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Richard C Trevino,1 Carolyn E Majcher,1 Adreain M Henry,1 Melinda Rodriguez,1 William E Sponsel1–3 1Rosenberg School of Optometry, University of the Incarnate Word, San Antonio, TX, USA; 2WESMDPA Baptist Medical Center Glaucoma Service, San Antonio, TX, USA; 3Department of Biomedical Engineering, University of Texas San Antonio, San Antonio, TX, USA Purpose: The purpose of this study was to evaluate the intrasession and intersession repeatability of visual evoked potentials in normal adults over 40 years of age as recorded using the Diopsys NOVA LX fixed protocol.Methods: Inclusion criteria were adults aged over 40 years with best corrected distance acuity of 20/40 or better in each eye. Subjects underwent three consecutive visual evoked potential examinations using the Diopsys NOVA LX fixed protocol. All examination procedures were carried out in accordance with the manufacturer recommendations. To assess intersession repeatability, nine subjects returned in 2–6 weeks for repeat examination.Results: A total of 46 subjects were recruited. Mean ± SD age: 53±9 years (range: 40–84 years); 69% of subjects were female and 80% were non-white. Coefficients of variation (CVs) and intraclass correlation coefficients (ICCs) revealed greater repeatability for P100 latency (CV: 3%–7%; ICC: 0.39–0.76) than for P100 amplitude (CV: 21%–33%; ICC: 0.34–0.69) and greater repeatability for recordings made with high contrast stimuli (amplitude CV: 21%–23%; latency CV: 3%–7%) than low contrast stimuli (amplitude CV: 24%–33%; latency CV: 6%–7%). Minimum detectable change values ranged between 4.50 and 9.95 µv for amplitude and 8.16–15.26 ms for latency. Repeatability was not influenced by age, sex, or race.Conclusion: The Diopsys NOVA LX fixed protocol demonstrated clinically acceptable intrasession and intersession repeatability in these healthy older adults, with latency being more repeatable than amplitude and examinations employing high contrast stimuli being more repeatable than those using low contrast stimuli. Keywords: electrophysiology, visual evoked potential, glaucoma, repeatability

Abstract Kidney injury disrupts the intricate renal architecture and triggers limited regeneration, together with injury-invoked inflammation and fibrosis. Deciphering the molecular pathways and cellular interactions driving these processes is challenging due to the complex tissue structure. Here, we apply single cell spatial transcriptomics to examine ischemia-reperfusion injury in the mouse kidney. Spatial transcriptomics reveals injury-specific and spatially-dependent gene expression patterns in distinct cellular microenvironments within the kidney and predicts Clcf1-Crfl1 in a molecular interplay between persistently injured proximal tubule cells and their neighboring fibroblasts. Immune cell types play a critical role in organ repair. Spatial analysis identifies cellular microenvironments resembling early tertiary lymphoid structures and associated molecular pathways. Collectively, this study supports a focus on molecular interactions in cellular microenvironments to enhance understanding of injury, repair and disease.

Abstract KRAS belongs to a family of small GTPases that act as binary switches upstream of several signalling cascades, controlling proliferation and survival of cells. Mutations in KRAS drive oncogenesis, especially in pancreatic, lung, and colorectal cancers (CRC). Although historic attempts at targeting mutant KRAS with small molecule inhibitors have proven challenging, there are recent successes with the G12C, and G12D mutations. However, clinically important RAS mutations such as G12V, G13D, Q61L, and A146T, remain elusive drug targets, and insights to their structural landscape is of critical importance to develop novel, and effective therapeutic concepts. We present a fully open, P-loop exposing conformer of KRAS G13D by X-ray crystallography at 1.4–2.4 Å resolution in Mg2+-free phosphate and malonate buffers. The G13D conformer has the switch-I region displaced in an upright position leaving the catalytic core fully exposed. To prove that this state is druggable, we developed a P-loop-targeting monoclonal antibody (mAb). The mAb displayed high-affinity binding to G13D and was shown using high resolution fluorescence microscopy to be spontaneously taken up by G13D-mutated HCT 116 cells (human CRC derived) by macropinocytosis. The mAb inhibited KRAS signalling in phosphoproteomic and genomic studies. Taken together, the data propose novel druggable space of G13D that is reachable in the cellular context. It is our hope that these findings will stimulate attempts to drug this fully open state G13D conformer using mAbs or other modalities.

This research investigates the stability and occurrence of Hopf bifurcation in a credit risk contagion model, which includes distributed delay, using the chain trick method. The model is a generalized version of those previously examined. The model is an expanded version of those previously studied. Comparative analysis showed that unlike earlier models, which only used the nonlinear resistance coefficient to determine the rate of credit risk infection, the credit risk contagion rate is also affected by the weight given to past behaviors of credit risk participants. Therefore, it is recommended to model the transmission of credit risk contagion using dispersed delays.

The paper considers the problem of least squares minimization with L1-norm regularization functional. It investigates various smoothing approximations for the L1-norm functional. It considers Quadratic, Sigmoid and Cubic Hermite functionals. A Tikhonov regularization is then applied to each of the resulting smooth least squares minimization problem. Results of numerical simulations for each smoothing approximation are presented. The results indicate that our regularization method is as good as any other non-smoothing method used in developed solvers.

