Search

Abstract Background There is increasing interest in the capacity of adaptive designs to improve the efficiency of clinical trials. However, relatively little work has investigated how economic considerations – including the costs of the trial – might inform the design and conduct of adaptive clinical trials. Methods We apply a recently published Bayesian model of a value-based sequential clinical trial to data from the ‘Hydroxychloroquine Effectiveness in Reducing symptoms of hand Osteoarthritis’ (HERO) trial. Using parameters estimated from the trial data, including the cost of running the trial, and using multiple imputation to estimate the accumulating cost-effectiveness signal in the presence of missing data, we assess when the trial would have stopped had the value-based model been used. We used re-sampling methods to compare the design’s operating characteristics with those of a conventional fixed length design. Results In contrast to the findings of the only other published retrospective application of this model, the equivocal nature of the cost-effectiveness signal from the HERO trial means that the design would have stopped the trial close to, or at, its maximum planned sample size, with limited additional value delivered via savings in research expenditure. Conclusion Evidence from the two retrospective applications of this design suggests that, when the cost-effectiveness signal in a clinical trial is unambiguous, the Bayesian value-adaptive design can stop the trial before it reaches its maximum sample size, potentially saving research costs when compared with the alternative fixed sample size design. However, when the cost-effectiveness signal is equivocal, the design is expected to run to, or close to, the maximum sample size and deliver limited savings in research costs.

Abstract A comprehensive understanding of meteorological, emission and chemical influences on severe haze is essential for air pollution mitigation. However, the nonlinearity of the atmospheric system greatly hinders this understanding. In this study, we developed the quantitative decoupling analysis (QDA) method by applying the Factor Separation (FS) method into the model processes to quantify the effects of emissions (E), meteorology (M), chemical reactions (C), and their nonlinear interactions and impact on fine particulate matter (PM2.5) pollution. Taking a heavy‐haze episode in Beijing as an example, we show that different from the integrated process rate (IPR) and the scenario analysis approach (SAA) in previous studies, the QDA method explicitly demonstrate the nonlinear effects by decomposing the variation of PM2.5 concentration into individual contributions of E, M and C terms as well as the contributions from interactions among these processes. Results showed that M dominated the hourly fluctuation of the PM2.5 concentration. The C terms increase with increasing the level of haze, reaching maximum (0.37 μg · m−3 · h−1) at the maintenance stage. Moreover, our method reveals that there are non‐negligible non‐linear effects of meteorological, emission, and chemical processes during pollution stage, with the mean accounting for 50% of the increase in PM2.5 concentrations, which is often ignored in the current air pollution control strategies. This study highlights that the QDA approach can be used to gain insight into the formation of heavy pollution, and to identify uncertainty in numerical models.

In the literature, auditory attention is explored through neural speech tracking, primarily entailing modeling and analyzing electroencephalography (EEG) responses to natural speech via linear filtering. Our study takes a novel approach, introducing an enhanced coherence estimation technique to assess the strength of neural speech tracking. This enables effective discrimination between attended and ignored speech. To mitigate the impact of colored noise in EEG, we address two biases–overall coherence-level bias and spectral peak-shifting bias. In a listening study involving 32 participants with hearing impairment, tasked with attending to competing talkers in background noise, our coherence-based method effectively discerns EEG representations of attended and ignored speech. We comprehensively analyze frequency bands, individual frequencies, and EEG channels. Frequency bands of importance are shown to be delta, theta and alpha, and the important EEG channels are the central. Lastly, we showcase coherence differences across different noise reduction settings implemented in hearing aids (HAs), underscoring our method's potential to objectively assess auditory attention and enhance HA efficacy.

