Restrictions of cigarette and e-cigarette flavor and filter ventilation on demand and substitution in the Experimental Tobacco Marketplace.

SIGNIFICANCE: Tobacco product design features, including flavors and cigarette filter ventilation, are subject to regulation. This study examined the effects of cigarette and e-cigarette flavors on demand and substitution by preferred cigarette flavor and ventilation in the Experimental Tobacco Marketplace (ETM). METHODS: In a mixed between-group (usual cigarette flavor and ventilation)/within-subject design (policy conditions), individuals who use tobacco (n=176 cigarette (60.5 % female); n=91 multiple products (26.7 % female)) were recruited using Ipsos and InnovateMR, completed purchasing trials with increasing cigarette prices in the ETM. Participants were exposed to four conditions in a 2×2 factorial design with cigarette flavors restricted or unrestricted and e-cigarette flavors restricted or unrestricted. RESULTS: In individuals who exclusively smoke cigarettes: 1) Cigarette menthol restrictions decreased willingness to purchase cigarettes (OR: 0.001; 95 % CI: 0.00002, 0.015) for individuals that prefer menthol cigarettes and increased willingness to purchase NRT (OR: 4.02; 95 % CI: 1.47, 11.0), 2) cigarette menthol restrictions reduced demand for cigarettes in individuals who smoke menthol cigarettes (p<0.001), 3) e-cigarette flavor restrictions reduced the degree of e-cigarette substitution in individuals who smoke menthol cigarettes (p=0.028), and 4) preference for higher cigarette filter ventilation was associated with higher demand for cigarettes (p=0.003) and lowered substitution of smokeless tobacco products (p=0.028). In individuals who use multiple tobacco products, restrictions did not impact product purchasing. CONCLUSION: Strategies to reduce flavored product sales and increase cessation resource accessibility may improve population health by reducing smoking and increasing NRT use in individuals who use menthol cigarettes.

Discovery of potent SARS-CoV-2 nsp3 macrodomain inhibitors uncovers lack of translation to cellular antiviral response.

A strategy for pandemic preparedness is the development of antivirals against a wide set of viral targets with complementary mechanisms of action. SARS-CoV-2 nsp3-mac1 is a viral macrodomain with ADP-ribosylhydrolase activity, which counteracts host immune response. Targeting the virus' immunomodulatory functionality offers a differentiated strategy to inhibit SARS-CoV-2 compared to approved therapeutics, which target viral replication directly. Here we report a fragment-based lead generation campaign guided by computational approaches. We discover tool compounds which inhibit nsp3-mac1 activity at low nanomolar concentrations, and with responsive structure-activity relationships, high selectivity, and drug-like properties. Using our inhibitors, we show that inhibition of nsp3-mac1 increases ADP-ribosylation, but surprisingly does not translate to demonstrable antiviral activity in cell culture and iPSC-derived pneumocyte models. Further, no synergistic activity is observed in combination with interferon gamma, a main protease inhibitor, nor a papain-like protease inhibitor. Our results question the extent to which targeting modulation of innate immunity-driven ADP-ribosylation can influence SARS-CoV-2 replication. Moreover, these findings suggest that nsp3-mac1 might not be a suitable target for antiviral therapeutics development.

Identifying novel chemical matter against the Chikungunya virus nsP3 macrodomain through crystallographic fragment screening.

Chikungunya virus (CHIKV) causes severe fever, rash and debilitating joint pain that can last for months1,2or even years. Millions of people have been infected with CHIKV, mostly in low and middle-income countries, and the virus continues to spread into new areas due to the geographical expansion of its mosquito hosts. Its genome encodes a macrodomain, which functions as an ADP-ribosyl hydrolase, removing ADPr from viral and host-cell proteins interfering with the innate immune response. Mutational studies have shown that the CHIKV nsP3 macrodomain is necessary for viral replication, making it a potential target for the development of antiviral therapeutics. We, therefore, performed a high-throughput crystallographic fragment screen against the CHIKV nsP3 macrodomain, yielding 109 fragment hits covering the ADPr-binding site and two adjacent subsites that are absent in the homologous macrodomain of SARS-CoV-2 but may be present in other alphaviruses, such as Venezuelan equine encephalitis virus (VEEV) and eastern equine encephalitis virus (EEEV). Finally, a subset of overlapping fragments was used to manually design three fragment merges covering the adenine and oxyanion subsites. The rich dataset of chemical matter and structural information discovered from this fragment screen is publicly available and can be used as a starting point for developing a CHIKV nsP3 macrodomain inhibitor.