Abstract RT-LAMP detection of SARS-CoV-2 has been shown to be a valuable approach to scale up COVID-19 diagnostics and thus contribute to limiting the spread of the disease. Here we present the optimization of highly cost-effective in-house produced enzymes, and we benchmark their performance against commercial alternatives. We explore the compatibility between multiple DNA polymerases with high strand-displacement activity and thermostable reverse transcriptases required for RT-LAMP. We optimize reaction conditions and demonstrate their applicability using both synthetic RNA and clinical patient samples. Finally, we validate the optimized RT-LAMP assay for the detection of SARS-CoV-2 in unextracted heat-inactivated nasopharyngeal samples from 184 patients. We anticipate that optimized and affordable reagents for RT-LAMP will facilitate the expansion of SARS-CoV-2 testing globally, especially in sites and settings where the need for large scale testing cannot be met by commercial alternatives.

Objective: Neonatal adiposity is a well-recognized complication of gestational diabetes mellitus (GDM). This study aimed to identify factors influencing adiposity in male and female infants of women treated for GDM.Research Design and Methods: This was a prospective study of 84 women with GDM. Daily blood glucose levels (BGLs) were retrieved from glucose meters, and overall mean fasting and mean 2-h postprandial BGLs were calculated for each woman. Infant body composition was measured at birth, and regression analysis was used to identify significant predictors of infant body fat separately in male and female infants.Results: Maternal fasting BGL was the major predictor of adiposity in male infants but had little relationship to adiposity in female infants. In male infants, percent fat was increased by 0.44% for each 0.1 mmol/L increase in mean maternal fasting BGL. Maternal BMI was the primary predictor in female infants but had little effect in males. In female infants, percent fat was increased by 0.11% for each 1 kg/m(2) increase in maternal prepregnancy BMI.Conclusions: Fetal sex may influence the impact that treatment strategies for GDM have on infant adiposity. [ABSTRACT FROM AUTHOR]

Proteins that contain disulfide bonds mainly mature in the oxidative environment of the eukaryotic endoplasmic reticulum or the periplasm of Gram-negative bacteria. In E. coli, disulfide bond containing recombinant proteins are often targeted to the periplasm by an N-terminal signal peptide that is removed once it passes through the Sec-translocon in the cytoplasmic membrane. Despite their conserved targeting function, signal peptides can impact recombinant protein production yields in the periplasm, as can the production rate. Here, we present a combined screen involving different signal peptides and varying production rates that enabled the identification of more optimal conditions for periplasmic production of recombinant proteins with disulfide bonds. The data was generated from two targets, a single chain antibody fragment (BL1) and human growth hormone (hGH), with four different signal peptides and a titratable rhamnose promoter-based system that enables the tuning of protein production rates. Across the screen conditions, the yields for both targets significantly varied, and the optimal signal peptide and rhamnose concentration differed for each protein. Under the optimal conditions, the periplasmic BL1 and hGH were properly folded and active. Our study underpins the importance of combinatorial screening approaches for addressing the requirements associated with the production of a recombinant protein in the periplasm.

Background: The use of linked data in the Semantic Web is a promising approach to add value to nutrition research. An ontology, which defines the logical relationships between well-defined taxonomic terms, enables linking and harmonizing research output. To enable the description of domain-specific output in nutritional epidemiology, we propose the Ontology for Nutritional Epidemiology (ONE) according to authoritative guidance for nutritional epidemiology. Methods: Firstly, a scoping review was conducted to identify existing ontology terms for reuse in ONE. Secondly, existing data standards and reporting guidelines for nutritional epidemiology were converted into an ontology. The terms used in the standards were summarized and listed separately in a taxonomic hierarchy. Thirdly, the ontologies of the nutritional epidemiologic standards, reporting guidelines, and the core concepts were gathered in ONE. Three case studies were included to illustrate potential applications: (i) annotation of existing manuscripts and data, (ii) ontology-based inference, and (iii) estimation of reporting completeness in a sample of nine manuscripts. Results: Ontologies for “food and nutrition” (n = 37), “disease and specific population” (n = 100), “data description” (n = 21), “research description” (n = 35), and “supplementary (meta) data description” (n = 44) were reviewed and listed. ONE consists of 339 classes: 79 new classes to describe data and 24 new classes to describe the content of manuscripts. Conclusion: ONE is a resource to automate data integration, searching, and browsing, and can be used to assess reporting completeness in nutritional epidemiology.

Reliable and safe access to drinking water is necessary to ensure the economic and social sustainable development of human communities. This task requires a multi-criteria decision analysis (MCDA) methodology to select alternatives for new water supply infrastructure. These alternatives represent significant financial resources and are established for a long lifespan. To support decision-making in the context of building new water supply infrastructure, this study developed an MCDA methodology that integrates a hierarchy of non-economic benefits and the expected costs into a global index. Our methodology was implemented in the city of Santa Marta, Colombia. This city currently has a 60% drinking water shortage, and urgently needs to expand its capacity to satisfy the increasing water demand. The results of this study support the implementation of the best alternative for addressing Santa Marta’s water supply problem by considering the preferences of stakeholders.

Kenya’s Grand Coalition Government was formed in the aftermath of a serious post-electoral crisis including widespread violence. No political progress has been recorded; in striking contrast to all expectations for more moderation and consensual preparation of a constitutional reform. Based on secondary data from textbooks, newspapers, journals, and documents from both governmental and non-governmental organisations, the author finds that the continuing wrangles within the Grand Coalition Government, the fear of the debilitating effects of a constitutional referendum and the hard-line positions on the contentious issues pose a big threat to the achievement of a new constitution before the 2012 Elections. Die Große Koalition in Kenia wurde im Anschluss an eine heftige, gewaltsam ausgetragene Nachwahlkrise gebildet. Entgegen aller Erwartung, jetzt werde eine moderate und gemeinsam abgestimmte Vorbereitung der Verfassungsreform möglich, wurden keine politischen Fortschritte erzielt. Der Autor analysiert Sekundärdaten aus Monografien, Zeitungs- und Zeitschriftenartikeln sowie Dokumenten von Regierungs- und Nichtregierungsorganisationen und kommt zu dem Schluss, dass der fortgesetzte Streit innerhalb der Koalitionsregierung, die Furcht vor den Unwegsamkeiten eines Verfassungsreferendums und die verhärteten Positionen zu den umstrittenen Fragen die Realisierung einer neuen Verfassung vor den Wahlen 2012 wenig wahrscheinlich machen.