Cellulose has advantages of easy availability, low price, renewability and biodegradability, making it a very promising substitute for fossil-based materials. A safe composite cellulose membrane for quasi-solid-state lithium ion batteries has been developed by coating cellulose separators with poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) and lithium aluminum titanium phosphate (LATP). This membrane exhibits excellent electrochemical performance, with an ionic conductivity as high as 2.1 mS cm−1, and a lithium-ion transference number of 0.57. The membrane shows good electrolyte wetting properties, with porosity and liquid electrolyte uptake of 47.2 % and 401.7 %, respectively. It has good thermal stability and can maintain its dimensional stability even at 200 ℃. The capacity retention of the quasi-solid-state LiFePO4/Li battery assembled with this membrane after 200 cycles at 0.2 C is about 86.7 %. The quasi-solid-state battery has good thermal stability and is not prone to thermal runaway.

The poly (ethylene oxide) (PEO) solid polymer electrolytes suffer from narrow electrochemical stability window and cannot match high voltage lithium cobalt oxide (LCO) cathode. Herein, an ultrathin Al2O3 nanolayer was uniformly deposited on the surface of LCO via powder atomic layer deposition (PALD) to realize poly (ethylene oxide) polymer electrolyte cycling stability. The PEO solid polymer electrolyte contains 20 % (w/w) lithium difluoro(oxalate)borate (LiDFOB) and 7.5 % (w/w) lithium titanium aluminum phosphate (LATP) with cellulose nonwoven as a support substrate. The electrolyte exhibitsionic conductivity of 1.2×10−4 S cm−1, an electrochemical stability window of 4.5 V (vs. Li+/Li) and lithium-ion transference number of 0.38. Al2O3@LCO/PEO-LiDFOB20%-LATP7.5%/Li cell at high cut-off 4.5 V delivered better initial discharge specific capacity of 178.5 mAh g−1 and achieved a capacity retention ratio of 81.6 % after 200 cycles under 0.1 C at 50 °C. Further analysis showed that Al2O3 layer served as stable a protective layer to suppress the generation of strong oxidative Co4+ and O– species and separate from the PEO solid polymer electrolyte, inhibiting the side reactions at the cathode-side interface. Therefore, architecting precise and ultrathin protective nanolayer interface on high voltage LCO cathode via PALD is conducive to cycling performance of solid polymer electrolyte.

Background In the UK, one in four patients are in work at the time of their hip or knee replacement surgery. These patients receive little support about their return to work (RTW). There is a need for an occupational support intervention that encourages safe and sustained RTW which can be integrated into National Health Service practice. We developed a two-arm intervention trial, based on a feasibility study, to assess whether an occupational support intervention (the OPAL (Occupational support for Patients undergoing Arthroplasty of the Lower limb) intervention) is effective in supporting a reduced time to full, sustained RTW compared with usual care in patients undergoing hip and knee replacement.Methods and analysis This is a multicentre, individually randomised controlled superiority trial comparing the OPAL intervention to usual care. 742 working adults listed for elective primary hip or knee replacement, who intend to RTW, will be randomised to the OPAL intervention or usual care. The intervention comprises: (1) multimedia information resources; and (2) support from a designated RTW coordinator. The primary outcome is time until ‘full’ sustained RTW without sick leave for a consecutive 4-week period. Secondary outcomes are: time to any RTW, measures of functional recovery, number of ‘sick days’ between surgery and ‘full’ sustained RTW and the use of workplace modifications to facilitate their return. A health economic evaluation and a mixed methods process evaluation will assess cost-effectiveness and the implementation, fidelity and acceptability of the intervention, respectively. Outcomes will be collected at baseline, 3, 6, 9 and 12-month follow-up time points, as well as a monthly RTW questionnaire.Ethics and dissemination Dissemination will focus on supporting the wider adoption and implementation of the intervention (if effective) and will target groups for whom the results will be relevant. This trial was approved by West Midlands—Edgbaston REC 23/WM/0013.Trial registration number ISRCTN13694911.

