Navitoclax safety, tolerability, and effect on biomarkers of senescence and neurodegeneration in aged nonhuman primates.

Alzheimer's disease (AD) is the most common global dementia and is universally fatal. Most late-stage AD disease-modifying therapies are intravenous and target amyloid beta (Aß), with only modest effects on disease progression: there remains a high unmet need for convenient, safe, and effective therapeutics. Senescent cells (SC) and the senescence-associated secretory phenotype (SASP) drive AD pathology and increase with AD severity. Preclinical senolytic studies have shown improvements in neuroinflammation, tau, Aß, and CNS damage; most were conducted in transgenic rodent models with uncertain human translational relevance. In this study, aged cynomolgus monkeys had significant elevation of biomarkers of senescence, SASP, and neurological damage. Intermittent treatment with the senolytic navitoclax induced modest reversible thrombocytopenia; no serious drug-related toxicity was noted. Navitoclax reduced several senescence and SASP biomarkers, with CSF concentrations sufficient for senolysis. Finally, navitoclax reduced TSPO-PET frontal cortex binding and showed trends of improvement in CSF biomarkers of neuroinflammation, neuronal damage, and synaptic dysfunction. Overall, navitoclax administration was safe and well tolerated in aged monkeys, inducing trends of biomarker changes relevant to human neurodegenerative disease.

Alzheimer's Disease Has Its Origins in Early Life via a Perturbed Microbiome.

Alzheimer's disease (AD) is a neurodegenerative disorder with limited therapeutic options. Accordingly, new approaches for prevention and treatment are needed. One focus is the human microbiome, the consortium of microorganisms that live in and on us, which contributes to human immune, metabolic, and cognitive development and that may have mechanistic roles in neurodegeneration. AD and Alzheimer's disease-related dementias (ADRD) are recognized as spectrum disorders with complex pathobiology. AD/ADRD onset begins before overt clinical signs, but initiation triggers remain undefined. We posit that disruption of the normal gut microbiome in early life leads to a pathological cascade within septohippocampal and cortical brain circuits. We propose investigation to understand how early-life microbiota changes may lead to hallmark AD pathology in established AD/ADRD models. Specifically, we hypothesize that antibiotic exposure in early life leads to exacerbated AD-like disease endophenotypes that may be amenable to specific microbiological interventions. We propose suitable models for testing these hypotheses.

The role of intestinal microbiota in physiologic and body compositional changes that accompany CLA-mediated weight loss in obese mice.

BACKGROUND: Obesity continues to be a major problem, despite known treatment strategies such as lifestyle modifications, pharmaceuticals, and surgical options, necessitating the development of novel weight loss approaches. The naturally occurring fatty acid, 10,12 conjugated linoleic acid (10,12 CLA), promotes weight loss by increasing fat oxidation and browning of white adipose tissue, leading to increased energy expenditure in obese mice. Coincident with weight loss, 10,12 CLA also alters the murine gut microbiota by enriching for microbes that produce short chain fatty acids (SCFAs), with concurrent elevations in fecal butyrate and plasma acetate. METHODS: To determine if the observed microbiota changes are required for 10,12 CLA-mediated weight loss, adult male mice with diet-induced obesity were given broad-spectrum antibiotics (ABX) to perturb the microbiota prior to and during 10,12 CLA-mediated weight loss. Conversely, to determine whether gut microbes were sufficient to induce weight loss, conventionally-raised and germ-free mice were transplanted with cecal contents from mice that had undergone weight loss by 10,12 CLA supplementation. RESULTS/CONCLUSION: While body weight was minimally modulated by ABX-mediated perturbation of gut bacterial populations, adult male mice given ABX were more resistant to the increased energy expenditure and fat loss that are induced by 10,12 CLA supplementation. Transplanting cecal contents from donor mice losing weight due to oral 10,12 CLA consumption into conventional or germ-free mice led to improved glucose metabolism with increased butyrate production. These data suggest a critical role for the microbiota in diet-modulated changes in energy balance and glucose metabolism, and distinguish the metabolic effects of orally delivered 10,12 CLA from cecal transplantation of the resulting microbiota.