Abstract Background Induction of labour (IOL) is one of the commonest obstetric interventions, with significant impact on both the individual woman and health service delivery. Outpatient IOL is an attractive option to reduce these impacts. To date there is little data comparing outpatient and inpatient IOL methods, and potential safety concerns (hyperstimulation) if prostaglandins, the standard inpatient IOL medications, are used in the outpatient setting. The purpose of this study was to assess feasibility, clinical effectiveness and patient acceptability of outpatient Foley catheter (OPC) vs. inpatient vaginal PGE2 (IP) for induction of labour (IOL) at term. Methods Women with an unfavourable cervix requiring IOL at term (N = 101) were randomised to outpatient care using Foley catheter (OPC, n = 50) or inpatient care using vaginal PGE2 (IP, n = 51). OPC group had Foley catheter inserted and were discharged overnight following a reassuring cardiotocograph. IP group received 2 mg/1 mg vaginal PGE2 if nulliparous or 1 mg/1 mg if multiparous. Main outcome measures were inpatient stay (prior to birth, in Birthing Unit, total), mode of birth, induction to delivery interval, adverse reactions and patient satisfaction. Results OPC group had shorter hospital stay prior to birth (21.3 vs. 32.4 hrs, p Conclusions OPC was feasible and acceptable for IOL of women with an unfavourable cervix at term compared to IP, however did not show a statistically significant reduction in total inpatient stay and was associated with increased oxytocin IOL. Trial registration Australian New Zealand Clinical Trials Registry, ACTRN:12609000420246.

Abstract Background Part-time training (PTT) is accessed by approximately 10% of Australian obstetrics and gynaecology trainees, a small but increasing minority which reflects the growing demand for improved work/life balance amongst the Australian medical workforce. This survey reports the attitudes and experiences of both full-time and part-time trainees to PTT. Methods An email-based anonymous survey was sent to all Australian obstetrics and gynaecology trainees in April 2009, collecting demographic and training status data, data on personal experiences of PTT and/or trainees, and attitudes towards PTT. Results 105 responses were received (20% response rate). These indicated strong support (90%) from both full-time (FT) and part-time (PT) trainees for the availability of PTT. PT trainees were significantly more likely than FT trainees to be female with children. Improved morale was seen as a particular advantage of PTT; decreased continuity of care as a disadvantage. Conclusions Although limited by poor response rate, both PT and FT Australian obstetric trainees were supportive of part-time training. Both groups recognised important advantages and disadvantages of this mode of training. Currently, part-time training is accessed primarily by female trainees with family responsibilities, with many more trainees considering part-time training than the number that access it.

Abstract Background Landmark based geometric morphometrics (GM) allows the quantitative comparison of organismal shapes. When applied to systematics, it is able to score shape changes which often are undetectable by traditional morphological studies and even by classical morphometric approaches. It has thus become a fast and low cost candidate to identify cryptic species. Due to inherent mathematical properties, shape variables derived from one set of coordinates cannot be compared with shape variables derived from another set. Raw coordinates which produce these shape variables could be used for data exchange, however they contain measurement error. The latter may represent a significant obstacle when the objective is to distinguish very similar species. Results We show here that a single user derived dataset produces much less classification error than a multiple one. The question then becomes how to circumvent the lack of exchangeability of shape variables while preserving a single user dataset. A solution to this question could lead to the creation of a relatively fast and inexpensive systematic tool adapted for the recognition of cryptic species. Conclusions To preserve both exchangeability of shape and a single user derived dataset, our suggestion is to create a free access bank of reference images from which one can produce raw coordinates and use them for comparison with external specimens. Thus, we propose an alternative geometric descriptive system that separates 2-D data gathering and analyzes.