In a recent phase 2a clinical trial, the candidate leishmaniasis vaccine ChAd63-KH was shown to be safe and immunogenic in Sudanese patients with post kala-azar dermal leishmaniasis (PKDL). However, its value as a stand-alone therapeutic was unknown. To assess the therapeutic efficacy of ChAd63-KH, we conducted a randomized, double-blind, placebo-controlled phase 2b trial (ClinicalTrials.gov: NCT03969134). Primary outcomes were safety and efficacy (≥90% improvement in clinical disease). Secondary outcomes were change in severity grade and vaccine-induced immune response. 86 participants with uncomplicated PKDL of ≥6 month duration were randomized to receive ChAd63-KH (7.5 × 1010 viral particles, once by the intramuscular route) or placebo. 75 participants (87%) completed the trial as per protocol. No severe or serious adverse events were observed. At day 90 post-vaccination, 6/40 (15%) and 4/35 (11%) participants in the vaccine and placebo groups, respectively, showed ≥90% clinical improvement (risk ratio [RR] 1.31 [95% confidence interval (CI), 0.40–4.28], p = 0.742). There were also no significant differences in PKDL severity grade between study arms. Whole-blood transcriptomic analysis identified transcriptional modules associated with interferon responses and monocyte and dendritic cell activation. Thus, a single vaccination with ChAd63-KH showed no therapeutic efficacy in this subset of Sudanese patients with PKDL.

This study explored wild edible plants’ (WEPs) contribution to dietary diversity and micronutrient intakes of women in Turkana County using a multi-method quantitative research design. In addition to the nutrient composition analysis of four vegetable plants and one edible fruit collected from the wild, two survey rounds were conducted – in 2020 during COVID (n = 360) and in 2022 during extreme drought (n = 600), to collect dietary intake data of women using 24-h recall. The study revealed that WEPs contribute 12% to 30% of the total daily food intake among women, and 0.6 to 1.4 food groups to dietary diversity, depending on the season. All the five WEPs tested contained on average 0.5 mg zinc, 6.4–25.5 mg iron, and 97.8–330.8 mg calcium per 100 g edible portion. This study demonstrates the significance of WEPs’ nutritional contribution to the Turkana communities’ diets, and their pivotal role during times of food scarcity, and recommends their promotion alongside measures to prevent their overexploitation.

Background: There is an imminent need to identify neural markers during preadolescence that are linked to developing depression during adolescence, especially among youth at elevated familial risk. However, longitudinal studies remain scarce and exhibit mixed findings. Here we aimed to elucidate functional connectivity (FC) patterns among preadolescents that interact with familial depression risk to predict depression two years later. Methods: 9–10 year-olds in the Adolescent Brain Cognitive Development (ABCD) Study were classified as healthy (i.e., no lifetime psychiatric diagnoses) at high familial risk for depression (HR; n=559) or at low familial risk for psychopathology (LR; n=1203). Whole-brain seed-to-voxel resting-state FC patterns with the amygdala, putamen, nucleus accumbens, and caudate were calculated. Multi-level, mixed-effects regression analyses were conducted to test whether FC at ages 9–10 interacted with familial risk to predict depression symptoms at ages 11–12. Results: HR youth demonstrated stronger associations between preadolescent FC and adolescent depression symptoms (ps0.001), primarily among amygdala/striatal FC with visual and sensory/somatomotor networks. Conclusions: Preadolescent amygdala and striatal FC may be useful biomarkers of adolescent-onset depression, particularly for youth with family histories of depression. This research may point to neurobiologically-informed approaches to prevention and intervention for depression in adolescents.

Abstract Hydroxyl radicals (OH) determine the tropospheric self-cleansing capacity, thus regulating air quality and climate. However, the state-of-the-art mechanisms still underestimate OH at low nitrogen oxide and high volatile organic compound regimes even considering the latest isoprene chemistry. Here we propose that the reactive aldehyde chemistry, especially the autoxidation of carbonyl organic peroxy radicals (R(CO)O2) derived from higher aldehydes, is a noteworthy OH regeneration mechanism that overwhelms the contribution of the isoprene autoxidation, the latter has been proved to largely contribute to the missing OH source under high isoprene condition. As diagnosed by the quantum chemical calculations, the R(CO)O2 radicals undergo fast H-migration to produce unsaturated hydroperoxyl-carbonyls that generate OH through rapid photolysis. This chemistry could explain almost all unknown OH sources in areas rich in both natural and anthropogenic emissions in the warm seasons, and may increasingly impact the global self-cleansing capacity in a future low nitrogen oxide society under carbon neutrality scenarios.