Momentary Associations Between Physical Activity, Affect, and Purpose in Life.

BACKGROUND: Physical activity is associated with both the hedonic (e.g., affect) and eudaimonic (e.g., purpose in life) aspects of well-being. While there is evidence linking momentary physical activity and affect in daily life, the examination of momentary purpose remains largely unexplored. PURPOSE: This study investigates the bidirectional associations between physical activity, positive and negative affect, and momentary purpose using Ecological Momentary Assessment (EMA) and accelerometer data. METHODS: Middle-aged participants (40-70 years old, n = 291) wore accelerometers and completed three daily EMA surveys on momentary experiences for 8 consecutive days. Physical activity (active time and counts) from 20- to 60-min periods before and after EMA surveys were used in the analyses. Multilevel models were adjusted for temporal and contextual factors, age, sex, education, work status, and race/ethnicity. RESULTS: When participants were more physically active than usual, they reported feeling more purpose-driven and positive affect. Similarly, when participants reported feeling more purpose-driven or experiencing positive affect, they engaged in more physical activity in the subsequent time period. These associations were similar for physical activity from 20- to 60-min periods before and after the EMA survey. Physical activity and negative affect were not related in either direction. CONCLUSIONS: In middle-aged adults' daily lives, physical activity has bidirectional relations with purpose and positive affect. This study highlights the dynamic associations between physical activity and the positive aspects of both hedonic and eudaimonic well-being. Future interventions or public health programs should integrate physical activity and mental well-being to maximize mutual benefits.

This study examined how physical activity relates to feelings of purpose and positive and negative affect in daily life among middle-aged adults (aged 40­70). Participants wore activity trackers and completed surveys on their smartphones about their feelings three times a day for 8 days. The study found that when participants were more physically active than usual, they experienced higher levels of purpose and more positive emotions. Conversely, feeling more purposeful or positive also led to more physical activity later on. The results suggest that physical activity and positive well-being are interconnected and reinforce each other in daily life.

Socioeconomic Indices Are Associated With Increased Resource Utilization, But Not 90-Day Complications Following Total Hip and Knee Arthroplasty.

INTRODUCTION: Socioeconomic disadvantage has been associated with negative outcomes following total hip (THA) and knee arthroplasty (TKA). The Area Deprivation Index (ADI) and Distressed Community Index (DCI) are composite rankings that score socioeconomic status (SES) using patients' home addresses. The purpose of this study was to examine the association of ADI and DCI with outcomes following THA and TKA while controlling for potential confounding covariates. METHODS: A series of 4,146 consecutive patients undergoing primary THA and TKA between January 2018 and May 2023 were queried from our institutional total joint registry. The 90-day medical and surgical complications and resource utilization were collected. The ADI and DCI scores were obtained for each patient, and the association between these scores and postoperative outcomes was analyzed. RESULTS: The ADI and DCI were both associated with patient age, sex, race, comorbidity burden, and smoking status. After controlling for these variables, higher ADI and DCI scores were associated with increased length of stay (P = 0.003 and P = 0.008, respectively), but were not associated with the occurrence of any 90-day complication, reoperation, or revision. CONCLUSION: The SES, as quantified by ADI and DCI, was associated with multiple known risk factors for complications following THA and TKA, but was not independently associated with complications, reoperations, or revision surgeries at 90 days postoperatively. While convenient metrics for the quantification of SES, in some populations, ADI and DCI may not be independently associated with detrimental outcomes following THA and TKA.

The impact of COVID-19 on people with epilepsy: Global results from the coronavirus and epilepsy study.

