Measuring social determinants of health in the All of Us Research Program.

To accelerate medical breakthroughs, the All of Us Research Program aims to collect data from over one million participants. This report outlines processes used to construct the All of Us Social Determinants of Health (SDOH) survey and presents the psychometric characteristics of SDOH survey measures in All of Us. A consensus process was used to select SDOH measures, prioritizing concepts validated in diverse populations and other national cohort surveys. Survey item non-response was calculated, and Cronbach's alpha was used to analyze psychometric properties of scales. Multivariable logistic regression models were used to examine associations between demographic categories and item non-response. Twenty-nine percent (N = 117,783) of eligible All of Us participants submitted SDOH survey data for these analyses. Most scales had less than 5% incalculable scores due to item non-response. Patterns of item non-response were seen by racial identity, educational attainment, income level, survey language, and age. Internal consistency reliability was greater than 0.80 for almost all scales and most demographic groups. The SDOH survey demonstrated good to excellent reliability across several measures and within multiple populations underrepresented in biomedical research. Bias due to survey non-response and item non-response will be monitored and addressed as the survey is fielded more completely.

Genomic evolution shapes prostate cancer disease type.

The development of cancer is an evolutionary process involving the sequential acquisition of genetic alterations that disrupt normal biological processes, enabling tumor cells to rapidly proliferate and eventually invade and metastasize to other tissues. We investigated the genomic evolution of prostate cancer through the application of three separate classification methods, each designed to investigate a different aspect of tumor evolution. Integrating the results revealed the existence of two distinct types of prostate cancer that arise from divergent evolutionary trajectories, designated as the Canonical and Alternative evolutionary disease types. We therefore propose the evotype model for prostate cancer evolution wherein Alternative-evotype tumors diverge from those of the Canonical-evotype through the stochastic accumulation of genetic alterations associated with disruptions to androgen receptor DNA binding. Our model unifies many previous molecular observations, providing a powerful new framework to investigate prostate cancer disease progression.

Development of a Wound-Healing Protocol for In Vitro Evaluation of Urothelial Cell Growth.

Urethral healing is plagued by strictures, impacting quality of life and medical costs. Various growth factors (GFs) have shown promise as therapeutic approaches to improve healing, but there is no protocol for in vitro comparison between GFs. This study focuses the development of a biomimetic in vitro urothelial healing assay designed to mimic early in vivo healing, followed by an evaluation of urothelial cell growth in response to GFs. METHODS: Wound-healing assays were developed with human urothelial cells and used to compared six GFs (EGF, FGF-2, IGF-1, PDGF, TGF-ß1, and VEGF) at three concentrations (1 ng/mL, 10 ng/mL, and 100 ng/mL) over a 48 h period. A commercial GF-containing medium (EGF, TGF-α, KGF, and Extract P) and a GF-free medium were used as controls. RESULTS: There was a statistically significant increase in cell growth for IGF-1 at 10 and 100 ng/mL compared to both controls (p < 0.05). There was a statistically significant increase in cell growth for EGF at all concentrations compared to the GF-free medium control (p < 0.05). CONCLUSION: This study shows the development of a clinically relevant wound-healing assay to evaluate urothelial cell growth. It is the first to compare GFs for future use in reconstructive techniques to improve urethral healing.

Evaluating Intersite Consistency Across 11 Geographically Distinct Pediatric Clerkship Training Sites: Providing Assurance That Educational Comparability Is Possible.

INTRODUCTION: We compared core pediatric clerkship student assessments across 11 geographically distinct learning environments following a major curriculum change. We sought to determine if intersite consistency existed, which can be used as a marker of program evaluation success. METHODS: We evaluated students' overall pediatric clerkship performance along with individual assessments that target our clerkship learning objectives. Using the data of graduating classes from 2015 to 2019 (N = 859), we conducted an analysis of covariance and multivariate logistic regression analysis to investigate whether the performance varied across training sites. RESULTS: Of the students, 833 (97%) were included in the study. The majority of the training sites did not show statistically significant differences from each other. After controlling for the Medical College Admission Test total score and the average pre-clerkship National Board of Medical Examiners final exam score, the clerkship site only explained a 3% additional variance of the clerkship final grade. CONCLUSIONS: Over the ensuing 5-year period after a curriculum overhaul to an 18-month, integrated module pre-clerkship curriculum, we found that student pediatric clerkship performance in clinical knowledge and skills did not differ significantly across 11 varied geographic teaching sites when controlling for students' pre-clerkship achievement. Specialty-specific curriculum resources, faculty development tools, and assessment of learning objectives may provide a framework for maintaining intersite consistency when faced with an expanding network of teaching facilities and faculty.