Context: The optimum use of brachytherapy (BT) combined with external beam radiotherapy (EBRT) for localised/locally advanced prostate cancer (PCa) remains uncertain., Objective: To perform a systematic review to determine the benefits and harms of EBRT-BT., Evidence Acquisition: Ovid MEDLINE, Embase, and EBM Reviews-Cochrane Central Register of Controlled Trials databases were systematically searched for studies published between January 1, 2000 and June 7, 2022, according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. Eligible studies compared low- or high-dose-rate EBRT-BT against EBRT ± androgen deprivation therapy (ADT) and/or radical prostatectomy (RP) ± postoperative radiotherapy (RP ± EBRT). The main outcomes were biochemical progression-free survival (bPFS), severe late genitourinary (GU)/gastrointestinal toxicity, metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS), at/beyond 5 yr. Risk of bias was assessed and confounding assessment was performed. A meta-analysis was performed for randomised controlled trials (RCTs)., Evidence Synthesis: Seventy-three studies were included (two RCTs, seven prospective studies, and 64 retrospective studies). Most studies included participants with intermediate-or high-risk PCa. Most studies, including both RCTs, used ADT with EBRT-BT. Generally, EBRT-BT was associated with improved bPFS compared with EBRT, but similar MFS, CSS, and OS. A meta-analysis of the two RCTs showed superior bPFS with EBRT-BT (estimated fixed-effect hazard ratio [HR] 0.54 [95% confidence interval {CI} 0.40-0.72], p < 0.001), with absolute improvements in bPFS at 5-6 yr of 4.9-16%. However, no difference was seen for MFS (HR 0.84 [95% CI 0.53-1.28], p = 0.4) or OS (HR 0.87 [95% CI 0.63-1.19], p = 0.4). Fewer studies examined RP ± EBRT. There is an increased risk of severe late GU toxicity, especially with low-dose-rate EBRT-BT, with some evidence of increased prevalence of severe GU toxicity at 5-6 yr of 6.4-7% across the two RCTs., Conclusions: EBRT-BT can be considered for unfavourable intermediate/high-risk localised/locally advanced PCa in patients with good urinary function, although the strength of this recommendation based on the European Association of Urology guideline methodology is weak given that it is based on improvements in biochemical control., Patient Summary: We found good evidence that radiotherapy combined with brachytherapy keeps prostate cancer controlled for longer, but it could lead to worse urinary side effects than radiotherapy without brachytherapy, and its impact on cancer spread and patient survival is less clear., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Objective: The European Association of Urology (EAU)-European Association of Nuclear Medicine (EANM)-European Society for Radiotherapy and Oncology (ESTRO)-European Society of Urogenital Radiology (ESUR)-International Society of Urological Pathology (ISUP)-International Society of Geriatric Oncology (SIOG) guidelines provide recommendations for the management of clinically localised prostate cancer (PCa). This paper aims to present a summary of the 2024 version of the EAU-EANM-ESTRO-ESUR-ISUP-SIOG guidelines on the screening, diagnosis, and treatment of clinically localised PCa., Methods: The panel performed a literature review of all new data published in English, covering the time frame between May 2020 and 2023. The guidelines were updated, and a strength rating for each recommendation was added based on a systematic review of the evidence., Key Findings and Limitations: A risk-adapted strategy for identifying men who may develop PCa is advised, generally commencing at 50 yr of age and based on individualised life expectancy. The use of multiparametric magnetic resonance imaging in order to avoid unnecessary biopsies is recommended. When a biopsy is considered, a combination of targeted and regional biopsies should be performed. Prostate-specific membrane antigen positron emission tomography imaging is the most sensitive technique for identifying metastatic spread. Active surveillance is the appropriate management for men with low-risk PCa, as well as for selected favourable intermediate-risk patients with International Society of Urological Pathology grade group 2 lesions. Local therapies are addressed, as well as the management of persistent prostate-specific antigen after surgery. A recommendation to consider hypofractionation in intermediate-risk patients is provided. Patients with cN1 PCa should be offered a local treatment combined with long-term intensified hormonal treatment., Conclusions and Clinical Implications: The evidence in the field of diagnosis, staging, and treatment of localised PCa is evolving rapidly. These PCa guidelines reflect the multidisciplinary nature of PCa management., Patient Summary: This article is the summary of the guidelines for "curable" prostate cancer. Prostate cancer is "found" through a multistep risk-based screening process. The objective is to find as many men as possible with a curable cancer. Prostate cancer is curable if it resides in the prostate; it is then classified into low-, intermediary-, and high-risk localised and locally advanced prostate cancer. These risk classes are the basis of the treatments. Low-risk prostate cancer is treated with "active surveillance", a treatment with excellent prognosis. For low-intermediary-risk active surveillance should also be discussed as an option. In other cases, active treatments, surgery, or radiation treatment should be discussed along with the potential side effects to allow shared decision-making., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background and Objective: The European Association of Urology (EAU)-European Association of Nuclear Medicine (EANM)-European Society for Radiotherapy and Oncology (ESTRO)-European Society of Urogenital Radiology (ESUR)-International Society of Urological Pathology (ISUP)-International Society of Geriatric Oncology (SIOG) guidelines on the treatment of relapsing, metastatic, and castration-resistant prostate cancer (PCa) have been updated. Here we provide a summary of the 2024 guidelines., Methods: The panel performed a literature review of new data, covering the time frame between 2020 and 2023. The guidelines were updated and a strength rating for each recommendation was added on the basis of a systematic review of the evidence., Key Findings and Limitations: Risk stratification for relapsing PCa after primary therapy may guide salvage therapy decisions. New treatment options, such as androgen receptor-targeted agents (ARTAs), ARTA + chemotherapy combinations, PARP inhibitors and their combinations, and prostate-specific membrane antigen-based therapy have become available for men with metastatic PCa., Conclusions and Clinical Implications: Evidence for relapsing, metastatic, and castration-resistant PCa is evolving rapidly. These guidelines reflect the multidisciplinary nature of PCa management. The full version is available online (http://uroweb.org/guideline/ prostate-cancer/)., Patient Summary: This article summarises the 2024 guidelines for the treatment of relapsing, metastatic, and castration-resistant prostate cancer. These guidelines are based on evidence and guide doctors in discussing treatment decisions with their patients. The guidelines are updated every year., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: To establish the clinical applicability of deep-learning organ-at-risk autocontouring models (DL-AC) for brain radiotherapy. The dosimetric impact of contour editing, prior to model training, on performance was evaluated for both CT and MRI-based models. The correlation between geometric and dosimetric measures was also investigated to establish whether dosimetric assessment is required for clinical validation., Method: CT and MRI-based deep learning autosegmentation models were trained using edited and unedited clinical contours. Autosegmentations were dosimetrically compared to gold standard contours for a test cohort. D1%, D5%, D50%, and maximum dose were used as clinically relevant dosimetric measures. The statistical significance of dosimetric differences between the gold standard and autocontours was established using paired Student's t-tests. Clinically significant cases were identified via dosimetric headroom to the OAR tolerance. Pearson's Correlations were used to investigate the relationship between geometric measures and absolute percentage dose changes for each autosegmentation model., Results: Except for the right orbit, when delineated using MRI models, the dosimetric statistical analysis revealed no superior model in terms of the dosimetric accuracy between the CT DL-AC models or between the MRI DL-AC for any investigated brain OARs. The number of patients where the clinical significance threshold was exceeded was higher for the optic chiasm D1% than other OARs, for all autosegmentation models. A weak correlation was consistently observed between the outcomes of dosimetric and geometric evaluations., Conclusions: Editing contours before training the DL-AC model had no significant impact on dosimetry. The geometric test metrics were inadequate to estimate the impact of contour inaccuracies on dose. Accordingly, dosimetric analysis is needed to evaluate the clinical applicability of DL-AC models in the brain., (© 2024 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Ylidenenorbornadienes (YNDs), prepared by [4 + 2] cycloadditions between fulvenes and acetylene carboxylates, react with thiol nucleophiles to yield mixtures of four to eight diastereomers depending on the symmetry of the YND substrate. The mixtures of diastereomers fragment via a retro-[4 + 2] cycloaddition with a large variation in rate, with half-lives ranging from 16 to 11,000 min at 80 °C. The diastereomer-enriched samples of propane thiol adducts [YND-propanethiol (PTs)] were isolated and identified by nuclear Overhauser effect spectroscopy (NOESY) correlations. Simulated kinetics were used to extrapolate the rate constants of individual diastereomers from the observed rate data, and it correlated well with rate constants measured directly and from isolated diastereomer-enriched samples. The individual diastereomers of a model system fragment at differing rates with half-lives ranging from 5 to 44 min in CDCl 3 . Density functional theory calculations were performed to investigate the mechanism of fragmentation and support an asynchronous retro-[4 + 2] cycloaddition transition state. The computations generally correlated well with the observed free energies of activation for four diastereomers of the model system as a whole, within 2.6 kcal/mol. However, the observed order of the fragmentation rates across the set of diastereomers deviated from the computational results. YNDs display wide variability in the rate of fragmentation, dependent on the stereoelectronics of the ylidene substituents. A Hammett study showed that the electron-rich aromatic rings attached to the ylidene bridge increase the fragmentation rate, while electron-deficient systems slow fragmentation rates.