Decline in the West Greenland population of a zooplanktivorous seabird, the little auk Alle alle.

The warming of the Arctic had lead to a diverse range of impacts on local biota, including northward shifts of some species range. Here, we report past and present distribution and abundance of an Arctic zooplanktivorous seabird, the little auk Alle alle in West Greenland south of 74° N, and examine the changes in sea surface temperature (SST) and sea ice concentration (SIC) in the birds foraging areas in 1850-2007. We estimated the little auk population in the studied region to be 5,200 pairs in the 1930s, 6,000-6,500 pairs in the 1940-1970s and 70-80 pairs by the 2000s. We found that periods with increased SST and reduced SIC, especially in the last few decades, coincided with little auk population declines. Besides, years with little auk presence in breeding sites were characterized by either low SST and low to moderate SIC or higher SST but moderate to high SIC. Observed contraction of the breeding range and a decrease in abundance of the little auk may be attributed to more complex climate-driven changes in the marine ecosystem at finer spatial and temporal scales and/or cannot be easily detected given the coarseness of data used. It is possible that the population in this region has never been very numerous being subjected to local impacts such as disease, bycatch, predation, etc. The climate warming that is currently being observed, along with corresponding shifts in zooplankton communities, may lead to extirpation of the studied little auk populations.

The more the better? Integration of vertebral pelvic angles (VPA) PJK thresholds to existing alignment schemas for prevention of mechanical complications after adult spinal deformity surgery.

PURPOSE: While existing adult spinal deformity (ASD) alignment schemas acknowledge the dynamic relationship between the pelvis and spine, consideration of vertebral pelvic angles (VPA) thresholds for PJK may provide further insight into the relationship of each individual vertebra to the pelvis, which may allow for greater individualization of operative targets. Herein, we examine VPA's utility in preventing mechanical complications and its possible unification with prevalent scoring systems. METHODS: In a retrospective cohort study of a prospectively collected database, operative ASD patients ≥ 18 years with complete baseline (BL) and two-year (Y) operative, radiographic, and health-related quality of life data were included. Descriptive analyses, means comparison, and logistic regression tests were applied to explore demographic and surgical differences, as well as the impact of alignment goals on outcomes. Cohorts were grouped as patients who met VPA non-PJK thresholds, as defined by Duvvuri et al. 2023 alone versus traditional GAP/SAAS alignment matching versus combined VPA + SAAS + GAP. The Non-PJK VPA validated mean for L1PA was 10.4 ± 7.0 and T9PA 8.9 ± 7.5. RESULTS: 398 patients met inclusion criteria (mean age 61 ± 14 years, 78% female, BL BMI 27 ± 6, BL CCI 2 ± 2). At baseline, mean vertebral pelvic angles were as follows: T1PA: 24 ± 14; T4PA 20 ± 13, T9PA 15 ± 12, L1PA 11 ± 10, L4PA 11 ± 6. Mean vertebral pelvic angles at 6 W postoperatively: T1PA 16 ± 10, T4PA 12 ± 10, T9PA 8 ± 9, L1PA 9 ± 8, L4PA 11 ± 5. 240 (60%) patients attained optimal L1PA, while 104 patients (26.1%) reached non-PJK mean for T9PA. 89 patients (22%) were optimal by both VPA standards. VPA-Optimal group demonstrated significantly lower rates of 1Y PJK (17% v 83%, p = 0.042) and PJF by 2Y (7% v. 93%, p = 0.038). When patients attained VPA goals in addition to GAP/SAAS goals at 6 W, they demonstrated significantly lower rates of Y1 PJK (p = 0.026) and Y1 and Y2 PJF. Those with optimal VPA registered greater SRS-22 scores across multiple domains (p < 0.02) as well as a greater rate of normal neurological examination at 6 W (p = 0.048). CONCLUSIONS: Vertebral pelvic angles are a reliable measure of global alignment, and respecting certain targets may help prevent development of PJK/PJF. The value of VPA can be augmented through integration with GAP/SAAS frameworks to prevent complications and improve quality of life.

