CYP1B1-RMDN2 Alzheimer's disease endophenotype locus identified for cerebral tau PET.

Determining the genetic architecture of Alzheimer's disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD.

Structural Transformations of Metal-Organic Cages through Tetrazine-Alkene Reactivity.

The assembly of metal-organic cages is governed by metal ion coordination preferences and the geometries of the typically rigid and planar precursor ligands. PdnL2n cages are among the most structurally diverse, with subtle differences in the metal-ligand coordination vectors resulting in drastically different assemblies, however almost all rely on rigid aromatic linkers to avoid the formation of intractable mixtures. Here we exploit the inverse electron-demand Diels-Alder (IEDDA) reaction between tetrazine linker groups and alkene reagents to trigger structural changes induced by post-assembly modification. The structure of the 1,4-dihydropyridazine produced by IEDDA (often an afterthought in click chemistry) is crucial; its two sp3 centers increase flexibility and nonplanarity, drastically changing the range of accessible coordination vectors. This triggers an initial Pd4L8 tetrahedral cage to transform into different Pd2L4 lantern cages, with both the transformation extent (thermodynamics) and rate (kinetics) dependent on the alkene dienophile selected. With cyclopentene, the unsymmetrical 1,4-dihydropyridazine ligands undergo integrative sorting in the solid state, with both head-to-tail orientation and enantiomer selection, leading to a single isomer from the 39 possible. This preference is rationalized through entropy, symmetry, and hydrogen bonding. Subsequent oxidation of the 1,4-dihydropyridazine to the aromatic pyridazine rigidifies the ligands, restoring planarity. The oxidized ligands no longer fit in the lantern structure, inducing further structural transformations into Pd4L8 tetrahedra and Pd3L6 double-walled triangles. The concept of controllable addition of limited additional flexibility and then its removal through well-defined reactivity we envisage being of great interest for structural transformations of any class of supramolecular architecture.

Phenotypic traits related to methane emissions from Holstein dairy cows challenged by low or high forage proportion.

Limited literature is available identifying phenotypical traits related to enteric methane (CH4) production from dairy cows, despite its relevance in relation to breeding for animals with a low CH4 yield (g/kg DMI), and the derived consequences hereof. This study aimed to investigate the relationships between CH4 yield and different animal phenotypes when 16 2nd parity dairy cows, fitted with a ruminal cannula, were fed 2 diets differing in forage:concentrate ratio in a crossover design. The diets had either a low forage proportion (35% on DM basis, F35) or a high forage proportion (63% on DM basis, F63). Gas exchange was measured by means of indirect calorimetry. Spot samples of feces were collected, and indigestible NDF (INDF) was used as an internal marker to determine total-tract digestibility. In addition, ruminal evacuations, monitoring of chewing activity, determination of ruminal VFA concentration, analysis of relative abundance of methanogens, and measurement of liquid passage rate were performed. Statistical differences were analyzed by a linear mixed model with diet, days in milk, and period as fixed effects, and cow as random effect. The random cow estimates (RCE) were extracted from the model to get the Pearson correlations (r) between RCE of CH4 yield with RCE of all other variables measured, to identify possible phenotypes related to CH4 yield. Significant correlations were observed between RCE of CH4 yield and RCE of OM digestibility (r = 0.63) and ruminal concentration of valeric acid (r = -0.61), acetic acid (r = 0.54), ammonium (r = 0.55), and lactic acid (r = ‒0.53). Additionally, tendencies were observed for correlations between RCE of CH4 yield and RCE of H2 yield in g/kg DM (r = 0.47, P = 0.07), and ruminal isobutyric acid concentration (r = 0.43, P = 0.09). No correlations were observed between RCE of CH4 yield and RCE of ruminal pool sizes, milk data, urinary measurements, or chewing activity. Cows had a lower DMI and ECM, when they were fed F63 compared with F35. Cows fed F63 had higher NDF digestibility, CH4 emissions (g/d, g/kg of DMI, and g/kg of ECM), ruminal concentration of acetic acid, ruminal pH, degradation rate of digestible NDF (DNDF, %/h), and longer rumen retention time (h). Also, rumination and total chewing time (min/kg DMI) were higher for cows fed F63. The results in the present study emphasize the positive relation between cow's ability to digest OM and their CH4 emissions. The derived consequences of breeding for lower CH4 emission might be cows with lower ability to digest OM, but more studies are warranted for further documentation of this relationship.