OBJECTIVE: To characterize the experience of people with epilepsy and aligned healthcare workers (HCWs) during the first 18 months of the COVID-19 pandemic and compare experiences in high-income countries (HICs) with non-HICs. METHODS: Separate surveys for people with epilepsy and HCWs were distributed online in April 2020. Responses were collected to September 2021. Data were collected for COVID-19 infections, the effect of COVID-related restrictions, access to specialist help for epilepsy (people with epilepsy), and the impact of the pandemic on work productivity (HCWs). The frequency of responses for non-HICs and HICs were compared using non-parametric Chi-square tests. RESULTS: Two thousand one hundred and  five individuals with epilepsy from 53 countries and 392 HCWs from 26 countries provided data. The same proportion of people with epilepsy in non-HICs and HICs reported COVID-19 infection (7%). Those in HICs were more likely to report that COVID-19 measures had affected their health (32% vs. 23%; p < 0.001). There was no difference between non-HICs and HICs in the proportion who reported difficulty in obtaining help for epilepsy. HCWs in non-HICs were more likely to report COVID-19 infection than those in HICs (18% vs 6%; p = 0.001) and that their clinical work had been affected by concerns about contracting COVID-19, lack of personal protective equipment, and the impact of the pandemic on mental health (all p < 0.001). Compared to pre-pandemic practices, there was a significant shift to remote consultations in both non-HICs and HICs (p < 0.001). SIGNIFICANCE: While the frequency of COVID-19 infection was relatively low in these data from early in the pandemic, our findings suggest broader health consequences and an increased psychosocial burden, particularly among HCWs in non-HICs. Planning for future pandemics should prioritize mental healthcare alongside ensuring access to essential epilepsy services and expanding and enhancing access to remote consultations. PLAIN LANGUAGE SUMMARY: We asked people with epilepsy about the effects of COVID-19 on their health and healthcare. We wanted to compare responses from people in high-income countries and other countries. We found that people in high-income countries and other countries had similar levels of difficulty in getting help for their epilepsy. People in high-income countries were more likely to say that their general health had been affected. Healthcare workers in non-high-income settings were more likely to have contracted COVID-19 and have the care they deliver affected by the pandemic. Across all settings, COVID-19 associated with a large shift to remote consultations.

Use of bovine-derived collagen matrix in the surgical treatment of empty nose syndrome.

KEY POINTS: Bovine-derived collagen matrix (BDCM) is a safe augmentation material in patients with empty nose syndrome. BDCM augmentation results in clinically and statistically significant improvement in nasal symptoms. Improvements in nasal symptoms with BDCM augmentation may be durable and can be seen up to 2 years postoperative.

Black hole jets on the scale of the cosmic web.

When sustained for megayears (refs. 1,2), high-power jets from supermassive black holes (SMBHs) become the largest galaxy-made structures in the Universe3. By pumping electrons, atomic nuclei and magnetic fields into the intergalactic medium (IGM), these energetic flows affect the distribution of matter and magnetism in the cosmic web4-6 and could have a sweeping cosmological influence if they reached far at early epochs. For the past 50 years, the known size range of black hole jet pairs ended at 4.6-5.0 Mpc (refs. 7-9), or 20-30% of a cosmic void radius in the Local Universe10. An observational lack of longer jets, as well as theoretical results11, thus suggested a growth limit at about 5 Mpc (ref. 12). Here we report observations of a radio structure spanning about 7 Mpc, or roughly 66% of a coeval cosmic void radius, apparently generated by a black hole between 4.4 - 0.7 + 0.2 and 6.3 Gyr after the Big Bang. The structure consists of a northern lobe, a northern jet, a core, a southern jet with an inner hotspot and a southern outer hotspot with a backflow. This system demonstrates that jets can avoid destruction by magnetohydrodynamical instabilities over cosmological distances, even at epochs when the Universe was 7 to 1 5 - 2 + 6 times denser than it is today. How jets can retain such long-lived coherence is unknown at present.

Lexically-specific syntactic restrictions in second-language speakers.

