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Abstract The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone. The combined presence of whole genome doubling (WGD) and TP53 co-mutations leads to increased genome instability and genomic copy number aberrations in genes implicated in EGFR TKI resistance. Using mouse models and an in vitro isogenic p53-mutant model system, we provide evidence that WGD provides diverse routes to drug resistance by increasing the probability of acquiring copy-number gains or losses relative to non-WGD cells. These data provide a molecular basis for mixed tumor responses to targeted therapy, within an individual patient, with implications for therapeutic strategies.

Abstract The growing scale and dimensionality of multiplexed imaging require reproducible and comprehensive yet user-friendly computational pipelines. TRACERx-PHLEX performs deep learning-based cell segmentation (deep-imcyto), automated cell-type annotation (TYPEx) and interpretable spatial analysis (Spatial-PHLEX) as three independent but interoperable modules. PHLEX generates single-cell identities, cell densities within tissue compartments, marker positivity calls and spatial metrics such as cellular barrier scores, along with summary graphs and spatial visualisations. PHLEX was developed using imaging mass cytometry (IMC) in the TRACERx study, validated using published Co-detection by indexing (CODEX), IMC and orthogonal data and benchmarked against state-of-the-art approaches. We evaluated its use on different tissue types, tissue fixation conditions, image sizes and antibody panels. As PHLEX is an automated and containerised Nextflow pipeline, manual assessment, programming skills or pathology expertise are not essential. PHLEX offers an end-to-end solution in a growing field of highly multiplexed data and provides clinically relevant insights.

BackgroundA smartphone app, Parent Positive, was developed to help parents manage their children’s conduct and emotional problems during the COVID-19 pandemic. A randomized controlled trial, Supporting Parents and Kids Through Lockdown Experiences (SPARKLE), found Parent Positive to be effective in reducing children’s emotional problems. However, app effectiveness may be influenced by a range of child, family, socioeconomic, and pandemic-related factors. ObjectiveThis study examined whether baseline factors related to the child, family, and socioeconomic status, as well as pandemic-related disruption circumstances, moderated Parent Positive’s effects on child conduct and emotional problems at 1- and 2-month follow-up. MethodsThis study was a secondary exploratory analysis of SPARKLE data. The data set included 646 children (4-10 years of age) with parents randomized to either Parent Positive (n=320) or follow-up as usual (n=326). Candidate baseline moderators included child age, gender, attention-deficit/hyperactivity disorder symptoms, parental psychological distress, family conflict, household income, employment status, household overcrowding, and pandemic-related disruption risk (ie, homeschooling, lockdown status, and isolation status). Child conduct and emotional problem outcomes measured at 1- (T2) and 2-months (T3) post randomization were analyzed using linear mixed-effects analysis of covariance models adjusting for baseline (T1) measure of outcome and including intervention and intervention by time point interaction terms allowing for different effects at the 2 time points. Moderation of intervention effects by baseline factors was assessed by replacing the intervention by time interaction terms with intervention by time point by baseline moderator interaction terms. ResultsChild gender was a significant moderator of the Parent Positive versus follow-up as usual effect on emotional problems (B=0.72, 95% CI 0.12-1.33; P=.02). Specifically, the effect of Parent Positive was close to significant (T2: B=–0.41, 95% CI –0.82 to 0.0004; P=.05) or significant (T3: B=–0.76, 95% CI –1.22 to –0.30; P

BackgroundElectronic medical record (EMR) systems have the potential to improve the quality of care and clinical outcomes for individuals with chronic and complex diseases. However, studies on the development and use of EMR systems for type 1 (T1) diabetes management in sub-Saharan Africa are few. ObjectiveThe aim of this study is to analyze the need for improvements in the care processes that can be facilitated by an EMR system and to develop an EMR system for increasing quality of care and clinical outcomes for individuals with T1 diabetes in Rwanda. MethodsA qualitative, cocreative, and multidisciplinary approach involving local stakeholders, guided by the framework for complex public health interventions, was applied. Participant observation and the patient’s personal experiences were used as case studies to understand the clinical care context. A focus group discussion and workshops were conducted to define the features and content of an EMR. The data were analyzed using thematic analysis. ResultsThe identified themes related to feature requirements were (1) ease of use, (2) automatic report preparation, (3) clinical decision support tool, (4) data validity, (5) patient follow-up, (6) data protection, and (7) training. The identified themes related to content requirements were (1) treatment regimen, (2) mental health, and (3) socioeconomic and demographic conditions. A theory of change was developed based on the defined feature and content requirements to demonstrate how these requirements could strengthen the quality of care and improve clinical outcomes for people with T1 diabetes. ConclusionsThe EMR system, including its functionalities and content, can be developed through an inclusive and cocreative process, which improves the design phase of the EMR. The development process of the EMR system is replicable, but the solution needs to be customized to the local context.