Nonconjugated Polyurethane Derivatives with Aggregation-Induced Luminochromism for Multicolor and White Photoluminescent Films.

A simple and effective strategy to obtain solid-state multicolor emitting materials is a particularly attractive topic. Nonconventional/nonconjugated polymers are receiving widespread attention because of their advantages of rich structural diversity, low cost, and good processability. However, it is difficult to control the molecular conformation or to obtain the crystal structure of amorphous molecules, which means it is a challenge to obtain nontraditional polymeric materials with multicolor emission. In this work, a polyurethane derivative (PUH) with red-shifted emission was synthesized by a simple one-pot polymerization reaction. By exploiting the aggregation-induced luminochromism of PUH, a series of plastic films with tunable emission from blue to orange, and white-light emission, was obtained by doping different amounts of PUH into poly(methyl methacrylate) (PMMA), thereby changing the aggregation degree of PUH. This work demonstrates the excellent promise of polyurethane derivatives for the simple fabrication of large-scale flexible luminescent films.

An Automated Purification Workflow Coupled with Material-Sparing High-Throughput 1H NMR for Parallel Medicinal Chemistry.

In medicinal chemistry, purification and characterization of organic compounds is an ever-growing challenge, with an increasing number of compounds being synthesized at a decreased scale of preparation. In response to this trend, we developed a parallel medicinal chemistry (PMC)-tailored platform, coupling automated purification to mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR) on a range of synthetic scales (∼3.0-75.0 µmol). Here, the generation and acquisition of 1.7 mm NMR samples is fully integrated into a high-throughput automated workflow, processing 36 000 compounds yearly. Utilizing dead volume, which is inaccessible in conventional liquid handling, NMR samples are generated on as little as 10 µg without consuming material prioritized for biological assays. As miniaturized PMC synthesis becomes the industry standard, we can now obtain quality NMR spectra from limited material. Paired with automated structure verification, this platform has the potential to allow NMR to become as important for high-throughput analysis as ultrahigh performance liquid chromatography (UPLC)-MS.

Adaptive integration of history variables in constrained mixture models for organ-scale growth and remodeling.

In the last decades, many computational models have been developed to predict soft tissue growth and remodeling (G&R). The constrained mixture theory describes fundamental mechanobiological processes in soft tissue G&R and has been widely adopted in cardiovascular models of G&R. However, even after two decades of work, large organ-scale models are rare, mainly due to high computational costs (model evaluation and memory consumption), especially in long-range simulations. We propose two strategies to adaptively integrate history variables in constrained mixture models to enable large organ-scale simulations of G&R. Both strategies exploit that the influence of deposited tissue on the current mixture decreases over time through degradation. One strategy is independent of external loading, allowing the estimation of the computational resources ahead of the simulation. The other adapts the history snapshots based on the local mechanobiological environment so that the additional integration errors can be controlled and kept negligibly small, even in G&R scenarios with severe perturbations. We analyze the adaptively integrated constrained mixture model on a tissue patch for a parameter study and show the performance under different G&R scenarios. To confirm that adaptive strategies enable large organ-scale examples, we show simulations of different hypertension conditions with a real-world example of a biventricular heart discretized with a finite element mesh. In our example, adaptive integrations sped up simulations by a factor of three and reduced memory requirements to one-sixth. The reduction of the computational costs gets even more pronounced for simulations over longer periods. Adaptive integration of the history variables allows studying more finely resolved models and longer G&R periods while computational costs are drastically reduced and largely constant in time.

Survival of men with metastatic hormone-sensitive prostate cancer and adrenal-permissive HSD3B1 inheritance.