In two structural priming experiments, we investigated the representations of lexically-specific syntactic restrictions of English verbs for highly proficient and immersed second language (L2) speakers of English. We considered the interplay of two possible mechanisms: generalization from the first language (L1) and statistical learning within the L2 (both of abstract structure and of lexically-specific information). In both experiments, L2 speakers with either Germanic or Romance languages as L1 were primed to produce dispreferred double-object structures involving non-alternating dative verbs. Priming occurred from ungrammatical double-object primes involving different non-alternating verbs (Experiment 1) and from grammatical primes involving alternating verbs (Experiment 2), supporting abstract statistical learning within the L2. However, we found no differences between L1-Germanic speakers (who have the double object structure in their L1) and L1-Romance speakers (who do not), inconsistent with the prediction for between-group differences of the L1-generalization account. Additionally, L2 speakers in Experiment 2 showed a lexical boost: There was stronger priming after (dispreferred) non-alternating same-verb double object primes than after (grammatical) alternating different-verb primes. Such lexically-driven persistence was also shown by L1 English speakers (Ivanova et al., 2012a) and may underlie statistical learning of lexically-dependent structural regularities. We conclude that lexically-specific syntactic restrictions in highly proficient and immersed L2 speakers are shaped by statistical learning (both abstract and lexically-specific) within the L2, but not by generalization from the L1.

Examining the causal effects of social exclusion on shame and dissociative detachment.

BACKGROUND AND OBJECTIVES: Dissociative detachment experiences (e.g., derealization, absorption) underpin much psychopathology and are often researched in relation to co-occurring affective states such as shame, the latter being known to occur in situations involving actual or perceived negative social evaluation. The association between shame and dissociative detachment may also be moderated by individual differences in people's need to belong. The goal of the present study was to experimentally investigate the effects of social exclusion on shame and dissociative detachment depending on perceivers' need to belong. METHODS: After measuring individual differences in need to belong and shame proneness, the Cyberball paradigm was utilized to communicate either social inclusion or exclusion. Following Cyberball, a sample of 281 participants completed measures of state shame and state dissociation. RESULTS: Social exclusion increased dissociative detachment, and these effects were mediated by increases in state shame. These effects were particularly evident among people with a high need to belong. LIMITATIONS: Other individual differences such as rejection sensitivity may also moderate the relationship between exclusion and shame. While Cyberball can be used to investigate shame, it can only induce shame via social exclusion, whereas shame can also be elicited in other ways such as performance failure. CONCLUSIONS: Social exclusion can elicit shame, which is most acutely felt by those with a strong need to belong, and this aversive experience appears to be managed by dissociative detachment.

Scalable mesoporous biochars from bagasse waste for Cu (II) removal: Process optimisation, kinetics and techno-economic analysis.

As the world faces the brink of climatological disaster, it is crucial to utilize all available resources to facilitate environmental remediation, especially by accommodating waste streams. Lignocellulosic waste residues can be transformed into mesoporous biochar structures with substantial pore capacity. While biochars are considered a method of carbon dioxide removal (CDR), they are in fact an environmental double-edged sword that can be used to extract metal ions from water bodies. Biochars possess high chemical affinities through chemisorption pathways that are tuneable to specific pH conditions. This work demonstrates how biochars can be enhanced to maximise their surface area and porosity for the removal of Cu (II) in solution. It was found that bagasse derived mesoporous biochars operate preferentially at high pH (basic conditions), with the 1.18 mKOH/mSCB material reaching 97.85% Cu (II) removal in 5 min. This result is in stark contrast with the majority of biochar adsorbents that are only effective at low pH (acidic conditions). As a result, the biochars produced in this work can be directly applied to ancestral landfill sites and carbonate-rich mine waters which are highly basic by nature, preventing further metal infiltration and reverse sullied water supplies. Furthermore, to assess the value in the use of biochars produced and applied in this way, a techno-economic assessment was carried out to determine the true cost of biochar synthesis, with possible routes for revenue post-Cu being removed from the biochar.

Time of day for vaccination, outcomes, and relative effectiveness of high-dose vs. standard-dose quadrivalent influenza vaccine: a post-hoc analysis of the DANFLU-1 randomized clinical trial.

