The impact of benign tissue within cancerous regions in the prostate: Characterizing sparse and dense prostate cancers on whole-mount histopathology and on multiparametric MRI.

PURPOSE: To establish the incidence, size, zonal location and Gleason Score(GS)/Gleason Grade Group(GG) of sparse versus dense prostate cancer (PCa) lesions and to identify the imaging characteristics of sparse versus dense cancers on multiparametric MRI (mpMRI). METHODS: Seventy-six men with untreated PCa were scanned prior to prostatectomy with endorectal-coil 3 T MRI including T2-weighted imaging, diffusion-weighted imaging and dynamic contrast-enhanced MRI. Cancerous regions were outlined and graded on the whole-mount, processed specimens, with tissue compositions estimated. Regions with cancer comprising <50 % and ≥ 50 % of the tissue were considered sparse and dense respectively. Regions of interest (ROI) were manually drawn on T2-weighted MRI. Within each patient, area-weighted ROI averages were calculated for each imaging measure for each tissue type, GS/GG, and sparse/dense composition. RESULTS: A large number of cancer regions were identified on histopathology (n = 1193: 939 (peripheral zone (PZ)) and 254 (transition zone (TZ))). Thirty-seven percent of these lesions were sparse. Sparse lesions were primarily low-grade with the majority of PZ and 100 % of TZ sparse lesions ≤GS3 + 3/GG1. Dense lesions were significantly larger than sparse lesions in both PZ and TZ, p < 0.0001. On imaging, 246/45 PZ and 109/8 TZ dense/sparse 2D cancerous ROIs were drawn. Sparse GS3 + 3 and sparse ≥GS3 + 4 cancers did not have significantly different MRI intensities to dense GS3 + 3 cancers, while sparse GS3 + 3/GG1 cancers differed from benign, p < 0.05. CONCLUSION: Histopathologically identified prostate cancer lesions were sparse in 37 % of cases. Sparse cancers were entirely low grade in TZ and predominantly low-grade in PZ and generally small, thus likely posing lower risk for spread and progression than dense lesions. Sparse lesions were not distinguishable from dense lesions on mpMRI, but could be distinguished from benign tissues.

Impairment of health-related quality of life among people with type 2 diabetes and advanced liver fibrosis.

People with type 2 diabetes mellitus (T2DM) show a high prevalence of steatotic liver disease (SLD), and especially metabolic dysfunction-associated steatotic liver disease (MASLD), with liver fibrosis. Their health-related quality of life (HRQL) is affected by multiple in part overlapping factors and aggravated by metabolic and liver-related comorbidities, including liver fibrosis stage. The aim of this study was to investigate the effect size of advanced fibrosis (AF) on the HRQL in people with T2DM. A total of 149 individuals with T2DM treated at a primary care provider within the German disease management program (DMP) were included in the final analysis. Vibration-controlled transient elastography (VCTE) was used to non-invasively detect steatosis and AF. The EQ-5D-3L questionnaire was used to assess the HRQL. Uni- and multivariable linear regression models were used to identify independent predictors of impaired HRQL. The majority was male (63.1%), and the median age was 67 years (IQR 59; 71). In the entire cohort, the prevalence of MASLD and AF was 70.7% and 19.5%, respectively. People with T2DM and AF had an overall lower HRQL in comparison to those without AF (p < 0.001). Obesity (ß: - 0.247; 95% CI - 0.419, - 0.077) and AF (ß: - 0.222; 95% CI - 0.383, - 0.051) remained independent predictors of a poor HRQL. In turn, T2DM-related comorbidities were not predictive of an impaired HRQL. Obesity and AF negatively affect the HRQL in patients with SLD and T2DM in primary care. Awareness of liver health and specific interventions may improve patient-reported and liver-related outcomes in people with T2DM.

Individual differences in belief updating and phasic arousal are related to psychosis proneness.