BACKGROUNDMetastatic hormone-sensitive prostate cancer (mHSPC) is androgen dependent, and its treatment includes androgen deprivation therapy (ADT) with gonadal testosterone suppression. Since 2014, overall survival (OS) has been prolonged with addition of other systemic therapies, such as adrenal androgen synthesis blockers, potent androgen receptor blockers, or docetaxel, to ADT. HSD3B1 encodes the rate-limiting enzyme for nongonadal androgen synthesis, 3ß-hydroxysteroid dehydrogenase-1, and has a common adrenal-permissive missense-encoding variant that confers increased synthesis of potent androgens from nongonadal precursor steroids and poorer prostate cancer outcomes.METHODSOur prespecified hypothesis was that poor outcome associated with inheritance of the adrenal-permissive HSD3B1 allele with ADT alone is reversed in patients with low-volume (LV) mHSPC with up-front ADT plus addition of androgen receptor (AR) antagonists to inhibit the effect of adrenal androgens. HSD3B1 genotype was obtained in 287 patients with LV disease treated with ADT + AR antagonist only in the phase III Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer (ENZAMET) trial and was associated with clinical outcomes.RESULTSPatients who inherited the adrenal-permissive HSD3B1 allele had more favorable 5-year clinical progression-free survival and OS when treated with ADT plus enzalutamide or ADT plus nonsteroidal antiandrogen compared with their counterparts who did not have adrenal-permissive HSD3B1 inheritance. HSD3B1 was also associated with OS after accounting for known clinical variables. Patients with both genotypes benefited from early enzalutamide.CONCLUSIONThese data demonstrated an inherited physiologic driver of prostate cancer mortality is associated with clinical outcomes and is potentially pharmacologically reversible.FUNDINGNational Cancer Institute, NIH; Department of Defense; Prostate Cancer Foundation, Australian National Health and Medical Research Council.

Lu-177 PSMA vs Comparator Treatments and Survival in Metastatic Castration-Resistant Prostate Cancer.

Importance: Observed treatment effects on overall survival (OS) differed substantially in the first 2 randomized clinical trials of lutetium Lu 177 vipivotide tetraxetan (Lu-177) prostate-specific membrane antigen (PSMA) in metastatic castration-resistant prostate cancer. Objective: To investigate factors associated with the observed difference in treatment effects on OS, including differences in the risk of crossover from randomized treatment after disease progression. Design, Setting, and Participants: This comparative effectiveness study used individual participant data from 2 randomized clinical trials, TheraP (A Randomised Phase 2 Trial of 177Lu-PSMA617 Theranostic Versus Cabazitaxel in Progressive Metastatic Castration Resistant Prostate Cancer [ANZUP Protocol 1603]) (n = 200), recruited from February 2018 to September 2019 in Australia, and published data from VISION (An International, Prospective, Open Label, Multicenter, Randomized Phase 3 Study of 177Lu-PSMA-617 in the Treatment of Patients With Progressive PSMA-Positive Metastatic Castration-Resistant Prostate Cancer) (n = 831), recruited from June 2018 to October 2019 in North America and Europe. Individual participant data for OS were reconstructed from VISION using the published survival curves. Data were analyzed February 6, 2018, to December 31, 2021, for TheraP and June 4, 2018, to January 27, 2021, for VISION. Interventions: TheraP randomized participants to receive treatment with Lu-177 PSMA or cabazitaxel. VISION randomized participants to receive treatment with or without Lu-177 PSMA in addition to physicians' choice of protocol-permitted treatments (PPT; approved hormonal treatments [such as abiraterone and enzalutamide], bisphosphonates, radiotherapy, denosumab, or glucocorticoids), excluding cabazitaxel. Main Outcomes and Measures: Patient characteristics, treatment protocols, and OS outcomes of the 2 trials were compared. Estimates of the effect on OS from TheraP were adjusted for crossover from randomly assigned treatment using a rank-preserving structural failure time model (RPSFTM) and inverse probability of censoring weights (IPCW) methods. Results: The 200 participants in TheraP and 831 participants in VISION were similar in age (median [range], 72 [49-86] vs 71 [40-94] years). Improved OS was observed in the comparator treatment group (cabazitaxel) in TheraP compared with VISION (PPT) (hazard ratio [HR], 0.53 [95% CI, 0.39-0.71]). The Lu-177 PSMA treatment groups in TheraP and VISION had similar OS (HR, 0.92 [95% CI, 0.70-1.19]). In TheraP, 20 of 101 participants in the cabazitaxel group crossed over to Lu-177 PSMA, while 32 of 99 participants in the Lu-177 PSMA arm crossed over to cabazitaxel. No statistically significant differences in OS between the Lu-177 PSMA and cabazitaxel groups of TheraP were observed after controlling for crossover to cabazitaxel: RPSFTM HR, 0.97 (95% CI, 0.60-1.58); IPCW HR, 0.92 (95% CI, 0.65-1.32); RPSFTM HR, 0.97 (95% CI, 0.60-1.58) and IPCW HR, 0.82 (95% CI, 0.54-1.24) for crossover to Lu-177 PSMA; RPSFTM HR, 0.96 (95% CI, 0.53-1.74) and IPCW HR, 0.82 (95% CI, 0.53-1.27) for crossover to either Lu-177 PSMA or cabazitaxel. Conclusions and Relevance: Findings of this secondary analysis of the TheraP and VISION randomized clinical trials suggest that the choice of comparator treatments (ie, cabazitaxel vs PPT) may explain the difference in the observed effect of Lu-177 PSMA on OS between the 2 trials. Causal inference methods such as RPSFTM and IPCW may help rule out crossover as a plausible explanation.