Objectives Malaria and curable sexually transmitted and reproductive tract infections (STIs/RTIs) are associated with adverse pregnancy outcomes. This study reports the prevalence and risk factors of curable STIs/RTIs, STI/RTI co-infection and STI/RTI and malaria co-infection among HIV-negative pregnant women at their first antenatal care visit in Kenya, Malawi and Tanzania.Methods HIV-negative pregnant women of all gravidae (n=4680) were screened for syphilis with point-of-care tests and treated if positive. Separately, women provided blood samples (n=4569) for rapid plasma reagin (RPR) testing; positive cases were confirmation by Treponema pallidum particle agglutination (TPPA). Women also provided dried blood spots for batch testing of malaria by retrospective polymerase chain reaction (PCR (n=4226) methods. A randomly selected subgroup of women provided vaginal swabs for chlamydia, gonorrhoea and trichomoniasis testing by retrospective PCR batch testing (n=1431), and bacterial vaginosis diagnosis by Nugent scoring (n=1402).Results Malaria prevalence was 14.6% (95% CI 13.6 to 15.7), 45.9% (43.4 to 48.4) of women were positive for at least one curable STI/RTI and 6.7% (5.5 to 8.1) were co-infected with malaria and a curable STI/RTI. Prevalence of individual STIs/RTIs ranged from 28.5% (26.2 to 30.9) for bacterial vaginosis to 14.5% (12.7 to 16.4) for trichomoniasis, 13.8% (12.1 to 15.7) for chlamydia, 2.7% (1.9 to 3.6) for gonorrhoea and 1.7% (1.4 to 2.2) for RPR/TPPA-confirmed syphilis. The prevalence of STI/RTI co-infection was 10.1% (8.7 to 11.8). Paucigravidae, at highest risk of malaria, were also at greater risk of having chlamydia, gonorrhoea and bacterial vaginosis than multigravidae.Conclusions Of women infected with malaria, 49.0% also had a curable STI/RTI and one in five women with at least one STI/RTI were co-infected with more than one STI/RTI. Current antenatal interventions that address malaria and curable STIs/RTIs remain suboptimal. New approaches to preventing and managing these infections in pregnancy are urgently needed.Trial registration number NCT03208179.

Abstract Background The Brief Educational Workshops in Secondary Schools Trial (BESST) is an England-wide school-based cluster randomised controlled trial assessing the clinical and cost-effectiveness of an open-access psychological workshop programme (DISCOVER) for 16–18-year-olds. This baseline paper describes the self-referral and other recruitment processes used in this study and the baseline characteristics of the enrolled schools and participants. Method We enrolled 900 participants from 57 Secondary schools across England from 4th October 2021 to 10th November 2022. Schools were randomised to receive either the DISCOVER day-long Stress workshop or treatment as usual which included signposting information. Participants will be followed up for 6 months with outcome data collection at baseline, 3-month, and 6-month post randomisation. Results Schools were recruited from a geographically and ethnically diverse sample across England. To reduce stigma, students were invited to self-refer into the study if they wanted help for stress. Their mean age was 17.2 (SD = 0.6), 641 (71%) were female and 411 (45.6%) were from ethnic minority groups. The general wellbeing of our sample measured using the Mood and Feelings Questionnaire (MFQ) found 314 (35%) of students exhibited symptoms of depression at baseline. Eighty percent of students reported low wellbeing on the Warwick Edinburgh Mental Wellbeing Scale (WEMWBS) suggesting that although the overall sample mean is below the cut-off for depression, the self-referral approach used in this study supports distressed students in coming forward. Conclusion The BESST study will continue to follow up participants to collect outcome data and results will be analysed once all the data have been collected. Trial registration ISRCTN registry ISRCTN90912799. Registered on 28 May 2020.

Abstract Recombinant native-like HIV-1 envelope glycoprotein (Env) trimers are used in candidate vaccines aimed at inducing broadly neutralizing antibodies. While state-of-the-art SOSIP or single-chain Env designs can be expressed as native-like trimers, undesired monomers, dimers and malformed trimers that elicit non-neutralizing antibodies are also formed, implying that these designs could benefit from further modifications for gene-based vaccination approaches. Here, we describe the triple tandem trimer (TTT) design, in which three Env protomers are genetically linked in a single open reading frame and express as native-like trimers. Viral vectored Env TTT induced similar neutralization titers but with a higher proportion of trimer-specific responses. The TTT design was also applied to generate influenza hemagglutinin (HA) trimers without the need for trimerization domains. Additionally, we used TTT to generate well-folded chimeric Env and HA trimers that harbor protomers from three different strains. In summary, the TTT design is a useful platform for the design of HIV-1 Env and influenza HA immunogens for a multitude of vaccination strategies.

The photochemistry of organic contaminants present in ice is receiving growing attention, given the wide presence of ice during winter in temperate regions as well as Polar and mountain environments. Differences between ice photochemistry and aqueous photochemistry, however, influence the quantitative fate and transformation of organic chemicals present in freshwater, marine and ice-cap environments and these differences need to be explored. Here we comparatively studied the ice and aqueous photochemistry of three antibiotics [levofloxacin (LVX), sulfamerazine (SM), and chlortetracycline (CTC)] under the same simulated sunlight (λ > 290 nm). Their photodegradation in ice/water followed pseudo-first-order kinetics, whereby the photolytic rates of LVX in ice and water were found to be similar, SM photodegraded faster in ice, while CTC underwent slower photodegradation in ice. Whether individual antibiotics underwent faster photodegradation in ice or not depends on the specific concentration effect and cage effect coexisting in the ice compartment. In most cases, the fastest photodegradation occurred in freshwater ice or in fresh water, and the slowest photolysis occurred in pure-water ice or in pure water. This can be attributed to the effects of key photochemical reactive constituents of Cl−, HA, NO3− and Fe(III), that exist in natural waters. These constituents at certain levels showed significant effects (P