Many decisions entail the updating of beliefs about the state of the environment by accumulating noisy sensory evidence. This form of probabilistic reasoning may go awry in psychosis. Computational theory shows that optimal belief updating in environments subject to hidden changes in their state requires a dynamic modulation of the evidence accumulation process. Recent empirical findings implicate transient responses of pupil-linked central arousal systems to individual evidence samples in this modulation. Here, we analyzed behavior and pupil responses during evidence accumulation in a changing environment in a community sample of human participants. We also assessed their subclinical psychotic experiences (psychosis proneness). Participants most prone to psychosis showed overall less flexible belief updating profiles, with diminished behavioral impact of evidence samples occurring late during decision formation. These same individuals also exhibited overall smaller pupil responses and less reliable pupil encoding of computational variables governing the dynamic belief updating. Our findings provide insights into the cognitive and physiological bases of psychosis proneness and open paths to unraveling the pathophysiology of psychotic disorders.

Longitudinal associations between exercise and biomarkers in autosomal dominant Alzheimer's disease.

INTRODUCTION: We investigated longitudinal associations between self-reported exercise and Alzheimer's disease (AD)-related biomarkers in individuals with autosomal dominant AD (ADAD) mutations. METHODS: Participants were 308 ADAD mutation carriers aged 39.7 ± 10.8 years from the Dominantly Inherited Alzheimer's Network. Weekly exercise volume was measured via questionnaire and associations with brain volume (magnetic resonance imaging), cerebrospinal fluid biomarkers, and brain amyloid beta (Aß) measured by positron emission tomography were investigated. RESULTS: Greater volume of weekly exercise at baseline was associated with slower accumulation of brain Aß at preclinical disease stages ß = -0.16 [-0.23 to -0.08], and a slower decline in multiple brain regions including hippocampal volume ß = 0.06 [0.03 to 0.08]. DISCUSSION: Exercise is associated with more favorable profiles of AD-related biomarkers in individuals with ADAD mutations. Exercise may have therapeutic potential for delaying the onset of AD; however, randomized controlled trials are vital to determine a causal relationship before a clinical recommendation of exercise is implemented. HIGHLIGHTS: Greater self-reported weekly exercise predicts slower declines in brain volume in autosomal dominant Alzheimer's disease (ADAD). Greater self-reported weekly exercise predicts slower accumulation of brain amyloid beta in ADAD. Associations varied depending on closeness to estimated symptom onset.

Depletion of monocytic myeloid-derived suppressor cells in LP-BM5 murine retroviral infection has a positive impact on virus-induced host immunodeficiency.

We have shown the induction of CD11b+Ly6C+ monocytic myeloid-derived suppressor cells (M-MDSCs) during infection of B6 mice by LP-BM5 immunodeficiency-inducing retrovirus. We published that the molecular mechanisms of these M-MDSCs vary, and depend on the cell type targeted by the suppression -defined by use of biochemical inhibitors, mouse M-MDSCs knock-out strains and blocking antibodies. These M-MDSCs suppressed proliferation and function of T cells, via nitric oxide synthase/nitric oxide; and that of B cells, ∼50% via INOS/NO along with the negative checkpoint regulator VISTA, reactive nitrogen and oxygen species, and other soluble mediators. Here, LP-BM5 infected mice were treated weekly with 5-Fluorouracil (5-FU), resulting in depletion of peripheral blood and splenic M-MDSCs, reduced MDSC activity, and significantly decreased standard disease parameters of: splenomegaly, impaired B-and T-cell ex vivo polyclonal responses, and viral load. In addition, 5-FU treatment significantly increased percentages of CD4+ and CD8+ T cells.

Disproportionality Analysis and Characterisation of Medication Errors in EudraVigilance: Exploring Findings on Sexes and Age Groups.

