When You Get to the Fork in the Road, Take It: The Challenges in Managing Patients With Advanced Prostate Cancer.

As is the case with most solid tumors, the heterogeneity of the disease biology of prostate cancer presents clinicians managing this disease with daily challenges. However, in contrast to other common cancers such as breast, lung, and colorectal cancers, there are unique challenges in prostate cancer management, including the variety of clinicians who manage aspects of the disease (urologists, medical oncologist, radiation oncologists) and the striking absence of prospective comparative data to inform the optimal sequence of systemic therapy in patients with metastatic castration-resistant disease. The purpose of this review is to attempt to assist practicing oncologists with sorting through the myriad of prostate cancer disease subsets and the challenges in making therapeutic decisions in multiple data-free zones given the absence of level 1 comparative clinical trials in the metastatic hormone-sensitive and castration-resistant states.

Periodic diffraction from an aperiodic monohedral tiling - the Spectre tiling. Addendum.

This article describes the diffraction pattern (2-periodic Fourier transform) from the vertices of a large patch of the recently discovered `Spectre' tiling - a strictly chiral aperiodic monotile. It was reported recently that the diffraction pattern of the related weakly chiral aperiodic `Hat' monotile was 2-periodic with chiral plane-group symmetry p6 [Kaplan et al. (2024). Acta Cryst. A80, 72-78]. The diffraction periodicity arises because the Hat tiling is a systematic aperiodic deletion of vertices from the 2-periodic hexagonal mta tiling. Despite the similarity of the Hat and Spectre tilings, the Spectre tiling is not aligned with a 2-periodic lattice, and its diffraction pattern is non-periodic with chiral point symmetry 6 about the origin.

Extreme Anomalous Conductance Enhancement in Neutral Diradical Acene-like Molecular Junctions.

We achieve, at room temperature, conductance enhancements over 2 orders of magnitude in single molecule circuits formed with polycyclic benzoquinoidal (BQn) diradicals upon increasing molecular length by ∼5 Å. We find that this extreme and atypical anti-ohmic conductance enhancement at longer molecular lengths is due to the diradical character of the molecules, which can be described as a topologically nontrivial electronic state, and results in constructive interference between the frontier molecular orbitals. The distinct feature of the compounds studied here as molecular wires is that they are characterized by moderate diradical character in the neutral state, allowing for robust and facile measurements of their transport properties. We adapt the 1D-SSH model, originally developed to examine electronic topological order in linear carbon chains, to the polycyclic systems studied here and find that it captures the anti-ohmic trends in this molecular series. Specifically, our model reveals that the mechanism of conductance enhancement with length in polycyclic systems is constructive quantum interference between the frontier orbitals with nontrivial topology, which is present in acene-like, but not in linear, molecular systems. Importantly, we use our model to predict and experimentally validate that anti-ohmic trends can be engineered through synthetic adjustments of the diradical character of the acene-like molecules. Overall, we achieve extreme anti-ohmic enhancement and mechanistic insight into electronic transport in a class of materials that we identify here as promising candidates for creating highly conductive and tunable nanoscale wires.

Concentrations and predictors of select nutrients in Canadian human milk samples from the MIREC pregnancy cohort.

BACKGROUND: Human milk (HM) composition data are widely used in clinical, regulatory, and public health initiatives. The existing HM profiles in U.S. and Canadian nutrient databanks are outdated and now considered inappropriate to estimate current nutrient intakes. Recent reviews have underscored the limited North American data available to generate a new profile. OBJECTIVE: To describe concentrations and sources of variability of nutrients in HM from a large cohort collected in Canada. METHODS: The Maternal-Infant Research on Environmental Chemicals (MIREC) study recruited participants in the first trimester of pregnancy from 10 Canadian cities between 2008-2011. HM samples (n=559-835, depending on nutrient) were collected 3-10 weeks post-partum and analyzed for minerals (calcium, magnesium, phosphorus, potassium, sodium, manganese, molybdenum, zinc, copper, iodine, selenium), vitamin D (vitamin D3, 25-(OH)D3), folate vitamers (folic acid, 5-methyltetrahydrofolate, total folates), and fatty acids (panel). We examined associations between participant characteristics and log-transformed nutrient concentrations using linear regression. RESULTS: Concentrations of HM components in MIREC samples were within the range observed in literature except for manganese, which was >100 fold lower than the value in the existing Canadian nutrient databank profile (2.43 [SD 2.84] compared to 260 ng/g). In multivariable models, concentrations of folate vitamers, vitamin D and fatty acids demonstrated greater variability with maternal and sample characteristics than minerals. Factors such as relevant supplement use, body mass index (BMI), and for vitamin D, skin color and season, had a larger impact on nutrient concentrations than characteristics typically standardized in HM research, such as maternal or infant health, and method of collection. CONCLUSION: HM mineral concentrations from this study meet the methodological inclusion criteria for updating nutrient databank values and dietary reference intakes. Consideration of factors such as diet, skin colour, and BMI will be important for selecting studies for developing representative reference values based on human milk.