Dietary patterns during pregnancy and maternal and birth outcomes in women with type 1 diabetes: the Environmental Determinants of Islet Autoimmunity (ENDIA) study.

AIMS/HYPOTHESIS: Dietary patterns characterised by high intakes of vegetables may lower the risk of pre-eclampsia and premature birth in the general population. The effect of dietary patterns in women with type 1 diabetes, who have an increased risk of complications in pregnancy, is not known. The aim of this study was to investigate the relationship between dietary patterns and physical activity during pregnancy and maternal complications and birth outcomes in women with type 1 diabetes. We also compared dietary patterns in women with and without type 1 diabetes. METHODS: Diet was assessed in the third trimester using a validated food frequency questionnaire in participants followed prospectively in the multi-centre Environmental Determinants of Islet Autoimmunity (ENDIA) study. Dietary patterns were characterised by principal component analysis. The Pregnancy Physical Activity Questionnaire was completed in each trimester. Data for maternal and birth outcomes were collected prospectively. RESULTS: Questionnaires were completed by 973 participants during 1124 pregnancies. Women with type 1 diabetes (n=615 pregnancies with dietary data) were more likely to have a 'fresh food' dietary pattern than women without type 1 diabetes (OR 1.19, 95% CI 1.07, 1.31; p=0.001). In women with type 1 diabetes, an increase equivalent to a change from quartile 1 to 3 in 'fresh food' dietary pattern score was associated with a lower risk of pre-eclampsia (OR 0.37, 95% CI 0.17, 0.78; p=0.01) and premature birth (OR 0.35, 95% CI 0.20, 0.62, p<0.001). These associations were mediated in part by BMI and HbA1c. The 'processed food' dietary pattern was associated with an increased birthweight (ß coefficient 56.8 g, 95% CI 2.8, 110.8; p=0.04). Physical activity did not relate to outcomes. CONCLUSIONS/INTERPRETATION: A dietary pattern higher in fresh foods during pregnancy was associated with sizeable reductions in risk of pre-eclampsia and premature birth in women with type 1 diabetes.

Taxonomy of Tobrilidae species from the Alkaline Lakes of the western Nebraska Sandhills.

Six distinct COI mitochondrial Haplotype Groups (HG) are morphologically, ecologically, and genetically characterized from the aquatic nematode family Tobrilidae. Collection locations included the extreme habitats of the Alkaline Lakes in the western Nebraska Sandhills and the contaminated stream, Johnson Creek, bordering the AltEn 2021 catastrophic pesticide release near the village of Mead in eastern Nebraska. Maximum likelihood and genetic distance metrics supported the genetic integrity of the haplotype groups. Discriminant function analysis of COI haplotype group datasets of combined morphological characters and soil chemistry attributes for both male and female Tobrilidae were classified correctly in all but one case. Scanning electron microscopy revealed new details about amphid apertures, male supplements, and spicules. Partial 18S gene phylogeny suggests that the genus Semitobrilus may not be a member of the subfamily Neotobrilinae, and three specimens in the 226 tobrilid dataset provide evidence of incongruence between COI and 18S derived phylogenies. Given the strong signal provided by the environmental chemistry data, tobrilid mitochondrial haplotypes may well have value as environmental indicators.

Perceived Effects of COVID-19 on Vaccine Hesitancy and Clinician Discussion: A Qualitative Study.