BACKGROUND: While medication errors (MEs) have been studied in the European Medicines Agency's EudraVigilance, extensive characterisation and signal detection based on sexes and age groups have not been attempted. OBJECTIVES: The aim of this study was to characterise all ME-related individual case safety reports in EudraVigilance and explore notable signals of disproportionate reporting (SDRs) among sexes and age groups for the 30 most frequently reported drugs. METHODS: Individual case safety reports were used from EudraVigilance reported between 2002 and 2021. An ME was defined as any Preferred Term from the narrow Standardised Medical Dictionary for Regulatory Activities® Query. Signals of disproportionate reporting were selected based on a lower boundary of the 95% confidence interval ≥ 1 of the reporting odds ratio, and at least 3 individual case safety reports. Analysed subgroups were female individuals, male individuals, and age groups 0-1 month, 2 months to 2 years, 3-11 years, 12-17 years, 18-64 years, 65-85 years, and >85 years. Heatmaps were utilised as a visual aid to identify striking SDRs. RESULTS: Of the 9,662,345 EudraVigilance reports, 267,262 (2.8%) contained at least one ME, with a total of 300,324 MEs, for 429,554 drugs. The most reported ME was "Inappropriate schedule of product administration" (52,646; 17.5%), followed by "Incorrect dose administered" (32,379; 10.8%) and "Wrong technique in product usage process" (26,831; 8.9%). Individual case safety reports with MEs were most frequently related to female individuals (148,009; 55.4%), most often submitted by healthcare professionals (155,711; 58.3%), originated predominantly from the USA (98,716; 36.9%), followed by France (26,678; 10.0%), and showed a median reported age of 50 years (interquartile range: 26-68). Most ME individual case safety reports (158,991; 59.5%) were associated with a serious health outcome. A total of 847 SDRs were identified, based on the entire EudraVigilance database; for subgroups, the number of SDRs ranged from 84 for the age group 0-1 month to 749 for female individuals. Signals of disproportionate reporting for female individuals and male individuals were very similar. Most MEs were reported for the vaccine against human papillomavirus (Anatomical Therapeutic Chemical [ATC]: J07BM01; 11,086 MEs, 57% being "inappropriate schedule of product administration"), with reporting odds ratios that range from 1.5 to 47.0 among age groups. The SDR for the live-attenuated vaccine against herpes zoster (ATC: J07BK02) had a reporting odds ratio that ranged from 26.6 to 78.1 among all subgroups. Signals of disproportionate reporting for oxycodone (ATC: N02AA05; 847 cases of "Accidental overdose", 35%), risperidone (ATC: N05AX08; 469 cases "Inappropriate schedule of product administration", 22.3%) and rivaroxaban (ATC: B01AF01; 1,377 cases of "Incorrect dose administered", 34.6%) stood out with higher magnitude SDRs for the age group 2 months to 2 years, with an reporting odds ratio range between 8.2 and 10.7, while for the entire EudraVigilance the reporting odds ratio ranged between 1.3 and 1.6 for the same drugs. CONCLUSIONS: This exploratory research provides an overview of characterised ME individual case safety reports and SDRs from the EudraVigilance database. Most conspicuous SDRs were identified in specific age groups. Signals of disproportionate reporting, not described in the literature, were found for vaccines, oxycodone, rivaroxaban and risperidone, and may prompt further examination by stakeholders. Top-reported MEs ("Inappropriate schedule of product administration", "Incorrect dose administered" and "Wrong technique in product usage process") emerged as a general priority focus to perform a further root-cause analysis involving healthcare providers, manufacturers and regulatory bodies, to improve the understanding and prevention of MEs.

The enigmatic Triassic ovulate reproductive structures of Dordrechtites are recurved cupules fundamentally comparable to the cupules of Doylea and similar plants.

Recent paleobotanical discoveries have renewed interest in the distinctively recurved, seed-bearing cupules of Mesozoic plants, which are important for understanding seed plant phylogeny and the origin of the second integument of the angiosperm ovule. Reanalysis of the enigmatic seed-bearing organ Dordrechtites elongatus from the Triassic of South Africa, the type species of the genus, combined with information from similar material from Antarctica, Argentina and Australia, indicates that Dordrechtites is a highly modified lateral branch of a seed cone. Short lateral projections from a primary cone axis each bear several Dordrechtites units. Each unit consists of a long stalk bearing a straight to sometimes recurved cupule with a long distal extension beyond the cupule apex. Each cupule is flattened in a plane perpendicular to the stalk and distal projection and contains up to two seeds. Structural similarities between Dordrechtites and the cupules of Doyleales indicate that they are homologous, providing new evidence for a close relationship. The persistent cupule stalk and apical extension of Dordrechtites, combined with the flattened cupule, suggests modification for wind and water dispersal.