The architecture of clonal expansions in morphologically normal tissue from cancerous and non-cancerous prostates.

BACKGROUND: Up to 80% of cases of prostate cancer present with multifocal independent tumour lesions leading to the concept of a field effect present in the normal prostate predisposing to cancer development. In the present study we applied Whole Genome DNA Sequencing (WGS) to a group of morphologically normal tissue (n = 51), including benign prostatic hyperplasia (BPH) and non-BPH samples, from men with and men without prostate cancer. We assess whether the observed genetic changes in morphologically normal tissue are linked to the development of cancer in the prostate. RESULTS: Single nucleotide variants (P = 7.0 × 10-03, Wilcoxon rank sum test) and small insertions and deletions (indels, P = 8.7 × 10-06) were significantly higher in morphologically normal samples, including BPH, from men with prostate cancer compared to those without. The presence of subclonal expansions under selective pressure, supported by a high level of mutations, were significantly associated with samples from men with prostate cancer (P = 0.035, Fisher exact test). The clonal cell fraction of normal clones was always higher than the proportion of the prostate estimated as epithelial (P = 5.94 × 10-05, paired Wilcoxon signed rank test) which, along with analysis of primary fibroblasts prepared from BPH specimens, suggests a stromal origin. Constructed phylogenies revealed lineages associated with benign tissue that were completely distinct from adjacent tumour clones, but a common lineage between BPH and non-BPH morphologically normal tissues was often observed. Compared to tumours, normal samples have significantly less single nucleotide variants (P = 3.72 × 10-09, paired Wilcoxon signed rank test), have very few rearrangements and a complete lack of copy number alterations. CONCLUSIONS: Cells within regions of morphologically normal tissue (both BPH and non-BPH) can expand under selective pressure by mechanisms that are distinct from those occurring in adjacent cancer, but that are allied to the presence of cancer. Expansions, which are probably stromal in origin, are characterised by lack of recurrent driver mutations, by almost complete absence of structural variants/copy number alterations, and mutational processes similar to malignant tissue. Our findings have implications for treatment (focal therapy) and early detection approaches.

Rare Germline Variants Are Associated with Rapid Biochemical Recurrence After Radical Prostate Cancer Treatment: A Pan Prostate Cancer Group Study.

BACKGROUND: Germline variants explain more than a third of prostate cancer (PrCa) risk, but very few associations have been identified between heritable factors and clinical progression. OBJECTIVE: To find rare germline variants that predict time to biochemical recurrence (BCR) after radical treatment in men with PrCa and understand the genetic factors associated with such progression. DESIGN, SETTING, AND PARTICIPANTS: Whole-genome sequencing data from blood DNA were analysed for 850 PrCa patients with radical treatment from the Pan Prostate Cancer Group (PPCG) consortium from the UK, Canada, Germany, Australia, and France. Findings were validated using 383 patients from The Cancer Genome Atlas (TCGA) dataset. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A total of 15,822 rare (MAF <1%) predicted-deleterious coding germline mutations were identified. Optimal multifactor and univariate Cox regression models were built to predict time to BCR after radical treatment, using germline variants grouped by functionally annotated gene sets. Models were tested for robustness using bootstrap resampling. RESULTS AND LIMITATIONS: Optimal Cox regression multifactor models showed that rare predicted-deleterious germline variants in "Hallmark" gene sets were consistently associated with altered time to BCR. Three gene sets had a statistically significant association with risk-elevated outcome when modelling all samples: PI3K/AKT/mTOR, Inflammatory response, and KRAS signalling (up). PI3K/AKT/mTOR and KRAS signalling (up) were also associated among patients with higher-grade cancer, as were Pancreas-beta cells, TNFA signalling via NKFB, and Hypoxia, the latter of which was validated in the independent TCGA dataset. CONCLUSIONS: We demonstrate for the first time that rare deleterious coding germline variants robustly associate with time to BCR after radical treatment, including cohort-independent validation. Our findings suggest that germline testing at diagnosis could aid clinical decisions by stratifying patients for differential clinical management. PATIENT SUMMARY: Prostate cancer patients with particular genetic mutations have a higher chance of relapsing after initial radical treatment, potentially providing opportunities to identify patients who might need additional treatments earlier.

