Previous research has identified ribose aminooxazoline as a potential intermediate in the prebiotic synthesis of the pyrimidine nucleotides with remarkable properties. It crystallizes spontaneously from reaction mixtures, with an enhanced enantiomeric excess if initially enantioenriched, which suggests that reservoirs of this compound might have accumulated on the early Earth in an optically pure form. Ribose aminooxazoline can be converted efficiently into α-ribocytidine by way of 2,2'-anhydroribocytidine, although anomerization to β-ribocytidine by ultraviolet irradiation is extremely inefficient. Our previous work demonstrated the synthesis of pyrimidine β-ribonucleotides, but at the cost of ignoring ribose aminooxazoline, using arabinose aminooxazoline instead. Here we describe a long-sought route through ribose aminooxazoline to the pyrimidine β-ribonucleosides and their phosphate derivatives that involves an extraordinarily efficient photoanomerization of α-2-thioribocytidine. In addition to the canonical nucleosides, our synthesis accesses β-2-thioribouridine, a modified nucleoside found in transfer RNA that enables both faster and more-accurate nucleic acid template-copying chemistry.

IMPORTANCE Although female representation has increased in clinical trials, little is known about how clinical trial representation compares with burden of disease or is associated with clinical trial features, including disease category. OBJECTIVE To describe the rate of sex reporting (ie, the presence of clinical trial data according to sex), compare the female burden of disease with the female proportion of clinical trial enrollees, and investigate the associations of disease category and clinical trial features with the female proportion of clinical trial enrollees. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study included descriptive analyses and logistic and generalized linear regression analyses with a logit link. Data were downloaded from the Aggregate Analysis of ClinicalTrials.gov database for all studies registered between March 1, 2000, and March 9, 2020. Enrollment was compared with data from the 2016 Global Burden of Disease database. Of 328 452 clinical trials, 70 095 were excluded because they had noninterventional designs, 167 936 because they had recruitment sites outside the US, 69 084 because they had no reported results, 1003 because they received primary funding from the US military, and 314 because they had unclear sex categories. A total of 20 020 interventional studies enrolling approximately 5.11 million participants met inclusion criteria and were divided into those with and without data on participant sex. EXPOSURES The primary exposure variable was clinical trial disease category. Secondary exposure variables included funding, study design, and study phase. MAIN OUTCOMES AND MEASURES Sex reporting and female proportion of participants in clinical trials. RESULTS Among 20 020 clinical trials from 2000 to 2020, 19 866 studies (99.2%) reported sex, and 154 studies (0.8%) did not. Clinical trials in the fields of oncology (46% of disability-adjusted lifeyears [DALYs]; 43% of participants), neurology (56% of DALYs; 53% of participants), immunology (49% of DALYs; 46% of participants), and nephrology (45% of DALYs; 42% of participants) had the lowest female representation relative to corresponding DALYs. Male participants were underrepresented in 8 disease categories, with the greatest disparity in clinical trials of musculoskeletal disease and trauma (11.3% difference between representation and proportion of DALYs). Clinical trials of preventive interventions were associated with greater female enrollment (adjusted relative difference, 8.48%; 95% CI, 3.77%-13.00%). Clinical trials in cardiology (adjusted relative difference, −18.68%; 95% CI, −22.87% to −14.47%) and pediatrics (adjusted relative difference, −20.47%; 95% CI, −25.77% to −15.16%) had the greatest negative association with female enrollment. (continued) Key Points Question How is disease burden associated with female representation in US-based clinical trials, and how are disease category and other clinical trial features associated with female representation in clinical trials? Findings In this cross-sectional study...

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a UV-driven photoredox processing of cyanocuprates can generate simple sugars necessary for prebiotic synthesis. We investigate the wavelength dependence of this process from 215 to 295 nm and generally observe faster rates at shorter wavelengths. The most efficient wavelengths are accessible to a range of potential prebiotic atmospheres, supporting the potential role of cyanocuprate photochemistry in prebiotic synthesis on the early Earth.