EYA-1 is required for genomic integrity independent of H2AX signalling in Caenorhabditis elegans.

BACKGROUND: Resolving genomic insults is essential for the survival of any species. In the case of eukaryotes, several pathways comprise the DNA damage repair network, and many components have high evolutionary conservation. These pathways ensure that DNA damage is resolved which prevents disease associated mutations from occurring in a de novo manner. In this study, we investigated the role of the Eyes Absent (EYA) homologue in Caenorhabditis elegans and its role in DNA damage repair. Current understanding of mammalian EYA1 suggests that EYA1 is recruited in response to H2AX signalling to dsDNA breaks. C. elegans do not possess a H2AX homologue, although they do possess homologues of the core DNA damage repair proteins. Due to this, we aimed to determine if eya-1 contributes to DNA damage repair independent of H2AX. METHODS AND RESULTS: We used a putative null mutant for eya-1 in C. elegans and observed that absence of eya-1 results in abnormal chromosome morphology in anaphase embryos, including chromosomal bridges, missegregated chromosomes, and embryos with abnormal nuclei. Additionally, inducing different types of genomic insults, we show that eya-1 mutants are highly sensitive to induction of DNA damage, yet show little change to induced DNA replication stress and display a mortal germline resulting in sterility over successive generations. CONCLUSIONS: Collectively, this study suggests that the EYA family of proteins may have a greater involvement in maintaining genomic integrity than previously thought and unveils novel roles of EYA associated DNA damage repair.

Uniportal VATS removal of a giant mediastinal goitre.

We demonstrate the technical nuances and operative strategy of uniportal video-assisted thoracoscopic surgical excision of a giant mediastinal goitre in a patient with a complex medical history, including a prior total thyroidectomy for multinodular goitre and partial gastrectomy for gastrointestinal stromal tumour. The video tutorial presents the surgical removal of a substantial mediastinal goitre, persisting post-total thyroidectomy performed 2 years prior via a collar incision. We opted for a thoracoscopic technique for the removal of the residual mediastinal mass. A 3-cm uniportal incision was made at the fifth intercostal space along the mid-axillary line. Pleural exploration confirmed the absence of adhesions. Subsequent dissection revealed a large retrocaval goitre adjacent to the trachea. Utilizing a combination of LigaSure technology for sharp dissection, and blunt dissection techniques using the peanuts, we severed the goitre's attachments to surrounding critical structures, including the trachea, superior vena cava and oesophagus. The dissection continued, extending into the cervical region from the thoracic approach. The mass was safely enclosed within an endobag and extracted through the uniportal incision. This case demonstrates the feasibility and effectiveness of the uniportal thoracoscopic approach for complex mediastinal pathology. This approach was successfully executed with an uneventful perioperative course and no complications, indicating positive outcomes in complex thoracic cases despite a minimally invasive approach for the resection of mediastinal masses.

MultiGreen: A multiplexing architecture for GreenGate cloning.

Genetic modification of plants fundamentally relies upon customized vector designs. The ever-increasing complexity of transgenic constructs has led to increased adoption of modular cloning systems for their ease of use, cost effectiveness, and rapid prototyping. GreenGate is a modular cloning system catered specifically to designing bespoke, single transcriptional unit vectors for plant transformation-which is also its greatest flaw. MultiGreen seeks to address GreenGate's limitations while maintaining the syntax of the original GreenGate kit. The primary limitations MultiGreen addresses are 1) multiplexing in series, 2) multiplexing in parallel, and 3) repeated cycling of transcriptional unit assembly through binary intermediates. MultiGreen efficiently concatenates bespoke transcriptional units using an additional suite of level 1acceptor vectors which serve as an assembly point for individual transcriptional units prior to final, level 2, condensation of multiple transcriptional units. Assembly with MultiGreen level 1 vectors scales at a maximal rate of 2*⌈log6n⌉+3 days per assembly, where n represents the number of transcriptional units. Further, MultiGreen level 1 acceptor vectors are binary vectors and can be used directly for plant transformation to further maximize prototyping speed. MultiGreen is a 1:1 expansion of the original GreenGate architecture's grammar and has been demonstrated to efficiently assemble plasmids with multiple transcriptional units. MultiGreen has been validated by using a truncated violacein operon from Chromobacterium violaceum in bacteria and by deconstructing the RUBY reporter for in planta functional validation. MultiGreen currently supports many of our in-house multi transcriptional unit assemblies and will be a valuable strategy for more complex cloning projects.

