced the total number of appointments required, compared to the ≤1000 mg regimen. Many of the patients who received ≤1000 mg of iron were eligible for >1000 mg, indicating that there was considerable underdosing in this study. Trial registration ClinicalTrials.gov NCT02546154 , 10 September 2015.

Abstract Background Long-lasting insecticidal nets (LLINs) are the most sustainable and effective malaria control tool currently available. Global targets are for 80% of the population living in malaria endemic areas to have access to (own) and use a LLIN. However, current access to LLINs in endemic areas is 56% due to system inefficiencies and budget limitations. Thus, cost-effective approaches to maximize access to effective LLINs in endemic areas are required. This study evaluated whether LLINs that had been stored for 5 years under manufacturer’s recommended conditions may be optimally effective against Anopheles mosquitoes, to inform malaria control programmes and governments on the periods over which LLINs may be stored between distributions, in an effort to maximize use of available LLINs. Methods Standard World Health Organization (WHO) bioassays (cone and tunnel test) were used to evaluate the bio-efficacy and wash resistance of Olyset® and DawaPlus® 2.0 (rebranded Tsara® Soft) LLINs after 5 years of storage at 25 °C to 33.4 °C and 40% to 100% relative humidity. In addition, a small scale Ifakara Ambient Chamber test (I-ACT) was conducted to compare the bio-efficacy of one long stored LLINs to one new LLIN of the same brand, washed or unwashed. LLINs were evaluated using laboratory reared fully susceptible Anopheles gambiae sensu stricto (s.s.) (Ifakara strain) and pyrethroid resistant Anopheles arabiensis (Kingani strain). Results After 5 years of storage, both unwashed and washed, Olyset® and DawaPlus® 2.0 (Tsara® Soft) LLINs passed WHO bio-efficacy criteria on knockdown (KD60) ≥ 95%, 24-h mortality ≥ 80% and ≥ 90% blood-feeding inhibition in WHO assays against susceptible An. gambiae s.s. DawaPlus® 2.0 LLINs also passed combined WHO bioassay criteria against resistant An. arabiensis. Confirmatory I-ACT tests using whole nets demonstrated that long-stored LLINs showed higher efficacy than new LLINs on both feeding inhibition and mortality endpoints against resistant strains. Conclusions Even after long-term storage of around 5 years, both Olyset® and DawaPlus® 2.0 LLINs remain efficacious against susceptible Anopheles mosquitoes at optimal storage range of 25 °C to 33.4 °C for temperature and 40% to 100% relative humidity measured by standard WHO methods. DawaPlus® 2.0 (Tsara® Soft) remained efficacious against resistant strain.

Fall risk assessment needs contemporary approaches based on habitual data. Currently, inertial measurement unit (IMU)-based wearables are used to inform free-living spatio-temporal gait characteristics to inform mobility assessment. Typically, a fluctuation of those characteristics will infer an increased fall risk. However, current approaches with IMUs alone remain limited, as there are no contextual data to comprehensively determine if underlying mechanistic (intrinsic) or environmental (extrinsic) factors impact mobility and, therefore, fall risk. Here, a case study is used to explore and discuss how contemporary video-based wearables could be used to supplement arising mobility-based IMU gait data to better inform habitual fall risk assessment. A single stroke survivor was recruited, and he conducted a series of mobility tasks in a lab and beyond while wearing video-based glasses and a single IMU. The latter generated topical gait characteristics that were discussed according to current research practices. Although current IMU-based approaches are beginning to provide habitual data, they remain limited. Given the plethora of extrinsic factors that may influence mobility-based gait, there is a need to corroborate IMUs with video data to comprehensively inform fall risk assessment. Use of artificial intelligence (AI)-based computer vision approaches could drastically aid the processing of video data in a timely and ethical manner. Many off-the-shelf AI tools exist to aid this current need and provide a means to automate contextual analysis to better inform mobility from IMU gait data for an individualized and contemporary approach to habitual fall risk assessment.