Radar is a valuable tool for noncontact vital-sign detection. Interference from respiratory harmonics presents a major challenge in radar cardiogram (RCG) extraction—mainly when the frequency of respiratory harmonics is close to or equal to that of the cardiac sub-signals. To address this problem, a respiratory harmonic suppression method employing correlation analysis and an optimized feedback notch filter is proposed, which is based on 7.29 GHz center-frequency impulse-radio ultra-wideband radar. A genetic optimization algorithm is employed to optimize the parameters of the notch filter. Performance comparison analysis is conducted on the conventional notch filter and the feedback notch filter. Contact (ECG) and non-contact (RCG) data from 10 subjects were analyzed. The results verified that the performance of the optimized feedback notch filter is much better than that of the conventional notch filter in overshoot, bandwidth, and notch depth, and the proposed method can effectively locate, identify, and suppress respiratory harmonics from the RCG band while preserving heartbeat components. Consequently, this approach markedly enhances the precision of RCG extraction. The technique shows considerable promise for deployment in diverse practical settings, including non-contact auxiliary monitoring systems in both intelligent medical environments and home healthcare.

Abstract The global food system's reliance on a few species threatens food and nutritional security. Species diversification, including indigenous species, is a viable option to address this issue. Diversity enhances food systems' resilience against climatic and economic shocks. It offers resources for improved breeds and allows farmers to mitigate risks. However, successful diversification demands collaboration among farmers, researchers, academics, professionals, retailers, consumers, and policymakers. This review analyzes the role of crop species diversity in food system transformation, focusing on monoculture vulnerabilities, diversification benefits, indigenous species' role in nutrition and food security, and the importance of integrated policies and multi‐stakeholder collaborations. We advocate for interdisciplinary research, participatory approaches, and supportive policies to foster diverse, resilient food systems that ensure food security, biodiversity conservation, and enhanced social well‐being amidst global challenges. While acknowledging the importance of diversity in animal species for food security, the focus of this review is on crop species diversity and its potential to transform food systems.

Abstract Aims Frozen shoulder and proximal humeral fracture can cause pain, stiffness and loss of function. The impact of these symptoms on patients can be measured using the comprehensively validated, 12-item Oxford Shoulder Score (OSS). Evidence suggests that pain and function may have a differential impact on patients’ experience of shoulder conditions, and this may be important for clinical management. We therefore explored the factor structure of the OSS within the UK FROST and PROFHER trial populations. Methods We performed exploratory factor analysis (EFA), followed by confirmatory factor analysis (CFA), on baseline UK FROST data from 490 of the 503 trial participants. Data at 6 months post-randomisation were used for 228 of the 250 participants for the PROFHER trial. Results UK FROST factor extraction results, using Velicer's Minimum Average Partial and Horn's Parallel Analysis tests, suggested a unifactorial solution, but two factors were weakly indicated by the less reliable ‘Kaiser’s eigenvalue > 1’ and scree tests. We explored this further using EFA. Eight items (2 to 7, 9 and 10) loaded onto a ‘Function’ factor, three on a ‘Pain’ factor (1, 8 and 12) and item 11 cross-loaded. However, one- and two-factor models were rejected in CFA. Factor extraction of PROFHER data at 6 months demonstrated a single first-order factor solution, which was also subsequently rejected in CFA. Conclusion Insufficient evidence was found, within the constraints of the data available, to support the use of ‘Pain’ and ‘Function’ sub-scales of the OSS in either patient population.