The Conductance and Thermopower Behavior of Pendent Trans-Coordinated Palladium(II) Complexes in Single-Molecule Junctions.

The present work provides insight into the effect of connectivity within isomeric 1,2-bis(2-pyridylethynyl)benzene (bpb) palladium complexes on their electron transmission properties within gold|single-molecule|gold junctions. The ligands 2,2'-((4,5-bis(hexyloxy)-1,2-phenylene)bis(ethyne-2,1-diyl))bis(4-(methylthio)pyridine) (Lm ) and 6,6'-((4,5-bis(hexyloxy)-1,2-phenylene)bis(ethyne-2,1-diyl))bis(3-(methylthio)pyridine) (Lp ) were synthesized and coordinated with PdCl2 to give the trans-Pd(Lm or p )Cl2 complexes. X-ray photoelectron spectroscopy (XPS) measurements shed light on the contacting modes of the molecules in the junctions. A combination of scanning tunneling microscopy-break junction (STM-BJ) measurements and density functional theory (DFT) calculations demonstrate that the typical lower conductance of meta- compared with para-connected isomers in a molecular junction was suppressed upon metal coordination. Simultaneously there was a modest increase in both conductance and Seebeck coefficient due to the contraction of the HOMO-LUMO gap upon metal coordination. It is shown that the low Seebeck coefficient is primarily a consequence of how the resonances shift relative to the Fermi energy.

Long-read sequencing and de novo genome assembly data of Candida parapsilosis HMC1 and Rhodotorula mucilaginosa LBMH1012, two novel isolates with antifungal resistance signatures.

Candida parapsilosis and Rhodotorula mucilaginosa are opportunistic pathogens affecting mostly immunocompromised hosts. Both species have emerged as causes of invasive candidiasis and sepsis respectively. Here we present high-quality long-read genome assemblies for a strain of C. parapsilosis isolated from human breast milk, with multiple predicted signatures consistent with Candida Drug Resistance CDR1/CDR2 and Multi Drug Resistance MDR1-type genes, also for an environmental strain of R. mucilaginosa with multiresistance to azole antifungals. The genome sequencing was performed using the R9.4.1 flowcell with the MinION Mk1B sequencer (Oxford Nanopore Technologies, Oxford, UK). The draft genome of C. parapsilosis HMC1 was assembled from 85,745 long-reads and has 13,114,208 bp in length and comprises 10 contigs making it a highly contiguous assembly. The R. mucilaginosa LBMH1012 assembly has 23,636,156 bp in length and comprises 54 contigs. The genome completeness was estimated as 94.02 % and 91.40 % respectively using BUSCO. These data may be useful to explore the genetic diversity landscape in both species, infer potential causal genes for antifungal resistance and virulence, and represent an addition to the useful sequence space on emerging fungal pathogens.