BACKGROUND AND OBJECTIVES: Studies note a high prevalence of pediatric coronavirus disease 2019 (COVID-19)-specific vaccine hesitancy in the United States. Our objective was to assess whether clinicians perceive a spillover effect of COVID-19 vaccine hesitancy onto other vaccines, and the impact of this spillover on their general recommendation behavior. METHODS: We conducted semistructured interviews with pediatricians in California and Colorado pediatric practices (January-March 2023). We transcribed, coded, and analyzed interviews using content analysis. RESULTS: We interviewed 21 pediatricians (10 in California, 11 in Colorado). Clinicians observed some spillover effect of vaccine-favorable changes among some parents and greater hesitancy among others regarding the risks and benefits of childhood vaccination in general. This spillover was informed by 2 divergent patterns of parental trust in health systems and individual clinicians caused by the COVID-19 pandemic. Factors driving perceived changes included media coverage, greater knowledge about vaccination, and misinformation. Some clinicians felt that their approach to vaccine recommendations became more patient-centered, whereas others reported declining engagement in persuading hesitant parents about vaccination. CONCLUSIONS: Clinicians described a hardening of parental views toward vaccines in both directions, which impacted their recommendation behavior. There is a need for vaccine hesitancy monitoring and better training and support for clinicians facing vaccine hesitant parents.

Frequency ratio of the 229mTh nuclear isomeric transition and the 87Sr atomic clock.

Optical atomic clocks1,2 use electronic energy levels to precisely keep track of time. A clock based on nuclear energy levels promises a next-generation platform for precision metrology and fundamental physics studies. Thorium-229 nuclei exhibit a uniquely low-energy nuclear transition within reach of state-of-the-art vacuum ultraviolet (VUV) laser light sources and have, therefore, been proposed for construction of a nuclear clock3,4. However, quantum-state-resolved spectroscopy of the 229mTh isomer to determine the underlying nuclear structure and establish a direct frequency connection with existing atomic clocks has yet to be performed. Here, we use a VUV frequency comb to directly excite the narrow 229Th nuclear clock transition in a solid-state CaF2 host material and determine the absolute transition frequency. We stabilize the fundamental frequency comb to the JILA 87Sr clock2 and coherently upconvert the fundamental to its seventh harmonic in the VUV range by using a femtosecond enhancement cavity. This VUV comb establishes a frequency link between nuclear and electronic energy levels and allows us to directly measure the frequency ratio of the 229Th nuclear clock transition and the 87Sr atomic clock. We also precisely measure the nuclear quadrupole splittings and extract intrinsic properties of the isomer. These results mark the start of nuclear-based solid-state optical clocks and demonstrate the first comparison, to our knowledge, of nuclear and atomic clocks for fundamental physics studies. This work represents a confluence of precision metrology, ultrafast strong-field physics, nuclear physics and fundamental physics.

Nonlinear dynamics of diamagnetically levitating resonators.

The ultimate isolation offered by levitation provides new opportunities for studying fundamental science and realizing ultra-sensitive floating sensors. Among different levitation schemes, diamagnetic levitation is attractive because it allows stable levitation at room temperature without a continuous power supply. While the dynamics of diamagnetically levitating objects in the linear regime are well studied, their nonlinear dynamics have received little attention. Here, we experimentally and theoretically study the nonlinear dynamic response of graphite resonators that levitate in permanent magnetic traps. By large amplitude actuation, we drive the resonators into nonlinear regime and measure their motion using laser Doppler interferometry. Unlike other magnetic levitation systems, here we observe a resonance frequency reduction with amplitude in a diamagnetic levitation system that we attribute to the softening effect of the magnetic force. We then analyze the asymmetric magnetic potential and construct a model that captures the experimental nonlinear dynamic behavior over a wide range of excitation forces. We also investigate the linearity of the damping forces on the levitating resonator, and show that although eddy current damping remains linear over a large range, gas damping opens a route for tuning nonlinear damping forces via the squeeze-film effect. Supplementary Information: The online version contains supplementary material available at 10.1007/s11071-024-10018-x.