Differences between women and men in prolonged weaning.

BACKGROUND: In recent years, the importance of sex as a factor influencing medical care has received increasing attention in the field of intensive care medicine. The objective of this study was to examine the influence of sex in prolonged weaning. METHODS: A retrospective analysis of patients undergoing prolonged weaning at Thoraxklinik, University Hospital Heidelberg between 12/08 and 12/23 was conducted. Patients with neuromuscular diseases were excluded from the analyses. The risk factors for weaning failure in men and women were identified through stepwise cox-regression analyses. RESULTS: A total of 785 patients were included, of whom 313 (39.9%) were women. 77.9% of the women and 75.4% of the men were successfully weaned from invasive ventilation. In group comparisons and multivariable analyses, sex was not found to be a risk factor for weaning failure. Cox regression analyses were performed separately for both sexes on the outcome of weaning failure, adjusting for relevant covariates. The results indicated that age ≥ 65 years (HR 2.38, p < 0.001) and the duration of IMV before transfer to the weaning centre (HR 1.01/day, p < 0.001) were independent risk factors in men. In women, however, the duration of IMV before transfer (HR 1.01, p < 0.001), previous non-invasive ventilation (HR 2.9, p 0.005), the presence of critical illness polyneuropathy (HR 1.82; p = 0.040) and delirium (HR 2.50, p = 0.017) were identified as relevant risk factors. In contrast delirium was associated with a favourable weaning outcome in men (HR 0.38, p = 0.020) and nosocomial pneumonia as a reason for prolonged weaning in women (HR 0.43; p = 0.032). CONCLUSION: The analyses indicate that there are sex-based differences in the risk factors associated with weaning failure. Further studies, ideally prospective, should confirm these findings to assess whether sex is a factor that should be taken into account to improve weaning outcomes.

Inhibition of Acinetobacter nosocomialis twitching motility by quinolones produced by Pseudomonas aeruginosa.

Twitching motility in A. nosocomialis is a key virulence factor linked to antibiotic resistance and pathogenicity. This study revealed that the Pseudomonas quinolone signal (PQS) and hydroxy-containing quinolones significantly inhibit motility without affecting bacterial growth, highlighting their potential as targets for controlling bacterial virulence.

Exploring "dark-matter" protein folds using deep learning.

De novo protein design explores uncharted sequence and structure space to generate novel proteins not sampled by evolution. A main challenge in de novo design involves crafting "designable" structural templates to guide the sequence searches toward adopting target structures. We present a convolutional variational autoencoder that learns patterns of protein structure, dubbed Genesis. We coupled Genesis with trRosetta to design sequences for a set of protein folds and found that Genesis is capable of reconstructing native-like distance and angle distributions for five native folds and three novel, the so-called "dark-matter" folds as a demonstration of generalizability. We used a high-throughput assay to characterize the stability of the designs through protease resistance, obtaining encouraging success rates for folded proteins. Genesis enables exploration of the protein fold space within minutes, unrestricted by protein topologies. Our approach addresses the backbone designability problem, showing that small neural networks can efficiently learn structural patterns in proteins. A record of this paper's transparent peer review process is included in the supplemental information.

LINE1 and PRC2 control nucleolar organization and repression of the 8C state in human ESCs.