Membranous nephropathy is a cause of the nephrotic syndrome in adults; it can be a primary or secondary process. Secondary causes include solid organ and lymphoid malignancies. Prostate cancer has been reported as the second most common causative malignancy. Remission of membranous nephropathy following treatment of metastatic prostate cancer is well established. In this case, we describe a patient with localised prostate cancer who developed severe nephrotic syndrome (urine protein creatinine ratio 1,616 mg/mmol and serum albumin 17 g/L) secondary to membranous nephropathy. The prostate cancer was deemed of low risk and so was being managed with active surveillance rather than medical treatment. Given the severity of the nephrotic syndrome a trial of androgen deprivation therapy with bicalutamide was agreed between the nephrology and urology teams. Full remission of the nephrotic syndrome was observed within 6 months of commencement of treatment (normalisation of serum albumin, non-nephrotic range urine protein creatinine ratio and resolution of oedema). The bicalutamide has been continued indefinitely.

Abstract Background Iron deficiency is frequent in haemodialysis (HD) patients with chronic kidney disease (CKD), and intravenous iron is an established therapy for these patients. This study assessed treatment routine, effectiveness, and safety of iron isomaltoside (IIM) 5% (Diafer®) in a HD cohort. Methods This prospective observational study included 198 HD patients converted from iron sucrose (IS) and treated with IIM according to product label and clinical routine. Data for IIM were compared to historic data for IS in 3-month intervals. The primary endpoint was to show non-inferiority for IIM versus IS in haemoglobin (Hb) maintenance. Results Most patients (> 60%) followed a fixed low-dose iron treatment protocol. Three minutes were required for preparation and administration of IIM. Erythropoiesis-stimulating agent (ESA) was used in > 80% of patients during both IIM and IS phases. The maintenance of Hb was similar with both iron drugs; the mean Hb level was 11 g/dL, and the mean change of 0.3 g/dL (95% confidence interval: 0.1, 0.5) for IIM 0–3 months compared to IS demonstrated non-inferiority. Nine adverse drug reactions were reported in 2% of patients administered IIM. All patients had uneventful recoveries. The frequency of metallic taste was higher with IS compared to IIM (34% versus 0.5%, p

Background: Strengthening capacity for public health research is essential to the generation of high-quality, reliable scientific data. This study focuses on a research capacity strengthening project supporting seven test facilities in Africa conducting studies on mosquito vector control products towards Good Laboratory Practice (GLP) certification. It captures the primary effects of the project on each facility’s research capacity, the secondary effects at the individual and institutional level, and the ripple effects that extend beyond the research system. The relationships between effects at different levels are identified and compared to an existing framework for the evaluation of research capacity strengthening initiatives. Methods: To capture the views of individuals engaged in the project at all levels within each facility, a maximum-variation purposive sampling strategy was used. This allowed triangulation between different data sources. Semi-structured interviews were conducted with individuals in three facilities and a combination of email and remote video-call interviews were conducted with individuals at two further facilities. Results: We found that, despite a focus of the GLP certification project at the institutional level, the project had effects also at individual (including enhanced motivation, furtherment of careers) and national/international levels (including development of regional expertise). In addition, we detected ripple effects of the project which extended beyond the research system. Conclusion: This study shows that research capacity strengthening interventions that are focussed on institutional level goals require actions also at individual and national/international levels. The effects of engagement at all three levels can be amplified by collaborative actions at the national/international level. These findings show that research capacity strengthening projects must develop plans that address and evaluate impact at all three levels. Capturing the ripple effects of investment in research capacity strengthening should also be planned for from the beginning of projects to support further engagement of all stakeholders.

Background Insecticidal mosquito vector control products are vital components of malaria control programmes. Test facilities are key in assessing the effectiveness of vector control products against local mosquito populations, in environments where they will be used. Data from these test facilities must be of a high quality to be accepted by regulatory authorities, including the WHO Prequalification Team for vector control products. In 2013–4, seven insecticide testing facilities across sub-Saharan Africa, with technical and financial support from Innovative Vector Control Consortium (IVCC), began development and implementation of quality management system compliant with the principles of Good Laboratory Practice (GLP) to improve data quality and reliability. Methods and principle findings We conducted semi-structured interviews, emails, and video-call interviews with individuals at five test facilities engaged in the IVCC-supported programme and working towards or having achieved GLP. We used framework analysis to identify and describe factors affeting progress towards GLP. We found that eight factors were instrumental in progress, and that test facilities had varying levels of control over these factors. They had high control over the training programme, project planning, and senior leadership support; medium control over infrastructure development, staff structure, and procurement; and low control over funding the availability and accessibility of relevant expertise. Collaboration with IVCC and other partners was key to overcoming the challenges associated with low and medium control factors. Conclusion For partnership and consortia models of research capacity strengthening, test facilities can use their own internal resources to address identified high-control factors. Project plans should allow additional time for interaction with external agencies to address medium-control factors, and partners with access to expertise and funding should concentrate their efforts on supporting institutions to address low-control factors. In practice, this includes planning for financial sustainability at the outset, and acting to strengthen national and regional training capacity.