Context: The optimal management for men with prostate cancer (PCa) with unconventional histology (UH) is unknown. The outcome for these cancers might be worse than for conventional PCa and so different approaches may be needed., Objective: To compare oncological outcomes for conventional and UH PCa in men with localized disease treated with curative intent., Evidence Acquisition: A systematic review adhering to the Referred Reporting Items for Systematic Reviews and Meta-Analyses was prospectively registered on PROSPERO (CRD42022296013) was performed in July 2021., Evidence Synthesis: We screened 3651 manuscripts and identified 46 eligible studies (reporting on 1 871 814 men with conventional PCa and 6929 men with 10 different PCa UHs). Extraprostatic extension and lymph node metastases, but not positive margin rates, were more common with UH PCa than with conventional tumors. PCa cases with cribriform pattern, intraductal carcinoma, or ductal adenocarcinoma had higher rates of biochemical recurrence and metastases after radical prostatectomy than for conventional PCa cases. Lower cancer-specific survival rates were observed for mixed cribriform/intraductal and cribriform PCa. By contrast, pathological findings and oncological outcomes for mucinous and prostatic intraepithelial neoplasia (PIN)-like PCa were similar to those for conventional PCa. Limitations of this review include low-quality studies, a risk of reporting bias, and a scarcity of studies that included radiotherapy., Conclusions: Intraductal, cribriform, and ductal UHs may have worse oncological outcomes than for conventional and mucinous or PIN-like PCa. Alternative treatment approaches need to be evaluated in men with these cancers., Patient Summary: We reviewed the literature to explore whether prostate cancers with unconventional growth patterns behave differently to conventional prostate cancers. We found that some unconventional growth patterns have worse outcomes, so we need to investigate if they need different treatments. Urologists should be aware of these growth patterns and their clinical impact., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: Radiation therapy (RT) and chemoRT for pelvic cancers increase survival but are associated with serious treatment-related symptoms. Electronic-patient self-Reporting of Adverse-events: Patient Information and aDvice (eRAPID) is a secure online system for patients to self-report symptoms, generating immediate advice for hospital contact or self-management. This pilot study aimed to establish feasibility and acceptability of the system., Methods and Materials: In a prospective 2-center randomized parallel-group pilot study, patients undergoing radical pelvic RT for prostate cancer (prostateRT) or chemoRT for lower gastrointestinal and gynecological cancers were randomized to usual care (UC) or eRAPID (weekly online symptom reporting for 12, 18, and 24 weeks). Primary outcomes were recruitment/attrition, study completion, and patient adherence. Secondary outcomes were effect on hospital services and performance of patient outcome measures. Missing data, floor/ceiling effects, and mean change scores were examined for Functional Assessment of Cancer Therapy (FACT-G), European Organisation for Research and Treatment of Cancer, Quality of Life (EORTC QLQ C-30), self-efficacy, and EuroQol (EQ5D)., Results: From 228 patients approached, 167 (73.2%) were consented and randomized (83, eRAPID; 84, UC; 87, prostateRT; 80, chemoRT); 150 of 167 completed 24 study weeks. Only 16 patients (9.6%) withdrew (10, eRAPID; 6, UC). In the eRAPID arm, completion rates were higher in patients treated with prostateRT compared with chemoRT (week 1, 93% vs 69%; week 2, 93% vs 68%; week 12, 69% vs 55%). Overall, over 50% of online reports triggered self-management advice for milder adverse events. Unscheduled hospital contact was low, with no difference between eRAPID and UC. Return rates for outcome measures were excellent in prostateRT (97%-91%; 6-24 weeks) but lower in chemoRT (95%-55%; 6-24 weeks). Missing data were low (1%-4.1%), ceiling effects were evident in EQ5D-5L, self-efficacy-scale, and FACT-Physical Wellbeing. At 6 weeks, the chemoRT-eRAPID group showed less deterioration in FACT-G, EORTC QLQ-C30, and EQ5D-Visual Analogue Scale than UC, after baseline adjustment., Conclusions: eRAPID was successfully added to UC at 2 cancer centers in different patient populations. Acceptability and feasibility were confirmed with excellent adherence by prostate patients, but lower by those undergoing chemoRT for gynecological cancers., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