Optimising recovery of DNA from minimally invasive sampling methods: Efficacy of buccal swabs, preservation strategy and DNA extraction approaches for amphibian studies.

Studies in evolution, ecology and conservation are increasingly based on genetic and genomic data. With increased focus on molecular approaches, ethical concerns about destructive or more invasive techniques need to be considered, with a push for minimally invasive sampling to be optimised. Buccal swabs have been increasingly used to collect DNA in a number of taxa, including amphibians. However, DNA yield and purity from swabs are often low, limiting its use. In this study, we compare different types of swabs, preservation method and storage, and DNA extraction techniques in three case studies to assess the optimal approach for recovering DNA in anurans. Out of the five different types of swabs that we tested, Isohelix MS-02 and Rapidry swabs generated higher DNA yields than other swabs. When comparing storage buffers, ethanol is a better preservative than a non-alcoholic alternative. Dried samples resulted in similar or better final DNA yields compared to ethanol-fixed samples if kept cool. DNA extraction via a Qiagen™ DNeasy Blood and Tissue Kit and McHale's salting-out extraction method resulted in similar DNA yields but the Qiagen™ kit extracts contained less contamination. We also found that samples have better DNA recovery if they are frozen as soon as possible after collection. We provide recommendations for sample collection and extraction under different conditions, including budgetary considerations, size of individual animal sampled, access to cold storage facilities and DNA extraction methodology. Maximising efficacy of all of these factors for better DNA recovery will allow buccal swabs to be used for genetic and genomic studies in a range of vertebrates.

Modelling the continuum of macrophage phenotypes and their role in inflammation.

Macrophages are a type of white blood cell that play a significant role in determining the inflammatory response associated with a wide range of medical conditions. They are highly plastic, having the capacity to adopt numerous polarisation states or 'phenotypes' with disparate pro- or anti-inflammatory roles. Many previous studies divide macrophages into two categorisations: M1 macrophages are largely pro-inflammatory in nature, while M2 macrophages are largely restorative. However, there is a growing body of evidence that the M1 and M2 classifications represent the extremes of a much broader spectrum of phenotypes, and that intermediate phenotypes can play important roles in the progression or treatment of many medical conditions. In this article, we present a model of macrophage dynamics that includes a continuous description of phenotype, and hence incorporates intermediate phenotype configurations. We describe macrophage phenotype switching via nonlinear convective flux terms that scale with background levels of generic pro- and anti-inflammatory mediators. Through numerical simulation and bifurcation analysis, we unravel the model's resulting dynamics, paying close attention to the system's multistability and the extent to which key macrophage-mediator interactions provide bifurcations that act as switches between chronic states and restoration of health. We show that interactions that promote M1-like phenotypes generally result in a greater array of stable chronic states, while interactions that promote M2-like phenotypes can promote restoration of health. Additionally, our model admits oscillatory solutions reminiscent of relapsing-remitting conditions, with macrophages being largely polarised toward anti-inflammatory activity during remission, but with intermediate phenotypes playing a role in inflammatory flare-ups. We conclude by reflecting on our observations in the context of the ongoing pursuance of novel therapeutic interventions.