Abstract Low-cost approaches for mass production of III–V-based photovoltaics are highly desired today. For the first time, this work presents industrially relevant mask and plate for front metallization of III–V-based solar cells replacing expensive photolithography. Metal contacts are fabricated by nickel (Ni) electroplating directly onto the solar cell’s front using a precisely structured mask. Inkjet printing offers low-cost and high-precision processing for application of an appropriate plating resist. It covers the solar cell’s front side with narrow openings for subsequent electroplating. The width of the resulting Ni contacts is as low as (10.5 ± 0.8) µm with sharp edges and homogenous shape. The 4 cm2-sized champion III–V-on-silicon triple-junction solar cell with mask and plate front metallization reaches a certified conversion efficiency η of (31.6 ± 1.1) % (AM1.5 g spectrum). It performs just as well as the reference sample with photolithography-structured evaporated front contacts, which reaches η = (31.4 ± 1.1) %.

The diets of women of reproductive age (WRA) in low-income countries have been reported to be inadequate in micronutrients which lead to undernutrition. The foods commonly consumed by women are usually starchy plant-based cereals, roots and tubers which are limited in micronutrients. Amidst Uganda producing abundance of fruits and vegetables which are sources of micronutrients, it seems that consumption patterns have a role to play. The aim of this study was, therefore, to evaluate the prevailing diets of women of reproductive age in Kayunga and Jinja districts. A cross- sectional study was conducted in August 2019. Four hundred and ninety two (492) women of reproductive age were purposively selected from the two sub-counties to participate in the study. A 24-hour recall questionnaire was used estimate the women's minimum dietary diversity for women of reproductive age (MDD-W) and it is contribution towards meeting micronutrient requirements. Means were computed for continuous variables, while proportions were computed for the descriptive variables that were placed under different themes and categories. Results revealed that more than 80% of women did not achieve the minimum dietary diversity. Less than 50% of the women consumed foods from plant and animal protein rich food groups that are major sources of iron, zinc, calcium, and vitamin B-12. In addition, more than 80% of the women's diets lacked vitamin A- rich fruits and vegetables and dark green leafy vegetables which are the rich food group sources for vitamin A and folate. Therefore, over 80% of the women in Kayunga and Jinja districts did not obtain the required micronutrients for their good health and that of their children and thus, are at risk of poor health due to micronutrient deficiencies. It is recommended to have nutrition education coupled with demonstrations to mothers on how to prepare a diversified diet. Key words: Women, dietary diversity, food groups, micronutrients, nutrient adequacy, INTRODUCTION Women of reproductive age (WRA) are often nutritionally vulnerable because of the physiological demands of pregnancy and lactation [1]. Poor nutritional status weakens a woman's ability to survive childbirth, [...]

Abstract Background ADHD polygenic scores (PGSs) have been previously shown to predict ADHD outcomes in several studies. However, ADHD PGSs are typically correlated with ADHD but not necessarily reflective of causal mechanisms. More research is needed to elucidate the neurobiological mechanisms underlying ADHD. We leveraged functional annotation information into an ADHD PGS to (1) improve the prediction performance over a non-annotated ADHD PGS and (2) test whether volumetric variation in brain regions putatively associated with ADHD mediate the association between PGSs and ADHD outcomes. Methods Data were from the Philadelphia Neurodevelopmental Cohort (N = 555). Multiple mediation models were tested to examine the indirect effects of two ADHD PGSs—one using a traditional computation involving clumping and thresholding and another using a functionally annotated approach (i.e., AnnoPred)—on ADHD inattention (IA) and hyperactivity-impulsivity (HI) symptoms, via gray matter volumes in the cingulate gyrus, angular gyrus, caudate, dorsolateral prefrontal cortex (DLPFC), and inferior temporal lobe. Results A direct effect was detected between the AnnoPred ADHD PGS and IA symptoms in adolescents. No indirect effects via brain volumes were detected for either IA or HI symptoms. However, both ADHD PGSs were negatively associated with the DLPFC. Conclusions The AnnoPred ADHD PGS was a more developmentally specific predictor of adolescent IA symptoms compared to the traditional ADHD PGS. However, brain volumes did not mediate the effects of either a traditional or AnnoPred ADHD PGS on ADHD symptoms, suggesting that we may still be underpowered in clarifying brain-based biomarkers for ADHD using genetic measures.