Ylidenenorbornadienes (YNDs), prepared by [4 + 2] cycloadditions between fulvenes and acetylene carboxylates, react with beta -mercaptoethanol to yield a mixture of four diastereomers. These four diastereomers fragment via a retro-[4 + 2] cycloaddition at differing rates. A simulated kinetics approach extrapolated the rate constants of the diastereomers from the observed rate data. YNDs display wide variability in rate of fragmentation, dependent on the stereoelectronics of the ylidene substituents. A substrate containing one carboxylic ester proved exceptionally stable to fragmentation.

Background: Early diagnosis of malignant spinal cord compression (SCC) is crucial because pretreatment neurological status is the major determinant of outcome. In metastatic castration-resistant prostate cancer, SCC is a clinically significant cause of disease-related morbidity and mortality. We investigated whether screening for SCC with spinal MRI, and pre-emptive treatment if radiological SCC (rSCC) was detected, reduced the incidence of clinical SCC (cSCC) in asymptomatic patients with metastatic castration-resistant prostate cancer and spinal metastasis., Methods: We did a parallel-group, open-label, randomised, controlled, phase 3, superiority trial. Patients with metastatic castration-resistant prostate cancer were recruited from 45 National Health Service hospitals in the UK. Eligible patients were aged at least 18 years, with an Eastern Co-operative Oncology Group performance status of 0-2, asymptomatic spinal metastasis, no previous SCC, and no spinal MRI in the past 12 months. Participants were randomly assigned (1:1), using a minimisation algorithm with a random element (balancing factors were treatment centre, alkaline phosphatase [normal vs raised, with the upper limit of normal being defined at each participating laboratory], number of previous systemic treatments [first-line vs second-line or later], previous spinal treatment, and imaging of thorax and abdomen), to no MRI (control group) or screening spinal MRI (intervention group). Serious adverse events were monitored in the 24 h after screening MRI in the intervention group. Participants with screen-detected rSCC were offered pre-emptive treatment (radiotherapy or surgical decompression was recommended per treating physician's recommendation) and 6-monthly spinal MRI. All patients were followed up every 3 months, and then at month 30 and 36. The primary endpoint was time to and incidence of confirmed cSCC in the intention-to-treat population (defined as all patients randomly assigned), with the primary timepoint of interest being 1 year after randomisation. The study is registered with ISRCTN, ISRCTN74112318, and is now complete., Findings: Between Feb 26, 2013, and April 25, 2017, 420 patients were randomly assigned to the control (n=210) or screening MRI (n=210) groups. Median age was 74 years (IQR 68 to 79), 222 (53%) of 420 patients had normal alkaline phosphatase, and median prostate-specific antigen concentration was 48 ng/mL (IQR 17 to 162). Screening MRI detected rSCC in 61 (31%) of 200 patients with assessable scans in the intervention group. As of data cutoff (April 23, 2020), at a median follow-up of 22 months (IQR 13 to 31), time to cSCC was not significantly improved with screening (hazard ratio 0·64 [95% CI 0·37 to 1·11]; Gray's test p=0·12). 1-year cSCC rates were 6·7% (95% CI 3·8-10·6; 14 of 210 patients) for the control group and 4·3% (2·1-7·7; nine of 210 patients) for the intervention group (difference -2·4% [95% CI -4·2 to 0·1]). Median time to cSCC was not reached in either group. No serious adverse events were reported within 24 h of screening., Interpretation: Despite the substantial incidence of rSCC detected in the intervention group, the rate of cSCC in both groups was low at a median of 22 months of follow-up. Routine use of screening MRI and pre-emptive treatment to prevent cSCC is not warranted in patients with asymptomatic castration-resistant prostate cancer with spinal metastasis., Funding: Cancer Research UK., Competing Interests: Declaration of interests EH reports grants from Cancer Research UK, during the conduct of the study and outside of the submitted work; grants and non-financial support from AstraZeneca and Bayer; and grants from Accuray, Varian Medical Systems, Janssen-Cilag, Roche Products, Merck Sharp & Dohme, and Pharma Limited (Sanofi). VH reports grants from Cancer Research UK, during the conduct of the study. GH reports speaker fees from Janssen outside the submitted work. CP reports speaker fees from Bayer and Janssen; advisory board fees from AAA, Clarity Pharmaceuticals, Myovant, ITM Radiopharma, and has an advisory board membership with Janssen and an education steering committee membership with Bayer, outside of the submitted work. DD reports grants from Cancer Research UK, during the conduct of the study; National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) grants; and a patent (EP1933709B1, issued for a localisation and stabilisation device), outside of the submitted work. AS reports NIHR BRC funding to The Royal Marsden Hospital, speaker fees from Pfizer, and being past president and on the executive board for International Cancer Imaging Society (without payment), outside the submitted work. MM reports participation on Data Monitoring Board and Advisory Board for Endocyte and Clovis, outside the submitted work. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: In the United States, approximately one quarter of individuals are living with disabilities and receiving healthcare services. The undergraduate medical school curriculum provides an opportunity to improve the attitudes and skills of physicians working with persons with disabilities (PWD)., Objective/hypothesis: The purpose of this study was to gain an understanding about fourth-year medical students' self-reported attitudes towards and experiences with PWD and disability education. We hypothesized that medical students would recall having education about disabilities, would be able to identify a pivotal disability education experience, and would report being less comfortable working with PWD than persons without disabilities., Methods: This mixed methods observational study was conducted via an online survey distributed to medical students during Winter 2020/2021. It contained an adapted instrument and a few short answer questions., Results: Our survey had 44 respondents, a 28% response rate. Though 98% of students reported receiving disability education during one or more courses, 80% felt their disability education during medical school has been inadequate. Additionally, 64% reported having an influential learning experience involving PWD. Despite their attitudes, education, and experiences, respondents reported feeling less comfortable obtaining a history, performing a physical exam, and establishing a differential diagnosis when working with PWD., Conclusions: This study highlights the need for continued development of disability curricula, which likely extends beyond the studied institution. Additional educational elements could be added to humanities sessions, as well as other courses and clerkships., Competing Interests: Conflict of interest The authors have nothing to disclose and have no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Context: There is uncertainty regarding the most appropriate criteria for recruitment, monitoring, and reclassification in active surveillance (AS) protocols for localised prostate cancer (PCa)., Objective: To perform a qualitative systematic review (SR) to issue recommendations regarding inclusion of intermediate-risk disease, biopsy characteristics at inclusion and monitoring, and repeat biopsy strategy., Evidence Acquisition: A protocol-driven, Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)-adhering SR incorporating AS protocols published from January 1990 to October 2020 was performed. The main outcomes were criteria for inclusion of intermediate-risk disease, monitoring, reclassification, and repeat biopsy strategies (per protocol and/or triggered). Clinical effectiveness data were not assessed., Evidence Synthesis: Of the 17 011 articles identified, 333 studies incorporating 375 AS protocols, recruiting 264 852 patients, were included. Only a minority of protocols included the use of magnetic resonance imaging (MRI) for recruitment (n = 17), follow-up (n = 47), and reclassification (n = 26). More than 50% of protocols included patients with intermediate or high-risk disease, whilst 44.1% of protocols excluded low-risk patients with more than three positive cores, and 39% of protocols excluded patients with core involvement (CI) >50% per core. Of the protocols, ≥80% mandated a confirmatory transrectal ultrasound biopsy; 72% (n = 189) of protocols mandated per-protocol repeat biopsies, with 20% performing this annually and 25% every 2 yr. Only 27 protocols (10.3%) mandated triggered biopsies, with 74% of these protocols defining progression or changes on MRI as triggers for repeat biopsy., Conclusions: For AS protocols in which the use of MRI is not mandatory or absent, we recommend the following: (1) AS can be considered in patients with low-volume International Society of Urological Pathology (ISUP) grade 2 (three or fewer positive cores and cancer involvement ≤50% CI per core) or another single element of intermediate-risk disease, and patients with ISUP 3 should be excluded; (2) per-protocol confirmatory prostate biopsies should be performed within 2 yr, and per-protocol surveillance repeat biopsies should be performed at least once every 3 yr for the first 10 yr; and (3) for patients with low-volume, low-risk disease at recruitment, if repeat systematic biopsies reveal more than three positive cores or maximum CI >50% per core, they should be monitored closely for evidence of adverse features (eg, upgrading); patients with ISUP 2 disease with increased core positivity and/or CI to similar thresholds should be reclassified., Patient Summary: We examined the literature to issue new recommendations on active surveillance (AS) for managing localised prostate cancer. The recommendations include setting criteria for including men with more aggressive disease (intermediate-risk disease), setting thresholds for close monitoring of men with low-risk but more extensive disease, and determining when to perform repeat biopsies (within 2 yr and 3 yearly thereafter)., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

The absorption spectra of a series of dithiocarboxylates were investigated in the ultraviolet-visible region. Two questions that this study aimed to address were as follows: (1) What transitions give rise to the features in the electronic spectra? And (2) what are the long- and short-range substituent effects on the absorption spectra? A series of 11 dithiocarboxylates were prepared as organic soluble salts. Time-dependent density functional theory (TDDFT) was used to calculate excited state energies and oscillator strengths of electronic transitions. TDDFT at the CAM-B3LYP/def2-TZVPD level of theory predicts two low-energy n → π* transitions and two π → π* transitions at higher energy, consistent with the experimental spectra. This state ordering and density is in contrast to the better studied thiocarbonyls for which only two transitions within the singlet manifold appear in the UV-visible region. For derivatives of dithiobenzoate, the energy of the three lowest energy states are insensitive to changes to substituents para to the dithiocarboxylate group. In contrast, the energy of the highest ππ* state varies by 0.78 eV. This work shows that the results of TDDFT calculations can be used to predict the electronic absorption spectra of dithiocarboxylates, providing a useful tool for designing dithiocarboxylate light absorbers., (© 2022. The Author(s), under exclusive licence to European Photochemistry Association, European Society for Photobiology.)