Apolipoproteins, lipids, lipid-lowering drugs and risk of amyotrophic lateral sclerosis and frontotemporal dementia: a meta-analysis and Mendelian randomisation study.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have clinical, pathological and genetic overlapping. Lipid pathways are implicated in ALS. This study examined the effect of blood lipid levels on ALS, FTD risk, and survival in ALS. METHODS: A systematic review and meta-analysis of high and low-density lipoprotein cholesterol (HDL-c and LDL-c), total cholesterol, triglycerides, apolipoproteins B and A1 levels with ALS was performed. Two-sample Mendelian randomisation (MR) analysis sought the causal effects of these exposures on ALS, FTD, and survival in ALS. The effect of lipid-lowering drugs was also examined using genetic proxies for targets of lipid-lowering medications. RESULTS: Three cohort studies met the inclusion criteria for meta-analysis. Meta-analysis indicated an association between higher LDL-c (HRper mmol/L = 1.07, 95%CI:1.02-1.12; I 2 =18%) and lower HDL-c (HRper mmol/L = 0.83, 95%CI:0.74-0.94; I 2 =0%) with an increased risk of ALS. MR suggested causal effects of higher LDL-c (ORIVW = 1.085, 95%:CI 1.008-1.168, pFDR = 0.0406), total cholesterol (ORIVW = 1.081, 95%:CI 1.013-1.154, pFDR = 0.0458) and apolipoprotein B (ORIVW = 1.104, 95%:CI 1.041-1.171, pFDR = 0.0061) increasing ALS risk, and higher apolipoprotein B level increasing FTD risk (ORIVW = 1.424, 95%CI 1.072-1.829, pFDR = 0.0382). Reducing LDL-c through APOB inhibition was associated with lower ALS (ORIVW = 0.84, 95%CI 0.759-0.929, pFDR = 0.00275) and FTD risk (ORIVW = 0.581, 95%CI 0.387-0.874, pFDR = 0.0362). CONCLUSION: These data support the influence of LDL-c and total cholesterol on ALS risk and apolipoprotein B on the risk of ALS and FTD. Potential APOB inhibition might decrease the risk of sporadic ALS and FTD. Further work in monogenic forms of ALS and FTD is necessary to determine whether blood lipids influence penetrance and phenotype.

Association between low total serum testosterone and body mass index in Australian survivors of testicular cancer: a retrospective analysis.

BACKGROUND: Primary hypogonadism is a recognised complication in survivors of testicular cancer. However, secondary hypogonadism can result from other causes that suppress the hypothalamic-pituitary axis, including obesity, high dose glucocorticoids, chronic end organ failure, and diabetes. The aim of this study was to explore low total serum testosterone in Australian survivors of testicular cancer and examine associations with body mass index, age, and prior chemotherapy use. METHODS: Clinical data including height, weight, diagnosis, treatment, and hormonal evaluations during follow-up were extracted from the Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group Chemocog study (2007-2012), accompanied by data from two Australian, high-volume testicular cancer centres included in the iTestis testicular cancer registry (2012-2019). Low testosterone was defined by a serum concentration of testosterone (T) < 10 nmol/L, and was classified as primary by a serum concentration of luteinising hormone (LH) > 8 IU/L, otherwise as secondary. RESULTS: Two hundred eighty-five individuals with either stage 1 or advanced testicular cancer were included. Of these, 105 (37%) were treated with orchidectomy and chemotherapy. Forty-nine (17%) met criteria for low testosterone during follow-up: 21 (43%) had primary and 27 (55%) had secondary low testosterone. Survivors of testicular cancer with higher body mass index were more likely to display low testosterone, both primary (p = 0.032) and secondary (p = 0.028). Our data did not show evidence of an association between older age or chemotherapy use and low testosterone in our cohort. CONCLUSIONS: Low total serum testosterone was common in survivors of testicular cancer, and associated with a higher body mass index prior to orchidectomy, suggesting that elevated body mass index may contribute to low testosterone in this population, and that body weight, diet, and exercise should be addressed in testicular cancer follow-up.