OBJECTIVES: Morning influenza vaccination enhances antibody response. In this posthoc analysis of the DANFLU-1 trial, we sought to evaluate the association between time of day for vaccination (ToV) and outcomes, and whether ToV modified the relative effectiveness of high-dose (QIV-HD) vs. standard-dose (QIV-SD) quadrivalent influenza vaccine. METHODS: DANFLU-1 was a pragmatic feasibility trial of QIV-HD vs. QIV-SD. Outcomes included hospitalizations and mortality. For subgroup analysis, the population was dichotomized at median ToV into two groups (early and late). RESULTS: The study population included 12,477 participants. Mean age was 71.7±3.9 years with 5,877 (47.1%) female participants. Median ToV was 11.29AM. Earlier ToV was associated with fewer respiratory hospitalizations independent of vaccine type, which persisted in adjusted analysis (IRR 0.88 per 1-hour decrement (95% CI 0.78- 0.98, p=0.025). No effect modification by continuous or dichotomous ToV was found. In subgroup analysis, effects consistently favored QIV-HD against hospitalizations for pneumonia or influenza (early: IRR 0.30; late: 0.29), all-cause hospitalizations (early: IRR 0.87; late: 0.86), and mortality (early: HR 0.53; late: 0.50). CONCLUSION: In this exploratory post-hoc analysis, earlier ToV was associated with fewer respiratory hospitalizations. The relative effectiveness of QIV-HD vs. QIV-SD was not modified by ToV. Further research is needed to confirm findings. TRIAL REGISTRATION: Clinicaltrials.gov: NCT05048589.

Extended-period AOSLO imaging in the living human retina without pupil dilation: a feasibility study.

In vivo imaging using an adaptive optics scanning laser ophthalmoscope (AOSLO) is challenging, especially over extended periods. Pharmacological agents, administered as eye drops, are commonly used to dilate the pupil and paralyse accommodation, to improve image quality. However, they are contraindicated in some scenarios. Here, we evaluate the feasibility and reproducibility of performing AOSLO imaging without pharmacological pupil dilation over 1.5 hours with visual stimulation. Through statistical analysis and theoretical modelling using a dataset of retinal and pupil images collected from six healthy, young, near-emmetropic participants between the ages of 20-30 years, we validate that the retinal image quality does not change significantly with time in the experimental session (p = 0.33), and that pupil size has a strong effect on image quality but is not the only contributing factor.

Autophagy unrelated transcriptional mechanisms of hydroxychloroquine resistance revealed by integrated multi-omics of evolved cancer cells.

Hydroxychloroquine (HCQ) and chloroquine are repurposed drugs known to disrupt autophagy, a molecular recycling pathway essential for tumor cell survival, chemotherapeutic resistance, and stemness. We pursued a multi-omic strategy in OVCAR3 ovarian cancer and CCL218 colorectal cancer cells. Two genome-scale screens were performed. In the forward genetic screen, cell populations were passaged for 15 drug pulse-chases with HCQ or vehicle control. Evolved cells were collected and processed for bulk RNA-seq, exome-seq, and single-cell RNA-seq (scRNA-seq). In the reverse genetic screen, a pooled CRISPR-Cas9 library was used in cells over three pulse-chases of HCQ or vehicle control treatments. HCQ evolved cells displayed remarkably few mutational differences, but substantial transcriptional differences. Transcriptomes revealed multiple pathways associated with resistance to HCQ, including upregulation of glycolysis, exocytosis, and chromosome condensation/segregation, or downregulation of translation and apoptosis. The Cas9 screen identified only one autophagy gene. Chromosome condensation and segregation were confirmed to be disrupted by HCQ in live cells and organelle-free in vitro extracts. Transcriptional plasticity was the primary mechanism by which cells evolved resistance to HCQ. Neither autophagy nor the lysosome were substantive hits. Our analysis may serve as a model for how to better position repurposed drugs in oncology.

Mechanisms of transcriptional regulation in Anopheles gambiae revealed by allele-specific expression.