Background Obstetric complications impact over a third of women globally, but are underrepresented in clinical research. Little is known about the comprehensive obstetric clinical trial landscape, how it compares to other fields, or factors associated with the successful completion of obstetric trials. Objectives To characterize obstetric clinical trials registered on ClinicalTrials.gov with the primary objective of identifying features associated with early discontinuation and results reporting. Study Design This is a cross-sectional study with descriptive, logistic regression and cox regression analyses of clinical trials registered on ClinicalTrials.gov . Our primary exposure variables were trial focus (obstetric or non-obstetric) and trial funding (industry, United States government or academic). We conducted additional exploratory analyses of other trial features including design, enrollment, and therapeutic focus. We examined the associations of exposure variables and other trial features with two primary outcomes: early discontinuation and results reporting. Results We downloaded data for all studies (n=332,417) registered on ClinicalTrials.gov from October 1, 2007 to March 9, 2020 from the Aggregate Analysis of the ClinicalTrials.gov database. We excluded studies with a non-interventional design (n=63,697) and those registered before October 1, 2007 (n=45,209). 4,276 (1.9%) obstetric trials (i.e. interventional studies), and 219,235 (98.1%) non-obstetric trials were compared. Among all trials, 2.8% of academic-funded trials, 1.9% of United States government-funded trials, and 0.4% of industry-funded trials focused on obstetrics. The quantity of obstetric trials increased over time (10.8% annual growth rate). Compared to non-obstetric trials, obstetric trials had a greater risk of early discontinuation (adjusted hazard ratio 1.40, 95% confidence interval: 1.21 to 1.62, p<0.0001) and similar odds of results reporting (adjusted odds ratio 0.89, 95% confidence interval: 0.72 to 1.10, p=0.19). Among obstetric trials funders after controlling for confounding variables, United States government-funded trials were at lowest risk of early discontinuation (US government adjusted hazard ratio 0.23, 95% confidence interval 0.07 to 0.69, p=0.009, industry reference; academic adjusted hazard ratio 1.04, 95% confidence interval 0.62 to 1.74, p=0.88). Academic-funded trials had the lowest odds of results reporting after controlling for confounding variables (academic institutions adjusted odds ratio 0.39, 95% confidence interval 0.22 to 0.68, p=0.0009; industry reference; US government adjusted odds ratio 1.06 95% confidence interval 0.53 to 2.09, p=0.87). Conclusions Obstetric trials represent only 1.9% of all clinical trials in ClinicalTrials.gov and have ...

BACKGROUND AND OBJECTIVES Representative enrollment of racial and ethnic minoritized populations in biomedical research ensures the generalizability of results and equitable access to novel therapies. Previous studies on pediatric clinical trial diversity are limited to subsets of journals or disciplines. We aimed to evaluate race and ethnicity reporting and representation in all US pediatric clinical trials on ClinicalTrials.gov. METHODS We performed a cross-sectional study of US-based clinical trials registered on ClinicalTrials.gov that enrolled participants aged &lt;18 years old between October 2007 and March 2020. We used descriptive statistics, compound annual growth rates, and multivariable logistic regression for data analysis. Estimates of US population statistics and disease burden were calculated with the US Census, Kids’ Inpatient Database, and National Survey of Children’s Health. RESULTS Among 1183 trials encompassing 405 376 participants, race and ethnicity reporting significantly increased from 27% in 2007 to 87% in 2018 (P &lt; .001). The median proportional enrollment of Asian American children was 0.6% (interquartile range [IQR], 0%–3.7%); American Indian, 0% (IQR, 0%–0%); Black, 12% (IQR, 2.9%–28.4%); Hispanic, 7.1% (IQR, 0%–18.6%); and white 66.4% (IQR, 41.5%–81.6%). Asian American, Black, and Hispanic participants were underrepresented relative to US population demographics. Compared with expected proportions based on disease prevalence and hospitalizations, Asian American and Hispanic participants were most consistently underrepresented across diagnoses. CONCLUSIONS While race and ethnicity reporting in pediatric clinical trials has improved, the representative enrollment of minoritized participants remains an ongoing challenge. Evidence-based and policy solutions are needed to address these disparities to advance biomedical innovation for all children.