The mechanisms that ensure developmental progression in the early human embryo remain largely unknown. Here, we show that the family of long interspersed nuclear element 1 (LINE1) transposons prevents the reversion of naive human embryonic stem cells (hESCs) to 8-cell-like cells (8CLCs). LINE1 RNA contributes to maintenance of H3K27me3 levels, particularly at chromosome 19 (Chr19). Chr19 is enriched for key 8C regulators, H3K27me3, and genes derepressed upon LINE1 knockdown or PRC2 inhibition. Moreover, Chr19 is strongly associated with the nucleolus in hESCs but less in 8CLCs. Direct inhibition of PRC2 activity induces the 8C program and leads to a relocalization of Chr19 away from the nucleolus. LINE1 KD or PRC2 inhibition induces nucleolar stress, and disruption of nucleolar architecture is sufficient to de-repress the 8C program. These results indicate that LINE1 RNA and PRC2 maintain H3K27me3-mediated gene repression and 3D nuclear organization to prevent developmental reversion of hESCs.

Identification of DLK1, a Notch ligand, as an immunotherapeutic target and regulator of tumor cell plasticity and chemoresistance in adrenocortical carcinoma.

Immunotherapeutic targeting of cell surface proteins is an increasingly effective cancer therapy. However, given the limited number of current targets, the identification of new surface proteins, particularly those with biological importance, is critical. Here, we uncover delta-like non-canonical Notch ligand 1 (DLK1) as a cell surface protein with limited normal tissue expression and high expression in multiple refractory adult metastatic cancers including small cell lung cancer (SCLC) and adrenocortical carcinoma (ACC), a rare cancer with few effective therapies. In ACC, ADCT-701, a DLK1 targeting antibody-drug conjugate (ADC), shows potent in vitro activity among established cell lines and a new cohort of patient-derived organoids as well as robust in vivo anti-tumor responses in cell line-derived and patient-derived xenografts. However, ADCT-701 efficacy is overall limited in ACC due to high expression and activity of the drug efflux protein ABCB1 (MDR1, P-glycoprotein). In contrast, ADCT-701 is extremely potent and induces complete responses in DLK1 + ACC and SCLC in vivo models with low or no ABCB1 expression. Genetic deletion of DLK1 in ACC dramatically downregulates ABCB1 and increases ADC payload and chemotherapy sensitivity through NOTCH1-mediated adrenocortical de-differentiation. Single cell RNA-seq of ACC metastatic tumors reveals significantly decreased adrenocortical differentiation in DLK low or negative cells compared to DLK1 positive cells. This works identifies DLK1 as a novel immunotherapeutic target that regulates tumor cell plasticity and chemoresistance in ACC. Our data support targeting DLK1 with an ADC in ACC and neuroendocrine neoplasms in an active first-in-human phase I clinical trial ( NCT06041516 ).

The International Climate Psychology Collaboration: Climate change-related data collected from 63 countries.

Climate change is currently one of humanity's greatest threats. To help scholars understand the psychology of climate change, we conducted an online quasi-experimental survey on 59,508 participants from 63 countries (collected between July 2022 and July 2023). In a between-subjects design, we tested 11 interventions designed to promote climate change mitigation across four outcomes: climate change belief, support for climate policies, willingness to share information on social media, and performance on an effortful pro-environmental behavioural task. Participants also reported their demographic information (e.g., age, gender) and several other independent variables (e.g., political orientation, perceptions about the scientific consensus). In the no-intervention control group, we also measured important additional variables, such as environmentalist identity and trust in climate science. We report the collaboration procedure, study design, raw and cleaned data, all survey materials, relevant analysis scripts, and data visualisations. This dataset can be used to further the understanding of psychological, demographic, and national-level factors related to individual-level climate action and how these differ across countries.

Exploring the Reactivity of Electrophilic Organic Carbonates and Thiocarbonates as Vehicles to Convert Hydrosulfide into COS and CS2.

Hydrogen sulfide (H2S) and other reactive sulfur species are important small molecules with biological significance. In addition to common reactive sulfur species like H2S, polysulfides, and persulfides, both carbonyl sulfide (COS) and carbon disulfide (CS2) have been postulated to be potential sources of reduced sulfur. To better understand this possible connection, we demonstrate that H2S can be converted to COS and CS2 by reaction with simple organic carbonate and thiocarbonate electrophiles, respectively.

The distinct roles of NEIL1 and XPA in limiting aflatoxin B1-induced mutagenesis in mice.