Malaria control relies on insecticides targeting the mosquito vector, but this is increasingly compromised by insecticide resistance, which can be achieved by elevated expression of detoxifying enzymes that metabolize the insecticide. In diploid organisms, gene expression is regulated both in cis, by regulatory sequences on the same chromosome, and by trans acting factors, affecting both alleles equally. Differing levels of transcription can be caused by mutations in cis-regulatory modules (CRM), but few of these have been identified in mosquitoes. We crossed bendiocarb-resistant and susceptible Anopheles gambiae strains to identify cis-regulated genes that might be responsible for the resistant phenotype using RNAseq, and CRM sequences controlling gene expression in insecticide resistance relevant tissues were predicted using machine learning. We found 115 genes showing allele-specific expression (ASE) in hybrids of insecticide susceptible and resistant strains, suggesting cis-regulation is an important mechanism of gene expression regulation in A. gambiae. The genes showing ASE included a higher proportion of Anopheles-specific genes on average younger than genes with balanced allelic expression.

A retrospective propensity-score-matched cohort study of the impact of procalcitonin testing on antibiotic use in hospitalized patients during the first wave of COVID-19.

BACKGROUND: Procalcitonin (PCT) is a blood marker used to help diagnose bacterial infections and guide antibiotic treatment. PCT testing was widely used/adopted during the COVID-19 pandemic in the UK. OBJECTIVES: Primary: to measure the difference in length of early (during first 7 days) antibiotic prescribing between patients with COVID-19 who did/did not have baseline PCT testing during the first wave of the pandemic. Secondary: to measure differences in length of hospital/ICU stay, mortality, total days of antibiotic prescribing and resistant bacterial infections between these groups. METHODS: Multi-centre, retrospective, observational, cohort study using patient-level clinical data from acute hospital Trusts/Health Boards in England/Wales. Inclusion: patients ≥16 years, admitted to participating Trusts/Health Boards and with a confirmed positive COVID-19 test between 1 February 2020 and 30 June 2020. RESULTS: Data from 5960 patients were analysed: 1548 (26.0%) had a baseline PCT test and 4412 (74.0%) did not. Using propensity-score matching, baseline PCT testing was associated with an average reduction in early antibiotic prescribing of 0.43 days [95% confidence interval (CI): 0.22-0.64 days, P < 0.001) and of 0.72 days (95% CI: 0.06-1.38 days, P = 0.03] in total antibiotic prescribing. Baseline PCT testing was not associated with increased mortality or hospital/ICU length of stay or with the rate of antimicrobial-resistant secondary bacterial infections. CONCLUSIONS: Baseline PCT testing appears to have been an effective antimicrobial stewardship tool early in the pandemic: it reduced antibiotic prescribing without evidence of harm. Our study highlights the need for embedded, rapid evaluations of infection diagnostics in the National Health Service so that even in challenging circumstances, introduction into clinical practice is supported by evidence for clinical utility. STUDY REGISTRATION NUMBER: ISRCTN66682918.

Cell swelling enhances ligand-driven ß-adrenergic signaling.

G protein-coupled receptors' conformational landscape can be affected by their local, microscopic interactions within the cell plasma membrane. We employ here a pleiotropic stimulus, namely osmotic swelling, to alter the cortical environment within intact cells and monitor the response in terms of receptor function and downstream signaling. We observe that in osmotically swollen cells the ß2-adrenergic receptor, a prototypical GPCR, favors an active conformation, resulting in cAMP transient responses to adrenergic stimulation that have increased amplitude. The results are validated in primary cell types such as adult cardiomyocytes, a model system where swelling occurs upon ischemia-reperfusion injury. Our results suggest that receptors' function is finely modulated by their biophysical context, and specifically that osmotic swelling acts as a potentiator of downstream signaling, not only for the ß2-adrenergic receptor, but also for other receptors, hinting at a more general regulatory mechanism.

Generating Synthetic Data for Medical Imaging.