RéSUMé: CONTEXTE: L'hypogonadisme primaire est une complication reconnue chez les survivants d'un cancer du testicule. Cependant, l'hypogonadisme secondaire peut résulter d'autres causes qui suppriment l'axe hypothalamo-hypophysaire, notamment l'obésité, les glucocorticoïdes à forte dose, la défaillance chronique des organes cibles et le diabète. Le but de cette étude était d'explorer un faible taux de testostérone totale sérique chez les survivants australiens d'un cancer du testicule, et d'examiner les associations avec l'indice de masse corporelle, l'âge et l'utilisation antérieure d'une chimiothérapie. Les données cliniques, y compris la taille, le poids, le diagnostic, le traitement et les évaluations hormonales au cours du suivi, ont été extraites de l'étude Chemocog de l'Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group (2007­2012), accompagnées de données, provenant de deux centres australiens à fort volume de prise en charge de cancers du testicule, incluses dans le registre du cancer du testicule iTestis (2012­2019). Un taux faible de testostérone a été défini par une concentration sérique de testostérone (T) < 10 nmol/L, et a été classé comme primaire pour une concentration sérique d'hormone lutéinisante (LH) > 8 UI/L, sinon comme secondaire. RéSULTATS: Deux cent quatre-vingt-cinq personnes atteintes d'un cancer des testicules de stade 1 ou avancé ont été incluses. Parmi ceux-ci, 105 (37%) ont été traités par orchidectomie et chimiothérapie. Quarante-neuf (17%) répondaient aux critères d'un taux faible de testostérone au cours du suivi: 21 (43%) avaient un taux faible de testostérone primaire et 27 (55%) un faible taux secondaire. Les survivants d'un cancer du testicule avec un indice de masse corporelle plus élevé étaient plus susceptibles de présenter un taux faible de testostérone, à la fois primaire (p = 0,032) et secondaire (p = 0,028). Nos données n'ont pas montré de preuve d'une association entre un âge avancé ou l'utilisation de la chimiothérapie, et un taux faible de testostérone, dans notre cohorte. CONCLUSIONS: Un faible taux de testostérone sérique totale était fréquent chez les survivants d'un cancer du testicule, et associé à un indice de masse corporelle plus élevé avant l'orchidectomie; ceci suggère qu'un indice de masse corporelle élevé peut contribuer à un faible taux de testostérone dans cette population, et que le poids corporel, l'alimentation et l'exercice devraient être pris en compte dans le suivi du cancer du testicule.

A robust time-delay selection criterion applied to convergent cross mapping.

This work presents a heuristic for the selection of a time delay based on optimizing the global maximum of mutual information in orthonormal coordinates for embedding a dynamical system. This criterion is demonstrated to be more robust compared to methods that utilize a local minimum, as the global maximum is guaranteed to exist in the proposed coordinate system for any dynamical system. By contrast, methods using local minima can be ill-posed as a local minimum can be difficult to identify in the presence of noise or may simply not exist. The performance of the global maximum and local minimum methods are compared in the context of causality detection using convergent cross mapping using both a noisy Lorenz system and experimental data from an oscillating plasma source. The proposed heuristic for time lag selection is shown to be more consistent in the presence of noise and closer to an optimal uniform time lag selection.

Long-wavelength triggered iridium(III) complex nanoparticles for photodynamic therapy against hypoxic cancer.

A long-wavelength triggered cationic iridium(III) complex, Ir5, and its corresponding nanoparticles with the ability to generate type I and type II reactive oxygen species have been synthesised. The complex targets mitochondria and achieves an excellent photodynamic therapy effect in hypoxic cancer cells.

Influence of learning strategies and motivation on anatomy test performance of undergraduate medical students.

To learn and comprehend the large amount of information in gross anatomy, undergraduate students must self-regulate their learning to be properly prepared for the exams within the available time. Even though there are many studies on learning strategies and their influence on test results and motivation, the aim of this study is to investigate characteristics of learning strategies in detail and in relation to the anatomy course of first semester students and how their use is related to anatomy test performance. For assessing the learning strategies, we used the short version of the questionnaire "Learning Strategies of University Students" (LIST-K) (Klingsieck, 2018). Further, we investigated potential influences of motivation and resources used during the self-regulated learning process. The participants in this study (N = 108) filled in the above-mentioned questionnaire LIST-K and a written multiple-choice anatomy test. A k-means cluster analysis revealed three groups of students differing in their self-reported use of learning strategies. Students used either (1) predominantly metacognitive and resource-related strategies, (2) predominantly cognitive strategies, or (3) no specific learning strategies at all. We found no significant overall relationships between the use of learning strategies and test performance. A stepwise linear regression identified the use of cognitive learning strategies (ß =.269) as a significant predictor for test performance (R² =.149, p =.003), possibly as these specific learning strategies help with a systematic and effective approach while studying anatomy and retrieving large amount of memorized information. Further, motivation was identified as a negative predictor (ß = -.277), which might be a result of the short time periods students have to study for exams. Overall findings underline the importance of self-regulated learning as a positive predictor for academic performance. By understanding these factors, a more student-centered approach could be adopted by educators to improve medical education and equip students with valuable approaches for their continuous education, even beyond university.