BackgroundTwo billion long-lasting insecticidal nets (LLINs) have been procured for malaria control. A functional LLIN is one that is present, is in good physical condition, and remains insecticidal, thereby providing protection against vector-borne diseases through preventing bites and killing disease vectors. The World Health Organization (WHO) prequalifies LLINs that remain adequately insecticidal 3 years after deployment. Therefore, institutional buyers often assume that prequalified LLINs are functionally identical with a 3-year lifespan. We measured the lifespans of 3 LLIN products, and calculated their cost per year of functional life, to demonstrate the economic and public health importance of procuring the most cost-effective LLIN product based on its lifespan.Methods and findingsA randomised double-blinded trial of 3 pyrethroid LLIN products (10,571 nets in total) was conducted at 3 follow-up points: 10 months (August-October 2014), 22 months (August-October 2015), and 36 months (October-December 2016) among 3,393 households in Tanzania using WHO-recommended methods. Primary outcome was LLIN functional survival (LLIN present and in serviceable condition). Secondary outcomes were (1) bioefficacy and chemical content (residual insecticidal activity) and (2) protective efficacy for volunteers sleeping under the LLINs (bite reduction and mosquitoes killed). Median LLIN functional survival was significantly different between the 3 net products (p = 0.001): 2.0 years (95% CI 1.7-2.3) for Olyset, 2.5 years (95% CI 2.2-2.8) for PermaNet 2.0 (hazard ratio [HR] 0.73 [95% CI 0.64-0.85], p = 0.001), and 2.6 years (95% CI 2.3-2.8) for NetProtect (HR = 0.70 [95% CI 0.62-0.77], p < 0.001). Functional survival was affected by accumulation of holes, leading to users discarding nets. Protective efficacy also significantly differed between products as they aged. Equivalent annual cost varied between US$1.2 (95% CI $1.1-$1.4) and US$1.5 (95% CI $1.3-$1.7), assuming that each net was priced identically at US$3. The 2 longer-lived nets (PermaNet and NetProtect) were 20% cheaper than the shorter-lived product (Olyset). The trial was limited to only the most widely sold LLINs in Tanzania. Functional survival varies by country, so the single country setting is a limitation.ConclusionsThese results suggest that LLIN functional survival is less than 3 years and differs substantially between products, and these differences strongly influence LLIN value for money. LLIN tendering processes should consider local expectations of cost per year of functional life and not unit price. As new LLIN products come on the market, especially those with new insecticides, it will be imperative to monitor their comparative durability to ensure that the most cost-effective products are procured for malaria control.

Abstract Background The Government of Tanzania is the main source of long-lasting insecticidal nets (LLINs) for its population. Mosquito nets (treated and untreated) are also available in the commercial market. To sustain investments and health gains in the fight against malaria, it is important for the National Malaria Control Programme to monitor LLIN coverage especially in the years between mass distributions and to understand what households do if their free nets are deemed unusable. The aim of this paper was to assess standard LLIN indicators by wealth status in Tanzania in 2013, 2 years after the last mass campaign in 2011, and extend the analysis to untreated nets (UTNs) to investigate how households adapt when nets are not continuously distributed. Methods Between October–December 2013, a household survey was conducted in 3398 households in eight districts in Tanzania. Using the Roll Back Malaria indicators, the study analysed: (1) household net ownership; (2) access to nets; (3) population net use and (4) net use:access ratio. Outcomes were calculated for LLINs and UTNs. Results were analysed by socio-economic quintiles and by district. Results Only three of the eight districts had household LLIN ownership of more than 80%. In 2013, less than a quarter of the households had one LLIN for every two people and only half of the population had access to an LLIN. Only the wealthier quintiles increased their net ownership and access to levels above 80% through the addition of UTNs. Overall net use of the population was low (LLINs: 32.8%; UTNs: 9.5%) and net use:access ratio was below target level (LLINs: 0.66; UTN: 0.50). Both measures varied significantly by district. Conclusions Two years after the last mass campaign, the percentage of households or population with access to LLINs was low. These findings indicate the average rate at which households in Tanzania lose their nets is higher than the rate at which they acquire new nets. The wealthiest households topped up their household net ownership with UTNs. Efforts to make LLINs available through commercial markets should be promoted, so those who can afford to buy nets purchase LLINs rather than UTNs. Net use was low around 40% and mostly explained by lack of access to nets. However, the use:access ratio was poor in Mbozi and Kahama districts warranting further investigations to understand other barriers to net use.