Objective When considering proposals to improve diets, it is important to understand how factors like price and income can affect saturated fat (SF) intake and demand. In this study, we examine and estimate the influence of price and income on intake across 160 countries, by age and sex, and derive sensitivity measures (price elasticities) that vary by age, sex and world region.Design We econometrically estimate intake responsiveness to income and prices across countries, accounting for differences by world region, age and sex. Intake data by age, sex and country were obtained from the 2018 Global Dietary Database. These data were then linked to global price data for select food groups from the World Bank International Comparison Programme and income data from the World Development Indicators Databank (World Bank).Results Intake differences due to price were highly significant, with a 1% increase in price associated with a lower SF intake (% energy/d) of about 4.3 percentage points. We also find significant differences across regions. In high-income countries, median (age 40) intake reductions were 1.4, 0.8 and 0.2 percentage points, given a 1% increase in the price of meat, dairy, and oils and fats, respectively. Price elasticities varied with age but not sex. Intake differences due to income were insignificant when regional binary variables were included in the analysis.Conclusion The results of this study show heterogeneous associations among prices and intake within and across countries. Policymakers should consider these heterogeneous effects as they address global nutrition and health challenges.

The decidual immunome is dynamic, dramatically changing its composition across gestation. Early pregnancy is dominated by decidual NK cells, with a shift towards T cells later in pregnancy. However, the degree, timing, and subset-specific nature of leukocyte traffic between the decidua and systemic circulation during gestation remains poorly understood. Herein, we employed intravascular staining in pregnant C57BL/6J mice and cynomolgus macaques (Macaca fascicularis) to examine leukocyte traffic into the decidual basalis during pregnancy. Timed-mated or virgin mice were tail-vein injected with labelled αCD45 antibodies 24 hours and 5 minutes before sacrifice. Pregnant cynomolgus macaques (GD155) were infused with labelled αCD45 at 2 hours or 5 mins before necropsy. Decidual cells were isolated and resulting suspensions analyzed by flow cytometry. We found that the proportion of intravascular (IVAs)-negative leukocytes (cells labeled by the 24h infusion of αCD45 or unlabeled) decreased across murine gestation while recent immigrants (24h label only) increased in mid- to late-gestation. In the cynomolgus model our data confirmed differential labeling of decidual leukocytes by the infused antibody, with the 5 min infused animal having a higher proportion of IVAs+ cells compared to the 2hr infused animal. Decidual tissue sections from both macaques showed the presence of intravascularly labeled cells, either in proximity to blood vessels (5min infused animal) or deeper into decidual stroma (2hr infused animal). These results demonstrate the value of serial intravascular staining as a sensitive tool for defining decidual leukocyte traffic during pregnancy.

Summary: Chromosome instability (CIN) contributes to resistance to therapies and tumor evolution. Although natural killer (NK) cells can eliminate cells with complex karyotypes, high-CIN human tumors have an immunosuppressive phenotype. To understand which CIN-associated molecular features alter immune recognition during tumor evolution, we overexpress Polo-like kinase 1 (Plk1) in a Her2+ breast cancer model. These high-CIN tumors activate a senescence-associated secretory phenotype (SASP), upregulate PD-L1 and CD206, and induce non-cell-autonomous nuclear factor κB (NF-κβ) signaling, facilitating immune evasion. Single-cell RNA sequencing from pre-neoplastic mammary glands unveiled the presence of Arg1+ macrophages, NK cells with reduced effector functions, and increased resting regulatory T cell infiltration. We further show that high PLK1-expressing human breast tumors display gene expression patterns associated with SASP, NF-κβ signaling, and immune suppression. These findings underscore the need to understand the immune landscape in CIN tumors to identify more effective therapies, potentially combining immune checkpoint or NF-κβ inhibitors with current treatments.