The battle of the sexes in humans is highly polygenic.

Sex-differential selection (SDS), which occurs when the fitness effects of alleles differ between males and females, can have profound impacts on the maintenance of genetic variation, disease risk, and other key aspects of natural populations. Because the sexes mix their autosomal genomes each generation, quantifying SDS is not possible using conventional population genetic approaches. Here, we introduce a method that exploits subtle sex differences in haplotype frequencies resulting from SDS acting in the current generation. Using data from 300K individuals in the UK Biobank, we estimate the strength of SDS throughout the genome. While only a handful of loci under SDS are individually significant, we uncover highly polygenic signals of genome-wide SDS for both viability and fecundity. Selection coefficients of [Formula: see text] may be typical. Despite its ubiquity, SDS may impose a mortality load of less than 1%. An interesting life-history tradeoff emerges: Alleles that increase viability more strongly in females than males tend to increase fecundity more strongly in males than in females. Finally, we find marginal evidence of SDS on fecundity acting on alleles affecting arm fat-free mass. Taken together, our findings connect the long-standing evidence of SDS acting on human phenotypes with its impact on the genome.

Direct C-H amidation of 1,3-azoles: light-mediated, photosensitiser-free vs. thermal.

We have developed one thermal and one light-mediated method for direct Minisci-type C-H amidation of 1,3-azoles, which are applicable to thiazoles, benzothiazoles, benzimidazoles, and for the first time, imidazoles. The new visible light-mediated approach can be rendered photosensitiser/photocatalyst-free and likely proceeds via an electron donor-acceptor (EDA) complex, the first direct Minisci-type amidation to do so.

Adult indication 13-valent pneumococcal conjugate vaccine clinical development overview: formulation, safety, immunogenicity (dosing and sequence), coadministration, and efficacy.

INTRODUCTION: There was no 13-valent pneumococcal conjugate vaccine (PCV13) adult antibody concentration threshold regulatory criterion for licensure - unlike the pediatric indication; consequently, for the adult indication, PCV13 serotype-specific opsonophagocytic activity (OPA) geometric mean titer (GMT) values were immunobridged to the 23-valent plain polysaccharide vaccine (PPV23) to infer efficacy against invasive pneumococcal disease (IPD). Subsequently, a double-blind, randomized, controlled PCV13 efficacy trial (CAPiTA) was performed in community-living, older adults to confirm efficacy against vaccine-serotype IPD (VT-IPD) and establish efficacy against vaccine-serotype pneumococcal community-acquired pneumonia (VT-CAP). AREAS COVERED: This article summarizes 31 publications from the PCV13 adult indication clinical development trials and other PCV13 clinical studies, organized by formulation, reactogenicity and safety, immunogenicity, coadministration, and clinical efficacy. EXPERT OPINION: PCV13 had a favorable safety profile with an OPA response generally greater than PPV23 irrespective of age and of previous pneumococcal vaccination. PCV13 primed for enhanced immune responses with subsequent PCV13 or PPV23 dosing. Conversely, PPV23 was shown to blunt the response to subsequent PCV13. CAPiTA demonstrated PCV13 efficacy for at least five years against both VT-IPD and VT-CAP. The PCV13 clinical development program provided fundamental insights into this vaccine's adult-specific immune responses and confirmed the advantages of conjugate over plain polysaccharide technology.