Caller ID for Risso's and Pacific White-sided dolphins.

Tracking species with expanding ranges is crucial to conservation efforts and some typically temperate marine species are spreading northward into the Arctic Ocean. Risso's (Gg) and Pacific white-sided (Lo) dolphins have been documented spreading poleward. Further, they make very similar sounds, so it is difficult for both human analysts and classification algorithms to tell them apart. Using automatic detectors and classifiers on large acoustic datasets would improve the efficiency of monitoring these species. variational mode decomposition (VMD) provides both an easier visualization tool for human analysts and exhibited robustness to background noise while extracting features in pulsed signals with very similar spectral properties. The goal of this work was to develop a new visualization tool using VMD and a statistics-based classification algorithm to differentiate similar pulsed signals. The proposed VMD method achieved 81% accuracy, even when using audio files with low SNR that did not have concurrent visual survey data. While many dolphins whistle, pulsed signals are one of the more useful vocalizations to use in detection and classification because of their species-specific acoustic features. Automating the VMD method and expanding it to other dolphin species that have very similar pulsed signals would complement current detection and classification methods and lead to a more complete understanding of ecosystem dynamics under a changing climate.

Do the materials matter? A review of the literature and analysis of the materials properties of urethral stents for hypospadias repair.

INTRODUCTION: Despite the prevalence of hypospadias surgery and the common use of postoperative urethral stents, there has been no evaluation of the material properties of common stents. Our study sets out to close this gap with a literature review of recent publications comparing outcomes after hypospadias surgery for different urethral stent types and an evaluation of the material properties of four common urethral stents. STUDY DESIGN: A review of the English language literature from 2011 to 2021 was performed. Thermal analysis and mechanical analysis of the Zaontz Urethral Stent, the Firlit-Kluge Urethral Stent, the Koyle Diaper Stent, and the Bard Premature Infant Feeding Tube was also undertaken. RESULTS: Out of 165 papers, four met inclusion criteria. There was limited research on this topic, and no significant evidence that different stent materials impacted surgical complication rates. One study found improved comfort with the Zaontz stent, and another found a reduction emergency room visits with the Koyle stent. Using a foley balloon was associated with increased fistula rates, though this was likely due to the balloon design and not the material. Analysis of stents shows that all four are rubbery polymers at body temperature (Summary Table). The Zaontz and Koyle stents are thermoplastic elastomers with strong melting transitions above body temperature, but the Firlit-Kluge stent is amorphous at 37 °C and is likely covalently cross-linked to generate the network. The Bard feeding tube was the stiffest, with a Young's Modulus of 14.0 ± 0.78 (compared to 4.12 ± 0.56 for Zaontz, 4.92 ± 0.63 for Firlit-Kluge, and 4.09 ± 0.49 for Koyle). The Bard Feeding Tube is also the least extensible, fracturing at just over 300% strain compared to the other stents that can be stretched to greater than 2000% strain before fracture. Cyclic deformation studies demonstrate that the Zaontz, Firlit-Kluge, and Koyle stents are able to stretch and recover their shape more completely, a finding determined by the lower amount of plastic deformation those stents display compared to the Bard Feeding Tube. DISCUSSION: While there is little information associating urethral stent type with outcomes after hypospadias surgery, material properties may account for findings of prior studies. Stiffer stents may contribute to decreased postoperative comfort, while a stent that is too soft and extensible may have issues with dislodgement, kinking and breaking. CONCLUSION: This study provides the foundation for future work optimizing urethral stents, designing support for regenerative medicine applications, and improving hypospadias outcomes.

Use of Web-Based Calculator for the Implementation of ACR TI-RADS Risk-Stratification System.