Dietary exposure to aflatoxin B1 (AFB1) is a risk factor for the development of hepatocellular carcinomas (HCCs). Following metabolic activation, AFB1 reacts with guanines to form covalent DNA adducts, which induce high-frequency G > T transversions. The molecular signature associated with these mutational events aligns with the single base substitution signature 24 (SBS24) in the Catalog of Somatic Mutations in Cancer (COSMIC) database. Deficiencies in either base excision repair (BER) due to the absence of Nei-like DNA glycosylase 1 (NEIL1) or nucleotide excision repair (NER) due to the absence of xeroderma complementation group A protein (XPA) contribute to HCCs in murine models. In the current study, ultra-low error duplex sequencing was used to characterize mutational profiles in liver DNAs of NEIL1-deficient, XPA-deficient, and DNA repair-proficient mice following neonatal injection of 1 mg/kg AFB1. Analyses of AFB1-induced mutations showed high cosine similarity to SBS24, regardless of repair proficiency status. The absence of NEIL1 resulted in an approximately 30% increase in the frequency of mutations, with distribution suggesting preferential NEIL1-dependent repair of AFB1 lesions in open chromatin regions. A trend of increased mutagenesis was also observed in the absence of XPA. Consistent with the role of XPA in transcription-coupled repair, mutational profiles in XPA-deficient mice showed disruption of the transcriptional bias in mutations associated with SBS24. Implications: Our findings define the roles of DNA repair pathways in AFB1-induced mutagenesis and carcinogenesis in murine models, with these findings having implications in human health for those with BER and NER deficiencies.

Excitonic Bose Polarons in Electron-Hole Bilayers.

Bose polarons are mobile particles of one kind dressed by excitations of the surrounding degenerate Bose gas of particles of another kind. These many-body objects have been realized in ultracold atomic gases and become a subject of intensive studies. In this work, we show that excitons in electron-hole bilayers offer new opportunities for exploring polarons in strongly interacting, highly tunable bosonic systems. We found that Bose polarons are formed by spatially direct excitons immersed in degenerate Bose gases of spatially indirect excitons (IXs). We detected both attractive and repulsive Bose polarons by measuring photoluminescence excitation spectra. We controlled the density of IX Bose gas by optical excitation and observed an enhancement of the energy splitting between attractive and repulsive Bose polarons with increasing IX density, in agreement with our theoretical calculations.

Deciphering the role of endothelial granulocyte macrophage-CSF in chronic inflammation associated with HIV.

People with HIV (PWH) experience endothelial dysfunction (ED) that is aggravated by chronic inflammation and microbial translocation across a damaged gut barrier. Although this paradigm is well-described, downstream pathways that terminate in endothelial dysfunction are only partially understood. This study found increased expression of granulocyte macrophage colony stimulating factor (GM-CSF), toll-like receptor-4 (TLR4), and myeloperoxidase in the aortic endothelium of PWH compared to those without HIV. Bacteria-derived lipopolysaccharide (LPS) heightened glucose uptake and induced GM-CSF expression in primary human endothelial cells. Exposure to sodium-glucose cotransporter-2 (SGLT2) inhibitors reduced glucose uptake, GM-CSF release, and ED in LPS-activated endothelial cells ex vivo, and PWH treated with SGLT2 inhibitors for diabetes had significantly lower plasma GM-CSF levels than non-diabetic PWH not on this medication. The findings suggest that microbial products trigger glucose uptake and GM-CSF expression in the endothelium, contributing to localized inflammation in PWH. Modifying this altered state could offer therapeutic benefits.

A Texting- and Internet-Based Self-Reporting System for Enhanced Vaccine Safety Surveillance With Insights From a Large Integrated Health Care System in the United States: Prospective Cohort Study.