Background: Most patients with prostate cancer are diagnosed with low-grade, localized disease and may not require definitive treatment. In 2012, the U.S. Preventive Services Task Force (USPSTF) recommended against prostate cancer screening to address overdetection and overtreatment. This study sought to determine the effect of guideline changes on prostate-specific antigen (PSA) screening and initial diagnostic stage for prostate cancer. Patients and Methods: A difference-in-differences analysis was conducted to compare changes in PSA screening (exposure) relative to cholesterol testing (control) after the 2012 USPSTF guideline changes, and chi-square test was used to determine whether there was a subsequent decrease in early-stage, low-risk prostate cancer diagnoses. Data were derived from a tertiary academic medical center’s electronic health records, a national commercial insurance database (OptumLabs), and the SEER database for men aged ≥35 years before (2008–2011) and after (2013–2016) the guideline changes. Results: In both the academic center and insurance databases, PSA testing significantly decreased for all men compared with the control. The greatest decrease was among men aged 55 to 74 years at the academic center and among those aged ≥75 years in the commercial database. The proportion of early-stage prostate cancer diagnoses (<T2) decreased across age groups at the academic center and in the SEER database. Conclusions: In primary care, PSA testing decreased significantly and fewer prostate cancers were diagnosed at an early stage, suggesting provider adherence to the 2012 USPSTF guideline changes. Long-term follow-up is needed to understand the effect of decreased screening on prostate cancer survival.

IMPORTANCE Randomized clinical trials (RCTs) are considered the criterion standard for clinical evidence. Despite their many benefits, RCTs have limitations, such as costliness, that may reduce the generalizability of their findings among diverse populations and routine care settings. OBJECTIVE To assess the performance of an RCT-derived prognostic model that predicts survival among patients with metastatic castration-resistant prostate cancer (CRPC) when the model is applied to real-world data from electronic health records (EHRs). DESIGN, SETTING, AND PARTICIPANTS The RCT-trained model and patient data from the RCTs were obtained from the Dialogue for Reverse Engineering Assessments and Methods (DREAM) challenge for prostate cancer, which occurred from March 16 to July 27, 2015. This challenge included 4 phase 3 clinical trials of patients with metastatic CRPC. Real-world data were obtained from the EHRs of a tertiary care academic medical center that includes a comprehensive cancer center. In this study, the DREAM challenge RCT-trained model was applied to real-world data from January 1, 2008, to December 31, 2019; the model was then retrained using EHR data with optimized feature selection. Patients with metastatic CRPC were divided into RCT and EHR cohorts based on data source. Data were analyzed from March 23, 2018, to October 22, 2020. EXPOSURES Patients who received treatment for metastatic CRPC. MAIN OUTCOMES AND MEASURES The primary outcome was the performance of an RCT-derived prognostic model that predicts survival among patients with metastatic CRPC when the model is applied to real-world data. Model performance was compared using 10-fold cross-validation according to time-dependent integrated area under the curve (iAUC) statistics. RESULTS Among 2113 participants with metastatic CRPC, 1600 participants were included in the RCT cohort, and 513 participants were included in the EHR cohort. The RCT cohort comprised a larger proportion of White participants (1390 patients [86.9%] vs 337 patients [65.7%]) and a smaller proportion of Hispanic participants (14 patients [0.9%] vs 42 patients [8.2%]), Asian participants (41 patients [2.6%] vs 88 patients [17.2%]), and participants older than 75 years (388 patients [24.3%] vs 191 patients [37.2%]) compared with the EHR cohort. Participants in the RCT cohort also had fewer comorbidities (mean [SD], 1.6 [1.8] comorbidities vs 2.5 [2.6] comorbidities, respectively) compared with those in the EHR cohort. Of the 101 variables used in the RCT-derived model, 10 were not available in the EHR data set, 3 of which were among the top 10 features in the DREAM challenge RCT model. The best-performing EHR-trained model included only 25 of the 101 variables included in the RCT-trained model. The performance of the RCT-trained and EHR-trained models was adequate in the EHR cohort (mean [SD] iAUC, 0.722 [0.118] and 0.762 [0.106], respectively); model optimization was associated with improved performance of the best-performing EHR model (mean [SD] iAUC, (continued) Key Points ...