Abstract Background The ability of external investigators to reproduce published scientific findings is critical for the evaluation and validation of biomedical research by the wider community. However, a substantial proportion of health research using electronic health records (EHR), data collected and generated during clinical care, is potentially not reproducible mainly due to the fact that the implementation details of most data preprocessing, cleaning, phenotyping and analysis approaches are not systematically made available or shared. With the complexity, volume and variety of electronic health record data sources made available for research steadily increasing, it is critical to ensure that scientific findings from EHR data are reproducible and replicable by researchers. Reporting guidelines, such as RECORD and STROBE, have set a solid foundation by recommending a series of items for researchers to include in their research outputs. Researchers however often lack the technical tools and methodological approaches to actuate such recommendations in an efficient and sustainable manner. Results In this paper, we review and propose a series of methods and tools utilized in adjunct scientific disciplines that can be used to enhance the reproducibility of research using electronic health records and enable researchers to report analytical approaches in a transparent manner. Specifically, we discuss the adoption of scientific software engineering principles and best-practices such as test-driven development, source code revision control systems, literate programming and the standardization and re-use of common data management and analytical approaches. Conclusion The adoption of such approaches will enable scientists to systematically document and share EHR analytical workflows and increase the reproducibility of biomedical research using such complex data sources.

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Background: End-stage renal disease is a long-term irreversible decline in kidney function requiring renal replacement therapy: kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation, followed by immunosuppressive therapy (induction and maintenance therapy) to reduce the risk of kidney rejection and prolong graft survival. Objectives: To review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect®, Novartis Pharmaceuticals UK Ltd) and rabbit anti-human thymocyte immunoglobulin (rATG) (Thymoglobulin®, Sanofi) as induction therapy, and immediate-release tacrolimus (TAC) (Adoport®, Sandoz; Capexion®, Mylan; Modigraf®, Astellas Pharma; Perixis®, Accord Healthcare; Prograf®, Astellas Pharma; Tacni®, Teva; Vivadex®, Dexcel Pharma), prolonged-release tacrolimus (Advagraf® Astellas Pharma), belatacept (BEL) (Nulojix®, Bristol-Myers Squibb), mycophenolate mofetil (MMF) (Arzip®, Zentiva; CellCept®, Roche Products; Myfenax®, Teva), mycophenolate sodium (MPS) (Myfortic®, Novartis Pharmaceuticals UK Ltd), sirolimus (SRL) (Rapamune®, Pfizer) and everolimus (EVL) (Certican®, Novartis) as maintenance therapy in adult renal transplantation. Methods: Clinical effectiveness searches were conducted until 18 November 2014 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science (via ISI), Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted until 18 November 2014 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Database (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and the American Economic Association’s electronic bibliography (via EconLit, EBSCOhost). Included studies were selected according to predefined methods and criteria. A random-effects model was used to analyse clinical effectiveness data (odds ratios for binary data and mean differences for continuous data). Network meta-analyses were undertaken within a Bayesian framework. A new discrete time–state transition economic model (semi-Markov) was developed, with acute rejection, graft function (GRF) and new-onset diabetes mellitus used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death. Results: Eighty-nine randomised controlled trials (RCTs), of variable quality, were included. For induction therapy, no treatment appeared more effective than another in reducing graft loss or mortality. Compared with placebo/no induction, rATG and BAS appeared more effective in reducing biopsy-proven acute rejection (BPAR) and BAS appeared more effective at improving GRF. For maintenance therapy, no treatment was better for all outcomes and no treatment appeared most effective at reducing graft loss. BEL + MMF appeared more effective than TAC + MMF and SRL + MMF at reducing mortality. MMF + CSA (ciclosporin), TAC + MMF, SRL + TAC, TAC + AZA (azathioprine) and EVL + CSA appeared more effective than CSA + AZA and EVL + MPS at reducing BPAR. SRL + AZA, TAC + AZA, TAC + MMF and BEL + MMF appeared to improve GRF compared with CSA + AZA and MMF + CSA. In the base-case deterministic and probabilistic analyses, BAS, MMF and TAC were predicted to be cost-effective at £20,000 and £30,000 per quality-adjusted life-year (QALY). When comparing all regimens, only BAS + TAC + MMF was cost-effective at £20,000 and £30,000 per QALY. Limitations: For included trials, there was substantial methodological heterogeneity, few trials reported follow-up beyond 1 year, and there were insufficient data to perform subgroup analysis. Treatment discontinuation and switching were not modelled. Future work: High-quality, better-reported, longer-term RCTs are needed. Ideally, these would be sufficiently powered for subgroup analysis and include health-related quality of life as an outcome. Conclusion: Only a regimen of BAS induction followed by maintenance with TAC and MMF is likely to be cost-effective at £20,000–30,000 per QALY. Study registration: This study is registered as PROSPERO CRD42014013189. Funding: The National Institute for Health Research Health Technology Assessment programme.