Artificial intelligence (AI) models for medical imaging tasks, such as classification or segmentation, require large and diverse datasets of images. However, due to privacy and ethical issues, as well as data sharing infrastructure barriers, these datasets are scarce and difficult to assemble. Synthetic medical imaging data generated by AI from existing data could address this challenge by augmenting and anonymizing real imaging data. In addition, synthetic data enable new applications, including modality translation, contrast synthesis, and professional training for radiologists. However, the use of synthetic data also poses technical and ethical challenges. These challenges include ensuring the realism and diversity of the synthesized images while keeping data unidentifiable, evaluating the performance and generalizability of models trained on synthetic data, and high computational costs. Since existing regulations are not sufficient to guarantee the safe and ethical use of synthetic images, it becomes evident that updated laws and more rigorous oversight are needed. Regulatory bodies, physicians, and AI developers should collaborate to develop, maintain, and continually refine best practices for synthetic data. This review aims to provide an overview of the current knowledge of synthetic data in medical imaging and highlights current key challenges in the field to guide future research and development.

Investigating the association between household exposure to Anopheles stephensi and malaria in Sudan and Ethiopia: A case-control study protocol.

BACKGROUND: Endemic African malaria vectors are poorly adapted to typical urban ecologies. However, Anopheles stephensi, an urban malaria vector formerly confined to South Asia and the Persian Gulf, was recently detected in Africa and may change the epidemiology of malaria across the continent. Little is known about the public health implications of An. stephensi in Africa. This study is designed to assess the relative importance of household exposure to An. stephensi and endemic malaria vectors for malaria risk in urban Sudan and Ethiopia. METHODS: Case-control studies will be conducted in 3 urban settings (2 in Sudan, 1 in Ethiopia) to assess the association between presence of An. stephensi in and around households and malaria. Cases, defined as individuals positive for Plasmodium falciparum and/or P. vivax by microscopy/rapid diagnostic test (RDT), and controls, defined as age-matched individuals negative for P. falciparum and/or P. vivax by microscopy/RDT, will be recruited from public health facilities. Both household surveys and entomological surveillance for adult and immature mosquitoes will be conducted at participant homes within 48 hours of enrolment. Adult and immature mosquitoes will be identified by polymerase chain reaction (PCR). Conditional logistic regression will be used to estimate the association between presence of An. stephensi and malaria status, adjusted for co-occurrence of other malaria vectors and participant gender. CONCLUSIONS: Findings from this study will provide evidence of the relative importance of An. stephensi for malaria burden in urban African settings, shedding light on the need for future intervention planning and policy development.

MYC is sufficient to generate mid-life high-grade serous ovarian and uterine serous carcinomas in a p53-R270H mouse model.

Genetically engineered mouse models (GEMM) have fundamentally changed how ovarian cancer etiology, early detection, and treatment is understood. MYC, an oncogene, is amongst the most amplified genes in high-grade serous ovarian cancer (HGSOC), but it has not previously been utilized to drive HGSOC GEMMs. We coupled Myc and dominant negative mutant p53-R270H with a fallopian tube epithelium-specific promoter Ovgp1 to generate a new GEMM of HGSOC. Female mice developed lethal cancer at an average of 14.5 months. Histopathological examination of mice revealed HGSOC characteristics including nuclear p53 and nuclear MYC in clusters of cells within the fallopian tube epithelium and ovarian surface epithelium. Unexpectedly, nuclear p53 and MYC clustered cell expression was also identified in the uterine luminal epithelium, possibly from intraepithelial metastasis from the fallopian tube epithelium (FTE). Extracted tumor cells exhibited strong loss of heterozygosity at the p53 locus, leaving the mutant allele. Copy number alterations in these cancer cells were prevalent, disrupting a large fraction of genes. Transcriptome profiles most closely matched human HGSOC and serous endometrial cancer. Taken together, these results demonstrate the Myc and Trp53-R270H transgene was able to recapitulate many phenotypic hallmarks of HGSOC through the utilization of strictly human-mimetic genetic hallmarks of HGSOC. This new mouse model enables further exploration of ovarian cancer pathogenesis, particularly in the 50% of HGSOC which lack homology directed repair mutations. Histological and transcriptomic findings are consistent with the hypothesis that uterine serous cancer may originate from the fallopian tube epithelium.