Cafeteria diet compromises natural adaptations of islet cell transdifferentiation and turnover in pregnancy.

BACKGROUND: Pancreatic islet ß-cell mass expands during pregnancy, but underlying mechanisms are not fully understood. This study examines the impact of pregnancy and cafeteria diet on islet morphology, associated cellular proliferation/apoptosis rates as well as ß-cell lineage. METHODS: Non-pregnant and pregnant Ins1Cre/+;Rosa26-eYFP transgenic mice were maintained on either normal or high-fat cafeteria diet, with pancreatic tissue obtained at 18 days gestation. Immunohistochemical changes in islet morphology, ß-/α-cell proliferation and apoptosis, as well as islet cell identity, neogenesis and ductal cell transdifferentiation were assessed. RESULTS: Pregnant normal diet mice displayed an increase in body weight and glycaemia. Cafeteria feeding attenuated this weight gain while causing overt hyperglycaemia. Pregnant mice maintained on a normal diet exhibited typical expansion in islet and ß-cell area, owing to increased ß-cell proliferation and survival as well as ductal to ß-cell transdifferentiation and ß-cell neogenesis, alongside decreased ß-cell dedifferentiation. Such pregnancy-induced islet adaptations were severely restricted by cafeteria diet. Accordingly, islets from these mice displayed high levels of ß-cell apoptosis and dedifferentiation, together with diminished ß-cell proliferation and lack of pregnancy-induced ß-cell neogenesis and transdifferentiation, entirely opposing islet cell modifications observed in pregnant mice maintained on a normal diet. CONCLUSION: Augmentation of ß-cell mass during gestation arises through various mechanisms that include proliferation and survival of existing ß-cells, transdifferentiation of ductal cells as well as ß-cell neogenesis. Remarkably, cafeteria feeding almost entirely annuls pregnancy-induced islet adaptations, which may contribute to the development of gestational diabetes in the setting of dietary provoked metabolic stress.

Quantum chemical investigation of electronic transitions of mitorubrin azaphilones.

Fungal azaphilones are a broad class of naturally-occurring pigments with diverse applications. Among the azaphilone pigments, mitorubrins are well recognized for their antiviral, antibacterial, antifungal, antiprotozoal, antidiabetic, and antiaging activities in addition to their well-known yellow-orange color. This makes these pigments interesting candidates for use in foods, as cosmetics, and as medicines. In particular, if it is desired to modify the properties of mitorubrin-based pigments, for example by derivatization, it is essential to have an understanding of the electronic spectra of the parent molecules. We have therefore undertaken a computational study of a series of mitorubrins, comparing our computed results with experimental UV/visible spectra. Both density-functional theory (DFT) and coupled-cluster (CC2) methods have been used, and in general, the results are in very good agreement with observation. In order to provide a simple and useful picture of the spectra we analyze the stronger transitions in terms of natural transition orbitals (NTOs).

Surface Reconstruction Regulation of Co3N Through Heterostructure Engineering Toward Efficient Oxygen Evolution Reaction.

Oxygen evolution reaction (OER) electrocatalysts generally experience structural and electronic modifications during electrocatalysis. This phenomenon, referred to as surface reconstruction, results in the formation of catalytically active species that act as real OER sites. Controlling surface reconstruction therefore is vital for enhancing the OER performance of electrocatalysts. In this study, a new approach is introduced of heterostructure engineering to facilitate the surface reconstruction of target catalysts. Using MnCo carbonate hydroxide (MnCo─CH)@Co3N as a demonstration, it is discovered that the surface reconstruction occurs more readily and rapidly on MnCo─CH@Co3N than on Co3N. More interestingly, during the reconstruction process, Mn species migrate to the surface, enabling the in situ formation of highly active Mn-doped CoOOH. Consequently, the MnCo─CH@Co3N catalyst after reconstruction exhibits a low overpotential of 257 mV at 10 mA cm-2, compared to 379 mV of individual Co3N. This work offers fresh perspectives on understanding the enhanced OER performance of heterostructure electrocatalysts and the role of heterostructure in promoting surface reconstruction.