By the 1570’s, Potosí, and its silver, had become the hub of acommodity revolution that reorganized Peru’s peoples and landscapes to serve capital and empire. This was a decisive moment in the world ecological revolution of the long seventeenth century. Primitive accumulation in Peru was particularly successful: the mita’s spatial program enabled the colonial state to marshal a huge supply of low-cost and tractable labor in the midst of sustained demographic contraction. The relatively centralized character of Peru’s mining frontier facilitated imperial control in a way the more dispersedsilver frontiers of New Spain did not. Historical capitalism has sustained itself on the basis of exploiting, and thereby undermining, a vast web of socio-ecological relations. As may be observed in colonial Peru, the commodity frontier strategy effected both the destruction and creation of premodern socio-ecological arrangements.

Malaria vector control relies on toxicity of insecticides used in long lasting insecticide treated nets and indoor residual spraying. This is despite evidence that sub-lethal insecticides reduce human-vector contact and malaria transmission. The impact of sub-lethal insecticides on host seeking and blood feeding of mosquitoes was measured. Taxis boxes distinguished between repellency and attraction inhibition of mosquitoes by measuring response of mosquitoes towards or away from Transfluthrin coils and humans. Protective effective distance of coils and long-term effects on blood feeding were measured in the semi-field tunnel and in a Peet Grady chamber. Laboratory reared pyrethroid susceptible Anopheles gambiae sensu stricto mosquitoes were used. In the taxis boxes, a higher proportion of mosquitoes (67%-82%) were activated and flew towards the human in the presence of Transfluthrin coils. Coils did not hinder attraction of mosquitoes to the human. In the semi-field Tunnel, coils placed 0.3 m from the human reduced feeding by 86% (95% CI [0.66; 0.95]) when used as a "bubble" compared to 65% (95% CI [0.51; 0.76]) when used as a "point source". Mosquitoes exposed to coils inside a Peet Grady chamber were delayed from feeding normally for 12 hours but there was no effect on free flying and caged mosquitoes exposed in the semi-field tunnel. These findings indicate that airborne pyrethroids minimize human-vector contact through reduced and delayed blood feeding. This information is useful for the development of target product profiles of spatial repellent products that can be used to complement mainstream malaria vector control tools.

This paper provides a critical study of current Australian and leading international policies aimed at supporting electrical energy storage for stationary power applications with a focus on battery and hydrogen storage technologies. It demonstrates that global leaders such as Germany and the U.S. are actively taking steps to support energy storage technologies through policy and regulatory change. This is principally to integrate increasing amounts of intermittent renewable energy (wind and solar) that will be required to meet high renewable energy targets. The relevance of this to the Australian energy market is that whilst it is unique, it does have aspects in common with the energy markets of these global leaders. This includes regions of high concentrations of intermittent renewable energy (Texas and California) and high penetration rates of residential solar photovoltaics (PV) (Germany). Therefore, Australian policy makers have a good opportunity to observe what is working in an international context to support energy storage. These learnings can then be used to help shape future policy directions and guide Australia along the path to a sustainable energy future.