In this article, we demonstrate the use of a software-based radiologist reporting tool for the implementation of American College of Radiology Thyroid Imaging, Reporting and Data System thyroid nodule risk-stratification. The technical details are described with emphasis on addressing the information security and patient privacy issues while allowing it to integrate with the electronic health record and radiology reporting dictation software. Its practical implementation is assessed in a quality improvement project in which guideline adherence and recommendation congruence were measured pre and post implementation. The descriptions of our solution and the release of the open-sourced codes may be helpful in future implementation of similar web-based calculators.

Tissue Engineering Opportunities for Vaginal Replacement in a Pediatric Population.

Treatment for children born with vaginal agenesis remains difficult, without a clear gold standard for tissue replacement. An autologous-engineered vaginal replacement would significantly improve quality of life for people born with this condition. The aim of this study was to critically review literature on the current state of tissue engineering for vaginal reconstruction in a pediatric population. An electronic literature search was conducted using PubMed for articles describing pediatric vaginal tissue engineering from January 2003 to December 2020. Nine studies met inclusion criteria and were reviewed. The model, methods, cell type and source, scaffold type, and time of analysis and evaluation were compared. Three studies used in vitro and six used an in vivo design. Of the six in vivo studies, one was able to investigate autologous vaginal epithelial cells in human clinical trials. This review discusses the current knowledge and progress of vaginal tissue engineered replacements that can potentially be used as a basis for both future preclinical animal and clinical human studies. Impact statement The current methods of treatment for congenital vaginal anomalies leave room for improvement. The state of tissue engineering may provide a method to improve the surgical interventions provided for these patients, in hopes of providing increased vaginal functionally and quality of life.

COVID-19 and the case for global development.

COVID-19 accentuates the case for a global, rather than an international, development paradigm. The novel disease is a prime example of a development challenge for all countries, through the failure of public health as a global public good. The COVID-19 pandemic has highlighted the falsity of any assumption that the global North has all the expertise and solutions to tackle global challenges, and has further highlighted the need for multi-directional learning and transformation in all countries towards a more sustainable and equitable world. We illustrate our argument for a global development paradigm by examining the implications of the COVID-19 pandemic across four themes or 'vignettes': global value chains, digitalisation, debt, and climate change. We conclude that development studies must adapt to a very different context from when the field emerged in the mid-20th century.

Author Correction: The evolutionary history of lethal metastatic prostate cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Diversity and inclusion for the All of Us research program: A scoping review.

The All of Us Research Program (All of Us) is a national effort to accelerate health research by exploring the relationship between lifestyle, environment, and genetics. It is set to become one of the largest research efforts in U.S. history, aiming to build a national resource of data from at least one million participants. All of Us aims to address the need for more diversity in research and set the stage for that diversity to be leveraged in precision medicine research to come. This paper describes how the program assessed demographic characteristics of participants who have enrolled in other U.S. biomedical research cohorts to better understand which groups are traditionally represented or underrepresented in biomedical research. We 1) reviewed the enrollment characteristics of national cohort studies like All of Us, and 2) surveyed the literature, focusing on key diversity categories essential to the program's enrollment aims. Based on these efforts, All of Us emphasizes enrollment of racial and ethnic minorities, and has formally designated the following additional groups as historically underrepresented: individuals-with inadequate access to medical care; under the age of 18 or over 65; with an annual household income at or below 200% of the federal poverty level; who have a cognitive or physical disability; have less than a high school education or equivalent; are intersex; identify as a sexual or gender minority; or live in rural or non-metropolitan areas. Research accounting for wider demographic variability is critical. Only by ensuring diversity and by addressing the very barriers that limit it, can we position All of Us to better understand and tackle health disparities.

Trace manganese detection via differential pulse cathodic stripping voltammetry using disposable electrodes: additively manufactured nanographite electrochemical sensing platforms.