Epidemiology of Invasive Candidiasis.

Invasive candidiasis (IC) is an increasingly prevalent, costly, and potentially fatal infection brought on by the opportunistic yeast, Candida. Previously, IC has predominantly been caused by C. albicans which is often drug susceptible. There has been a global trend towards decreasing rates of infection secondary to C. albicans and a rise in non-albicans species with a corresponding increase in drug resistance creating treatment challenges. With advances in management of malignancies, there has also been an increase in the population at risk from IC along with a corresponding increase in incidence of breakthrough IC infections. Additionally, the emergence of C. auris creates many challenges in management and prevention due to drug resistance and the organism's ability to transmit rapidly in the healthcare setting. While the development of novel antifungals is encouraging for future management, understanding the changing epidemiology of IC is a vital step in future management and prevention.

Should pelvic incidence influence realignment strategy? A detailed analysis in adult spinal deformity.

OBJECTIVE: The purpose of this study was to assess how various realignment strategies affect mechanical failure and clinical outcomes in pelvic incidence (PI)-stratified cohorts following adult spinal deformity (ASD) surgery. METHODS: Median and interquartile range statistics were calculated for demographics and surgical details. Further statistical analysis was used to define subsets within PI generating significantly different rates of mechanical failure. These subsets of PI were further analyzed as subcohorts for the outcomes and effects of realignment within each subcohort. Multivariate logistic regression analysis controlling for baseline frailty and lumbar lordosis (LL; L1-S1) analyzed the association of age-adjusted realignment and Global Alignment and Proportion (GAP) strategies with the incidence of mechanical failure and clinical improvement within PI-stratified groups. RESULTS: A parabolic relationship between PI and mechanical failure was noted, whereas patients with either < 51° (n = 174, 39.1% of cohort) or > 63° (n = 114, 25.6% of cohort) of PI generated higher rates of mechanical failure (18.0% and 20.0%, respectively) and lower rates of good outcome (80.3% and 77.6%, respectively) than those with moderate PI (51°-63°). Patients with lower PI more often met good outcome criteria when undercorrected in age-adjusted PI-LL mismatch and sagittal age-adjusted score, and those not meeting good outcome criteria were more likely to deteriorate in GAP relative LL from first to final follow-up (OR 13.4, 95% CI 1.3-139.2). In those with moderate PI, patients were more likely to meet good outcome when aligned on the GAP lordosis distribution index (LDI; OR 1.7, 95% CI 0.9-3.3). Patients with higher PI meeting good outcome were more likely to be overcorrected in sagittal vertical axis (OR 2.4, 95% CI 1.1-5.2) at first follow-up and less likely to be undercorrected in T1 pelvic angle (OR 0.4, 95% CI 0.2-0.9) by final follow-up. When assessing GAP alignment, patients were more likely to meet good outcome when aligned on GAP LDI (OR 3.5, 95% CI 1.4-8.9). CONCLUSIONS: There was a parabolic relationship between PI and both mechanical failure and clinical improvement following deformity correction in this study. Understanding the associations between this fixed parameter and poor outcomes can aid the surgeon in strategical planning when seeking to realign ASD.

The efficiency of detecting seabird behaviour from movement patterns: the effect of sampling frequency on inferring movement metrics in Procellariiformes.