Incidence of pregnancy related pulmonary embolism in Spain 2016-2021: an observational population-based retrospective study.

OBJECTIVE: This study aimed to estimate the overall and annual age-standardized incidence of pregnancy-related pulmonary embolism (PE) in Spain from 2016 to 2021, explore the distribution of PE events during pregnancy and the postpartum period, identify potential risk factors, and estimate mortality rates during hospital admission. METHODS: In a retrospective, observational, population-based study, data from the Spanish National Hospital Discharge Database were analyzed to identify women with hospital episodes of pregnancy-related-PE. The primary outcome was the overall and annual age-standardized incidence of pregnancy-related-PE, with secondary aims including the distribution of events during pregnancy and postpartum and the calculation of age-standardized mortality rates during admission. RESULTS: Among 2,178,805 births from 2016 to 2021, 522 women were diagnosed with pregnancy-related PE, yielding an overall age-standardized incidence of 2.83 cases per 10,000 births. A non-significant increasing trend was observed from 2.43 to 4.18 cases per 10,000 births (p = 0.06). Comorbidities were low, with a notable association between PE and SARS-CoV-2 infection during the last two years. The mortality rate among women with pregnancy-related PE was 2.8%, with a higher incidence of PE reported during the postpartum period. CONCLUSION: The incidence of pregnancy-related-PE in Spain exhibits a non-significant increasing trend, with a significant risk of mortality. The association with SARS-CoV-2 infection underscores the importance of vigilant monitoring and management of pregnant women, particularly during pandemics. This study contributes specific data on the incidence and characteristics of pregnancy-related-PE in Spain, emphasizing the need to consider PE in the differential diagnosis and management strategies for pregnant and postpartum women.

Colonic Adenosquamous Carcinoma: A Single-Center Review of Patient Clinicopathologic Characteristics, Genetics, and Clinical Outcomes.

(1) Background: Adenosquamous carcinoma (ASC) is a rare subtype of colon cancer. Its rarity makes characterization challenging, although colonic ASC is believed to present at more advanced stages and have worse outcomes versus adenocarcinoma. This study aims to characterize the clinicopathological characteristics and clinical outcomes of colonic ASC. (2) Methods: This is a single-center, retrospective review of patients diagnosed with colonic ASC from 2000 to 2020. Data extracted included patient demographics, staging at diagnosis, tumor clinicopathologic and genetic characteristics, and clinical outcomes. (3) Results: Among 61,126 patients with colorectal cancer, 13 (0.02%) had colonic ASC, with a mean age at diagnosis of 48.7 years. The cecum/ascending colon was the most common primary site (6/13, 46.2%), and all except one patient was diagnosed with Stage III or IV disease. Among the eight patients with mismatch repair genetics available, only one was mismatch repair deficient. Eleven patients (84.6%) underwent surgery, and 11 likewise received some form of chemotherapy. Recurrence occurred in 7 of 13 patients (53.8%), and the overall five-year survival rate was 38.5%. The median survival rate was 39.4 months overall (30.5 months for Stage III, 23.7 months for Stage IV). (4) Conclusions: Overall, colonic ASC is rare, and this cohort of colonic ASC patients demonstrated advanced stage at diagnosis, frequent recurrence, and poor overall survival. Additional research remains to compare these characteristics with those of comparably staged adenocarcinoma and to develop specific management recommendations.