Additive manufacturing is a promising technology for the rapid and economical fabrication of portable electroanalytical devices. In this paper we seek to determine how our bespoke additive manufacturing feedstocks act as the basis of an electrochemical sensing platform towards the sensing of manganese(ii) via differential pulse cathodic stripping voltammetry (DPCSV), despite the electrode comprising only 25 wt% nanographite and 75 wt% plastic (polylactic acid). The Additive Manufactured electrodes (AM-electrodes) are also critically compared to graphite screen-printed macroelectrodes (SPEs) and both are explored in model and real tap-water samples. Using optimized DPCSV conditions at pH 6.0, the analytical outputs using the AM-electrodes are as follows: limit of detection, 1.6 × 10-9 mol L-1 (0.09 µg L-1); analytical sensitivity, 3.4 µA V µmol-1 L; linear range, 9.1 × 10-9 mol L-1 to 2.7 × 10-6 mol L-1 (R2 = 0.998); and RSD 4.9% (N = 10 for 1 µmol L-1). These results are compared to screen-printed macroelectrodes (SPEs) giving comparable results providing confidence that AM-electrodes can provide the basis for useful electrochemical sensing platforms. The proposed electroanalytical method (both AM-electrodes and SPEs) is shown to be successfully applied for the determination of manganese(ii) in tap water samples and in the analysis of a certified material (drinking water). The proposed method is feasible to be applied for in-loco analyses due to the portability of sensing; in addition, the use of AM-printed electrodes is attractive due to their low cost.

Tailoring the electrochemical properties of 2D-hBN via physical linear defects: physicochemical, computational and electrochemical characterisation.

Monolayer hexagonal-boron nitride films (2D-hBN) are typically reported within the literature to be electrochemically inactive due to their considerable band gap (ca. 5.2-5.8 eV). It is demonstrated herein that introducing physical linear defects (PLDs) upon the basal plane surface of 2D-hBN gives rise to electrochemically useful signatures. The reason for this transformation from insulator to semiconductor (inferred from physicochemical and computational characterisation) is likely due to full hydrogenation and oxygen passivation of the boron and/or nitrogen at edge sites. This results in a decrease in the band gap (from ca. 6.11 to 2.36/2.84 eV; theoretical calculated values, for the fully hydrogenated oxygen passivation at the N or B respectively). The 2D-hBN films are shown to be tailored through the introduction of PLDs, with the electrochemical behaviour dependent upon the surface coverage of edge plane-sites/defects, which is correlated with electrochemical performance towards redox probes (hexaammineruthenium(iii) chloride and Fe2+/3+) and the hydrogen evolution reaction. This manuscript de-convolutes, for the first time, the fundamental electron transfer properties of 2D-hBN, demonstrating that through implementation of PLDs, one can beneficially tailor the electrochemical properties of this nanomaterial.

A Multicentre Analysis of the Detection of Clinically Significant Prostate Cancer Following Transperineal Image-fusion Targeted and Nontargeted Systematic Prostate Biopsy in Men at Risk.

BACKGROUND: Prostate biopsy guided by magnetic resonance imaging (MRI) is increasingly used to obtain tissue from men with suspected prostate cancer (PC). OBJECTIVE: To report a multicentre series of image-fusion transperineal prostate biopsies and compare the diagnostic yield of clinically significant PC (csPC) between targeted and nontargeted biopsies. DESIGN, SETTING, AND PARTICIPANTS: The study included 640 consecutive patients with elevated prostate specific antigen (PSA) presenting for first biopsy or following a previous negative transrectal biopsy under the care of 13 urologists in 11 centres in the UK (April 2014-June 2017). INTERVENTION: Multiparametric MRI was carried out in 61 approved prostate MRI centres with transperineal targeted alone (n=283) or targeted plus nontargeted (n=357) transperineal rigid image-fusion targeted biopsy (MIM-Symphony-DX). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Rates of csPC and insignificant cancer detection in targeted and nontargeted biopsies were measured using a number of thresholds to define clinical significance. The primary definition was Gleason≥4+3 or any grade ≥6mm. RESULTS AND LIMITATIONS: The mean age, median PSA, and median prostate volume for the cohort were 63.8yr (standard deviation [SD] 8.4), 6.3 ng/ml (SD 5.8), and 42.0cm3 (SD 24.7), respectively. Overall, 276/640 men (43.1%) were diagnosed with csPC. csPC was detected from targeted biopsies alone in 263/640 cases (41.1%). Of the 357 men who underwent nontargeted biopsies, three (0.8%) had csPC exclusively in nontargeted cores, with no evidence of cancer in targeted cores. Overall, 32/357 (9.0%) had csPC in nontargeted biopsies regardless of the targeted biopsy findings. Clinically insignificant disease in nontargeted biopsies was detected in 93/357 men (26.1%). Our findings were consistent across all other thresholds of clinical significance. Limitations include the lack of nontargeted biopsies in all men. CONCLUSIONS: In this large multicentre series, nontargeted prostate biopsy cores had a low yield of csPC and a high yield of clinically insignificant PC. An image-fusion targeted-biopsy-only approach maintains high detection for csPC and low detection of clinically insignificant cancers. PATIENT SUMMARY: In this report, we found that following prostate multiparametric magnetic resonance imaging and targeted transperineal biopsies of suspicious areas, the clinical value of performing additional extensive unguided biopsies of nonsuspicious areas is limited and can often find insignificant cancers that do not need treatment.