Differences between individual human houses can confound results of studies aimed at evaluating indoor vector control interventions such as insecticide treated nets (ITNs) and indoor residual insecticide spraying (IRS). Specially designed and standardised experimental huts have historically provided a solution to this challenge, with an added advantage that they can be fitted with special interception traps to sample entering or exiting mosquitoes. However, many of these experimental hut designs have a number of limitations, for example: 1) inability to sample mosquitoes on all sides of huts, 2) increased likelihood of live mosquitoes flying out of the huts, leaving mainly dead ones, 3) difficulties of cleaning the huts when a new insecticide is to be tested, and 4) the generally small size of the experimental huts, which can misrepresent actual local house sizes or airflow dynamics in the local houses. Here, we describe a modified experimental hut design - The Ifakara Experimental Huts- and explain how these huts can be used to more realistically monitor behavioural and physiological responses of wild, free-flying disease-transmitting mosquitoes, including the African malaria vectors of the species complexes Anopheles gambiae and Anopheles funestus, to indoor vector control-technologies including ITNs and IRS. Important characteristics of the Ifakara experimental huts include: 1) interception traps fitted onto eave spaces and windows, 2) use of eave baffles (panels that direct mosquito movement) to control exit of live mosquitoes through the eave spaces, 3) use of replaceable wall panels and ceilings, which allow safe insecticide disposal and reuse of the huts to test different insecticides in successive periods, 4) the kit format of the huts allowing portability and 5) an improved suite of entomological procedures to maximise data quality.

Pacific herring (Clupea pallasi) are an abundant and important component of the coastal ecosystems for the west coast of North America. Current Canadian federal herring management assumes five regional herring populations in British Columbia with a high degree of exchange between units, and few distinct local populations within them. Indigenous traditional knowledge and historic sources, however, suggest that locally adapted, distinct regional herring populations may have been more prevalent in the past. Within the last century, the combined effects of commercial fishing and other anthropogenic factors have resulted in severe declines of herring populations, with contemporary populations potentially reflecting only the remnants of a previously more abundant and genetically diverse metapopulation. Through the analysis of 85 archaeological herring bones, this study attempted to reconstruct the genetic diversity and population structure of ancient herring populations using three different marker systems (mitochondrial DNA (mtDNA), microsatellites and SNPs). A high success rate (91%) of DNA recovery was obtained from the extremely small herring bone samples (often

HLA-C is an important ligand for killer immunoglobulin like receptors (KIR) that regulate natural killer (NK) cell function. Based on KIR specificity HLA-C molecules are allocated into two groups, HLA-C1 or HLA-C2; HLA-C2 is more inhibiting to NK cell function than HLA-C1. We studied the clinical importance of HLA-C genotypes on the long-term graft survival of 760 kidney transplants performed at our centre utilising a population based genetic study and cell culture model to define putative mechanisms.Genotyping was performed using conventional DNA PCR techniques and correlations made to clinical outcomes. We found that transplant recipients with HLA-C2 had significantly better long-term graft survival than transplant recipients with HLA-C1 (66% versus 44% at 10 years, log-rank p = 0.002, HR = 1.51, 95%CI = 1.16-1.97). In in-vitro NK and dendritic cell (DC) co-culture model we made several key observations that correlated with the population based genetic study. We observed that donor derived NK cells, on activation with IL-15, promoted differential HLA-C genotype dependent DC maturation. In NK-DC co-culture, the possession of HLA-C2 by DC was associated with anti-inflammatory cytokine production (IL-1RA/IL-6), diminished DC maturation (CD86, HLA-DR), and absent CCR7 expression. Conversely, possession of HLA-C1 by DC was associated with pro-inflammatory cytokine synthesis (TNF-α, IL-12p40/p70), enhanced DC maturation and up-regulation of CCR7 expression. By immunohistochemistry the presence of donor NK cells was confirmed in pre-transplant kidneys.We propose that after kidney transplantation IL-15 activated donor derived NK cells interact with recipient DC with less activation of indirect allo-reactivity in HLA-C2 positive recipients than HLA-C1 positive recipients; this has implications for long-term graft survival. Early events following kidney transplantation involving NK-DC interaction via KIR and HLA-C immune synapse may have a central role in long-term kidney transplant outcomes.