BACKGROUND: Recent technological advances have resulted in low-cost GPS loggers that are small enough to be used on a range of seabirds, producing accurate location estimates (± 5 m) at sampling intervals as low as 1 s. However, tradeoffs between battery life and sampling frequency result in studies using GPS loggers on flying seabirds yielding locational data at a wide range of sampling intervals. Metrics derived from these data are known to be scale-sensitive, but quantification of these errors is rarely available. Very frequent sampling, coupled with limited movement, can result in measurement error, overestimating movement, but a much more pervasive problem results from sampling at long intervals, which grossly underestimates path lengths. METHODS: We use fine-scale (1 Hz) GPS data from a range of albatrosses and petrels to study the effect of sampling interval on metrics derived from the data. The GPS paths were sub-sampled at increasing intervals to show the effect on path length (i.e. ground speed), turning angles, total distance travelled, as well as inferred behavioural states. RESULTS: We show that distances (and per implication ground speeds) are overestimated (4% on average, but up to 20%) at the shortest sampling intervals (1-5 s) and underestimated at longer intervals. The latter bias is greater for more sinuous flights (underestimated by on average 40% when sampling > 1-min intervals) as opposed to straight flight (11%). Although sample sizes were modest, the effect of the bias seemingly varied with species, where species with more sinuous flight modes had larger bias. Sampling intervals also played a large role when inferring behavioural states from path length and turning angles. CONCLUSIONS: Location estimates from low-cost GPS loggers are appropriate to study the large-scale movements of seabirds when using coarse sampling intervals, but actual flight distances are underestimated. When inferring behavioural states from path lengths and turning angles, moderate sampling intervals (10-30 min) may provide more stable models, but the accuracy of the inferred behavioural states will depend on the time period associated with specific behaviours. Sampling rates have to be considered when comparing behaviours derived using varying sampling intervals and the use of bias-informed analyses are encouraged.

Autism likelihood in infants born to mothers with asthma is associated with blood inflammatory gene biomarkers in pregnancy.

Mothers with asthma or atopy have a higher likelihood of having autistic children, with maternal immune activation in pregnancy implicated as a mechanism. This study aimed to determine, in a prospective cohort of mothers with asthma and their infants, whether inflammatory gene expression in pregnancy is associated with likelihood of future autism. Mothers with asthma were recruited to the Breathing for Life Trial. RNA was extracted from blood samples collected at mid-pregnancy. 300 ng total RNA was hybridized with the nCounter Human Inflammation gene expression panel (Nanostring Technologies, 249 inflammation-related genes). Parents completed the First Year Inventory (FYI) at 12-month follow-up, which assessed an infant's likelihood for autism across 2 behavioural domains: social communication and sensory regulation. A total score ≥19.2 indicated increased likelihood for future autism. Inflammatory gene expression was profiled from 24 mothers: four infants scored in the high autism likelihood range; 20 scored in the low autism likelihood range. Six inflammatory genes were differentially expressed and significantly up-regulated in the high autism likelihood group: CYSLTR2, NOX1, C1QA, CXCL10, C8A, IL23R. mRNA count significantly correlated with social communication FYI score for CYSLTR2 (Pearson r = 0.46, p = 0.024) and CXCL10 (r = 0.43, p = 0.036) and with sensory regulation score for ALOX5 (r = -0.43, p = 0.038) and MAFK (r = -0.46, p = 0.022). In this proof-of-concept study, inflammatory gene expression during pregnancy in mothers with asthma was associated with an infant's likelihood of future autism as well as scores relating to social communication and sensory regulation.

Prostaglandins in the Inflamed Central Nervous System: Potential Therapeutic Targets.

The global burden of neurological disorders is evident, yet there remains limited efficacious therapeutics for their treatment. There is a growing recognition of the role of inflammation in diseases of the central nervous system (CNS); among the numerous inflammatory mediators involved, prostaglandins play a crucial role. Prostaglandins are small lipid mediators derived from arachidonic acid via multi-enzymatic pathways. The actions of prostaglandins are varied, with each prostaglandin having a specific role in maintaining homeostasis. In the CNS, prostaglandins can have neuroprotective or neurotoxic properties depending on their specific G-protein receptor. These G-protein receptors have varying subfamilies, tissue distribution, and signal transduction cascades. Further studies into the impact of prostaglandins in CNS-based diseases may contribute to the clarification of their actions, hopefully leading to the development of efficacious therapeutic strategies. This review focuses on the roles played by prostaglandins in neural degeneration, with a focus on Alzheimer's Disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis in both preclinical and clinical settings. We further discuss current prostaglandin-related agonists and antagonists concerning suggestions for their use as future therapeutics.