Quick Test for Determination of N-Bombs (Phenethylamine Derivatives, NBOMe) Using High-Performance Liquid Chromatography: A Comparison between Photodiode Array and Amperometric Detection.

The emergence of a new class of novel psychoactive substances, N-benzyl-substituted phenethylamine derivatives so-called "NBOMes" or "Smiles", in the recreational drug market has forced the development of new sensitive analytical methodologies for their detection and quantitation. NBOMes' hallucinogenic effects mimic those of the illegal psychedelic drug lysergic acid diethylamide (LSD) and are typically sold as LSD on blotter papers, resulting in a remarkable number of fatalities worldwide. In this article, four halide derivatives of NBOMe, namely, 2-(4-fluoro-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethan-1-amine, 2-(4-chloro-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethan-1-amine, 2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethan-1-amine, and 2-(4-iodo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethan-1-amine, were detected and quantified simultaneously using a high-performance liquid chromatographic method, and two detection systems were compared: photodiode array detection (detection system I) and amperometric detection via a commercially available impinging jet flow-cell system incorporating embedded graphite screen-printed macroelectrodes (detection system II). Under optimized experimental conditions, linear calibration plots were obtained in the concentration range of 10-300 and 20-300 µg mL-1, for detection systems I and II, respectively. Detection limit (limit of detection) values were between 4.6-6.7 and 9.7-18 µg mL-1, for detection systems I and II, respectively. Both detectors were employed for the analysis of the four NBOMe derivatives in the bulk form, in the presence of LSD and adulterants commonly found in street samples (e.g. paracetamol, caffeine, and benzocaine). Furthermore, the method was applied for the analysis of simulated blotter papers, and the obtained percentage recoveries were satisfactory, emphasizing its advantageous applicability for the routine analysis of NBOMes in forensic laboratories.

Complete Additively Manufactured (3D-Printed) Electrochemical Sensing Platform.

Herein, we report a complete additively manufactured (AM) electrochemical sensing platform. In this approach, a fully AM/3D-printed electrochemical system, using a conventional low-cost 3D printer (fused deposition modeling) fabricating both the conductive electrodes and the nonconductive/chemically inert electrochemical cell is reported. The electrodes (working, counter, and pseudo-reference) are AM using a conductive fused-filament comprised of a mixture of carbon black nanoparticles and polylactic acid (CB/PLA). AM components partially coated with silver ink presented a similar behavior to a conventional Ag/AgCl reference electrode. The performance of the AM working electrode was evaluated after a simple and fast polishing procedure on sandpaper and electrochemical activation in a NaOH solution (0.5 mol L-1). Following the electrochemical activation step, a considerable improvement in the electrochemical behavior (current intensity and voltammetric profile) was obtained for model analytes, such as dopamine, hexaammineruthenium(III) chloride, ferricyanide/ferrocyanide, uric acid, and ascorbic acid. Excellent repeatability (RSD = 0.4%, N = 10) and limit of detection (0.1 µmol L-1) were obtained with the all complete AM electrochemical system for dopamine analysis. The electrochemical performance of the developed system (after simple electrochemical activation of the working electrode) was similar or better than those obtained using commercial glassy carbon and screen-printed carbon electrodes. The results shown here represents a significant advance in AM (3D printing) technology for analytical chemistry.