Introduction: Stereotactic Ablative Radiotherapy (SABR) is increasingly used to treat metastatic oligorecurrence and locoregional recurrences but limited evidence/guidance exists in the setting of pelvic re-irradiation. An international Delphi study was performed to develop statements to guide practice regarding patient selection, pre-treatment investigations, treatment planning, delivery and cumulative organs at risk (OARs) constraints., Materials and Methods: Forty-one radiation oncologists were invited to participate in three online surveys. In Round 1, information and opinion was sought regarding participants' practice. Guidance statements were developed using this information and in Round 2 participants were asked to indicate their level of agreement with each statement. Consensus was defined as ≥75% agreement. In Round 3, any statements without consensus were re-presented unmodified, alongside a summary of comments from Round 2., Results: Twenty-three radiation oncologists participated in Round 1 and, of these, 21 (91%) and 22 (96%) completed Rounds 2 and 3 respectively. Twenty-nine of 44 statements (66%) achieved consensus in Round 2. The remaining 15 statements (34%) did not achieve further consensus in Round 3. Consensus was achieved for 10 of 17 statements (59%) regarding patient selection/pre-treatment investigations; 12 of 13 statements (92%) concerning treatment planning and delivery; and 7 of 14 statements (50%) relating to OARs. Lack of agreement remained regarding the minimum time interval between irradiation courses, the number/size of pelvic lesions that can be treated and the most appropriate cumulative OAR constraints., Conclusions: This study has established consensus, where possible, in areas of patient selection, pre-treatment investigations, treatment planning and delivery for pelvic SABR re-irradiation for metastatic oligorecurrence and locoregional recurrences. Further research into this technique is required, especially regarding aspects of practice where consensus was not achieved., Competing Interests: Declarations/conflicts of interest statement FS is a Clinical Research Fellow supported by a Cancer Research UK Centres Network Accelerator Award to the ART-NET consortium (grant number A21993). FA reports speaker honoraria and consultancy for Varian and Elekta. BAJF reports institutional research funding grants from Italian Association for Cancer Research (AIRC), FIEO-CCM & FUV and Accuray, outside of the submitted work. BAJF reports travel expenses/speaker fees from Janssen, Ferring, Bayer, Roche, Astellas, Elekta, Carl Zeiss, Ipsen, Accuray and IBA, outside of the submitted work. MAH is supported by funding from the NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust. AMH is supported by grants from Cancer Research UK (award number 108036), National Institute for Health Research (NIHR) (award number 111218), Medical Research Council (MRC) (award number 107154) and Sir John Fisher Foundation (charity, no award number). LJM is an associate professor supported by a Yorkshire Cancer Research funded by Yorkshire Cancer Research (award number L389LM)., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Limited evidence exists showing the benefit of magnetic resonance (MR)-only radiotherapy treatment planning for anal and rectal cancers. This study aims to assess the impact of MR-only planning on target volumes (TVs) and treatment plan doses to organs at risks (OARs) for anal and rectal cancers versus a computed tomography (CT)-only pathway., Materials and Methods: Forty-six patients (29 rectum and 17 anus) undergoing preoperative or radical external beam radiotherapy received CT and T2 MR simulation. TV and OARs were delineated on CT and MR, and volumetric arc therapy treatment plans were optimized independently (53.2 Gy/28 fractions for anus, 45 Gy/25 fractions for rectum). Further treatment plans assessed gross tumor volume (GTV) dose escalation. Differences in TV volumes and OAR doses, in terms of Vx Gy (organ volume (%) receiving x dose (Gy)), were assessed., Results: MR GTV and primary planning TV (PTV) volumes systematically reduced by 13 cc and 98 cc (anus) and 44 cc and 109 cc (rectum) respectively compared to CT volumes. Statistically significant OAR dose reductions versus CT were found for bladder and uterus (rectum) and bladder, penile bulb, and genitalia (anus). With GTV boosting, statistically significant dose reductions were found for sigmoid, small bowel, vagina, and penile bulb (rectum) and vagina (anus)., Conclusion: Our findings provide evidence that the introduction of MR (whether through MR-only or CT-MR pathways) to radiotherapy treatment planning for anal and rectal cancers has the potential to improve treatments. MR-related OAR dose reductions may translate into less treatment-related toxicity for patients or greater ability to dose escalate., (© 2021 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

The neocortex is disproportionately expanded in human compared with mouse 1,2 , both in its total volume relative to subcortical structures and in the proportion occupied by supragranular layers composed of neurons that selectively make connections within the neocortex and with other telencephalic structures. Single-cell transcriptomic analyses of human and mouse neocortex show an increased diversity of glutamatergic neuron types in supragranular layers in human neocortex and pronounced gradients as a function of cortical depth 3 . Here, to probe the functional and anatomical correlates of this transcriptomic diversity, we developed a robust platform combining patch clamp recording, biocytin staining and single-cell RNA-sequencing (Patch-seq) to examine neurosurgically resected human tissues. We demonstrate a strong correspondence between morphological, physiological and transcriptomic phenotypes of five human glutamatergic supragranular neuron types. These were enriched in but not restricted to layers, with one type varying continuously in all phenotypes across layers 2 and 3. The deep portion of layer 3 contained highly distinctive cell types, two of which express a neurofilament protein that labels long-range projection neurons in primates that are selectively depleted in Alzheimer's disease 4,5 . Together, these results demonstrate the explanatory power of transcriptomic cell-type classification, provide a structural underpinning for increased complexity of cortical function in humans, and implicate discrete transcriptomic neuron types as selectively vulnerable in disease., (© 2021. The Author(s).)