Performance evaluation of a combination Plasmodium dual-antigen CRP rapid diagnostic test in Lambaréné, Gabon.

PURPOSE: The consequent use of malaria rapid diagnostic tests (RDTs) preceding a treatment decision has improved the global management of malaria. A combination RDT, including an inflammation marker to potentially guide antibiotic prescription, could improve the management of acute febrile illness (AFI). METHODS: We performed a prospective, cross-sectional study in Gabon evaluating the STANDARD Malaria/CRP DUO (S-DUO) RDT. Participants aged 2 to 17 years with fever at presentation and/or a history of fever < 7 days were enrolled. Expert microscopy, SD Bioline Malaria Ag P.f/Pan test for malaria detection, and NycoCard CRP device for CRP were used as comparators. AFI cases were classified on a spectrum encompassing bacterial vs. non-bacterial infection. RESULTS: 415 participants with AFI were enrolled. S-DUO RDT sensitivity and specificity for malaria detection vs. microscopy were 99·1% (95·2-100%) and 72·7% (64·3-80·1%); and for CRP detection (20 mg/L and above) 86·9% (80-92%) and 87% (79·2-92·7%), respectively. The difference in CRP levels between bacterial infection (mean = 41·2 mg/L) and other causes of fever, measured from our study population using the Nycocard device, was statistically significant (p < 0·01); CRP precision-recall AUC to distinguish bacterial infection class vs. non-bacterial classifications was 0·79. CONCLUSION: S-DUO RDT is suitable for malaria detection in moderate-to-high malaria transmission settings such as in Lambaréné; however, a CRP band detection limit > 40 mg/L is more adequate for indication of antibiotic prescription for AFI cases in Gabon.

Micro blood analysis technology (µBAT): multiplexed analysis of neutrophil phenotype and function from microliter whole blood samples.

There is an ongoing need to do more with less and provide highly multiplexed analysis from limited sample volumes. Improved "sample sparing" assays would have a broad impact across pediatric and other rare sample type studies in addition to enabling sequential sampling. This capability would advance both clinical and basic research applications. Here we report the micro blood analysis technology (µBAT), a microfluidic platform that supports multiplexed analysis of neutrophils from a single drop of blood. We demonstrate the multiplexed orthogonal capabilities of µBAT including functional assays (phagocytosis, neutrophil extracellular traps, optical metabolic imaging) and molecular assays (gene expression, cytokine secretion). Importantly we validate our microscale platform using a macroscale benchmark assay. µBAT is compatible with lancet puncture or microdraw devices, and its design facilitates rapid operations without the need for specialized equipment. µBAT offers a new method for investigating neutrophil function in populations with restricted sample amounts.

Impact of TP53 mutations on brain metastasis control in non-small cell lung cancer patients undergoing stereotactic radiosurgery.

Purpose: To investigate whether TP53 variants may be correlated with overall survival and local control following stereotactic radiosurgery (SRS) for brain metastases (BMs) from non-small cell lung cancer (NSCLC). Methods: Patients undergoing an initial course of SRS for NSCLC brain metastases between 1/2015 and 12/2020 were retrospectively identified. Overall survival and freedom from local intracranial progression (FFLIP) were estimated via Kaplan-Meier method. Cox models assessed TP53 variant status (pathogenic variant, PV; variant not detected, ND). Results: 255 patients underwent molecular profiling for TP53, among whom 144 (56%) had a TP53 PV. Median follow-up was 11.6 months. OS was not significantly different across TP53 status. A trend toward superior FFLIP was observed for PV (95% CI 62.9 months-NR) versus ND patients (95% CI 29.4 months-NR; p=0.06). Superior FFLIP was observed for patients with one TP53 variant versus those with TP53 ND. Conclusion: Among NSCLC patients with BMs, the potential association between TP53 status and post-SRS FFLIP warrants further investigation in a larger prospective cohort.