BACKGROUND: SMS text messaging- and internet-based self-reporting systems can supplement existing vaccine safety surveillance systems, but real-world participation patterns have not been assessed at scale. OBJECTIVE: This study aimed to describe the participation rates of a new SMS text messaging- and internet-based self-reporting system called the Kaiser Permanente Side Effect Monitor (KPSEM) within a large integrated health care system. METHODS: We conducted a prospective cohort study of Kaiser Permanente Southern California (KPSC) patients receiving a COVID-19 vaccination from April 23, 2021, to July 31, 2023. Patients received invitations through flyers, SMS text messages, emails, or patient health care portals. After consenting, patients received regular surveys to assess adverse events up to 5 weeks after each dose. Linkage with medical records provided demographic and clinical data. In this study, we describe KPSEM participation rates, defined as providing consent and completing at least 1 survey within 35 days of COVID-19 vaccination. RESULTS: Approximately, 8% (164,636/2,091,975) of all vaccinated patients provided consent and completed at least 1 survey within 35 days. The lowest participation rates were observed for parents of children aged 12-17 years (1349/152,928, 0.9% participation rate), and the highest participation was observed among older adults aged 61-70 years (39,844/329,487, 12.1%). Persons of non-Hispanic White race were more likely to participate compared with other races and ethnicities (13.1% vs 3.9%-7.5%, respectively; P<.001). In addition, patients residing in areas with a higher neighborhood deprivation index were less likely to participate (5.1%, 16,503/323,122 vs 10.8%, 38,084/352,939 in the highest vs lowest deprivation quintiles, respectively; P<.001). Invitations through the individual's Kaiser Permanente health care portal account and by SMS text message were associated with the highest participation rate (19.2%, 70,248/366,377 and 10.5%, 96,169/914,793, respectively), followed by email (19,464/396,912, 4.9%) and then QR codes on flyers (25,882/2,091,975, 1.2%). SMS text messaging-based surveys demonstrated the highest sustained daily response rates compared with internet-based surveys. CONCLUSIONS: This real-world prospective study demonstrated that a novel digital vaccine safety self-reporting system implemented through an integrated health care system can achieve high participation rates. Linkage with participants' electronic health records is another unique benefit of this surveillance system. We also identified lower participation among selected vulnerable populations, which may have implications when interpreting data collected from similar digital systems.

Epidemiological comparison of emergency department presentations with seasonal influenza or COVID-19 and an outcome of intensive care admission or death: A population-based records linkage study in New South Wales, Australia.

BACKGROUND: COVID-19 and seasonal influenza are endemic causes of morbidity and mortality. This study aimed to compare the epidemiology of severe illness and risk of death among patients following emergency department (ED) presentation with either infection. METHODS: De-identified, population-based, emergency department records in New South Wales, Australia, were probabilistically linked to population-level health outcome databases for the period 1 January 2015 to 28 February 2023. Included were patients allocated an ED diagnosis consistent with an acute respiratory infection. Logistic regression was used to examine the association of infecting virus with risk of a severe outcome (intensive care unit admission or death). RESULTS: Influenza infection was notified in 2335 and COVID-19 in 5053 patients with a severe outcome. The age distribution was similar for both viruses, except in <15-year-olds, where severe influenza was nearly three times more frequent. Overall, the odds of death among patients with COVID-19 was 1.65 (95% CI 1.43, 1.89) times higher than among those with influenza. This declined to 1.49 (95% CI 1.08, 2.06) times during the COVID-19 Omicron variant period. CONCLUSIONS: The Omicron variant arrived when background population COVID-19 vaccination coverage was >90%. Despite that, death was more frequent for COVID-19 than influenza.

Perioperative Glycemic Variability Influences Infection Rates Differently Following Revision Hip and Knee Arthroplasty.

INTRODUCTION: Recent investigations have determined that abnormal postoperative glycemia following primary total joint arthroplasty is associated with adverse events. Our study aimed to determine if hyperglycemia and glycemic variability following aseptic revision total joint arthroplasty (rTJA) were associated with periprosthetic joint infection (PJI) within two years postoperatively. METHODS: A retrospective review was performed of 2,208 patients within a single institution undergoing aseptic rTJA from 2012 to 2019. Postoperative glucose values were recorded. Glycemic variability was measured via three parameters: coefficient of variation (%CV), mean amplitude of glycemic excursions (MAGE), and J-index. Logistic regression analyses were performed to examine associations with PJI at 90-day, 1-, and 2-year follow-up. RESULTS: In revision hips, all glycemic measures were not associated with PJI at any timepoint in logistic regression analyses, except for MAGE, which predicted PJI at one year (P = 0.045); body mass index (BMI) was the only factor associated with PJI at all timepoints in all models. In revision knees, all glycemic measures were not associated with PJI at any timepoint in logistic regression analyses; however, PJI rates differed between diabetics and non-diabetics at all time-points (P < 0.05). CONCLUSIONS: Our findings illustrate that decreasing preoperative BMI and postoperative glycemic variability may be critical in reducing PJI rates in revision hips. Furthermore, patients who have diabetes should be counseled that they remain at higher risk of PJI regardless of perioperative glucose control after revision knee surgery.