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Current clinical research does not reflect the diversity of patient populations, despite continued recommendations to increase enrollment of underrepresented racial and ethnic groups. The ramifications of this lack of trial diversity are important because of potential differences between races and ethnicities in response to therapies, which have been observed for drugs across indications. Nonrepresentative research populations limit the generalizability of study results, which may lead to questions about safety and efficacy in certain subgroups of patients and hinder regulators, healthcare providers, and patients in their ability to adequately consider the benefits and risks of a therapeutic treatment across all populations. Renewed efforts to address healthcare disparities and increase diversity in clinical trials have demonstrated that inclusive trials are achievable and can provide scientifically rigorous results, and thus should stimulate greater action across all stakeholders. Ensuring that studies throughout the clinical development process include representative populations is a scientific imperative to advance health equity, racial justice, and trust in the safety and efficacy of medical therapies. This article reviews the long-standing lack of diversity and barriers to enrollment of diverse and representative populations in clinical trials, outlines the current evolving trial landscape and the efforts of stakeholders, and provides examples from scientifically rigorous inclusive trials. The goal is to share learnings in a wider context of opportunities to enhance diversity, equity, and inclusion in clinical development while ensuring the safety and efficacy of medical therapies in all populations of patients, and in doing provide wider patient access to therapeutic treatments.

In contrast to bacterial, yeast and animal systems, topoisomerases (topo) from plants have not been well studied. In this report, we generated four truncated topoisomerase II (Topo II) cDNA fragments encoding different functional domains of Nicotiana tabacum topo II (NtTopoII). Each of these recombinant polypeptides was expressed alone or in combination in temperature-sensitive topoisomerase II yeast mutants. Recombinant NtTopoII with truncated polypeptides fails to target the yeast nuclei and does not rescue the temperature-sensitive phenotype. In contrast complementation was achieved with the full-length NtTopoII, which localized to the yeast nucleus. These observations suggested the presence of a potent nuclear localization signal (NLS) in the extreme C-terminal 314 amino acid residues of NtTopoII that functioned effectively in the heterologous yeast system. Biochemical characterization of purified recombinant full-length and the partial NtTopoII polypeptides revealed that the ATP-binding and hydrolysis region of NtTopoIIwas located at 413 amino acid N-terminal region and this ATPase domain is functional both when it is expressed as a separate polypeptide or as part of the holoenzyme. The present findings also revealed that all NtTopoII truncated polypeptides were detrimental for in vitro supercoiled DNA relaxation and/or DNA nicking and ligation activity. Further, we discuss the possible disruption of coordinated macromolecular interface movements and the dimer interactions in truncated NtTopoII that are required for functional topoisomerase activity.

This study describes the baseline characteristics and treatment patterns of US patients hospitalized with a diagnosis of coronavirus disease 2019 (COVID‐19) and pulmonary involvement. Patients hospitalized with pulmonary involvement due to COVID‐19 (first hospitalization) were identified in the IBM Explorys® electronic health records database. Demographics, baseline clinical characteristics, and in‐hospital medications were assessed. For evaluation of in‐hospital medications, results were stratified by race, geographic region, age, and month of admission. Of 6564 hospitalized patients with COVID‐19‐related pulmonary involvement, 50.4% were male, and mean (SD) age was 62.6 (16.4) years; 75.2% and 23.6% of patients were from the South and Midwest, respectively, and 50.2% of patients were African American. Compared with African American patients, a numerically higher proportion of White patients received dexamethasone (19.7% vs. 31.8%, respectively), nonsteroidal anti‐inflammatory drugs (NSAIDs; 27.1% vs. 34.9%), bronchodilators (19.8% vs. 29.5%), and remdesivir (9.3% vs. 21.0%). Numerically higher proportions of White patients than African American patients received select medications in the South but not in the Midwest. Compared with patients in the South, a numerically higher proportion of patients in the Midwest received dexamethasone (20.1% vs. 34.5%, respectively), NSAIDs (19.6% vs. 55.7%), bronchodilators (15.9% vs. 41.3%), and remdesivir (10.6% vs. 23.1%). Inpatient use of hydroxychloroquine decreased over time, whereas the use of dexamethasone and remdesivir increased over time. Among US patients predominantly from the South and Midwest hospitalized with COVID‐19 and pulmonary involvement, differences were seen in medication use between different races, geographic regions, and months of hospitalization., Research Highlights In this retrospective, electronic health records study, including US patients hospitalized with COVID‐19 and pulmonary involvement, a numerically higher proportion of patients in the Midwest received dexamethasone, nonsteroidal anti‐inflammatory drugs, bronchodilators, and remdesivir than patients in the South. Analysis of select medication use by the US region showed that, in the South, numerically higher proportions of White patients than African American patients received multiple select medications, including dexamethasone and remdesivir; however, in the Midwest, select medication use was generally comparable among White and African American patients. These study results demonstrating differences in rates of medication use between different geographic regions, in addition to differences in the race within some regions and among different age groups, warrant further study.

Tobacco abuse is a major risk factor associated with the development of oral squamous cell carcinoma. Differences in molecular aberrations induced by tobacco exposure by chewing or smoking form are not well studied in case of oral cancer. We used tandem mass tag-based quantitative proteomic approach to delineate proteomic alterations in oral cancer patients based on their history of tobacco using habits (patients who chewed tobacco, patients who smoked tobacco, and those with no history of tobacco consumption). Our data identified distinct dysregulation of biological processes and pathways in each patient cohort. Bioinformatics analysis of dysregulated proteins identified in our proteomic study revealed dysregulation of collagen formation and antigen processing/presentation pathway in oral cancer patients who smoked tobacco, whereas proteins associated with the process of keratinization showed enrichment in patients who chewed tobacco. In addition, we identified overexpression of proteins involved in immune pathways and downregulation of muscle contraction-mediated signaling events in all three cohorts, irrespective of tobacco using habits. This study lays the groundwork for identification of protein markers that may aid in identification of high-risk patients for cancer development based on the history of tobacco exposure habits.

Radiation therapy is an effective treatment modality for a variety of cancers. Despite several advances in delivery techniques, its main drawback remains the deposition of dose in normal tissues which can result in toxicity. Common practices of evaluating toxicity, using questionnaires and grading systems, provide little underlying information beyond subjective scores, and this can limit further optimization of treatment strategies. Nuclear medicine imaging techniques can be utilised to directly measure regional baseline function and function loss from internal/external radiation therapy within normal tissues in an in vivo setting with high spatial resolution. This can be correlated with dose delivered by radiotherapy techniques to establish objective dose-effect relationships, and can also be used in the treatment planning step to spare normal tissues more efficiently. Toxicity in radionuclide therapy typically occurs due to undesired off-target uptake in normal tissues. Molecular imaging using diagnostic analogues of therapeutic radionuclides can be used to test various interventional protective strategies that can potentially reduce this normal tissue uptake without compromising tumour uptake. We provide an overview of the existing literature on these applications of nuclear medicine imaging in diverse normal tissue types utilising various tracers, and discuss its future potential.

ObjectiveTo assess outcomes in giant cell arteritis (GCA) patients during and after long-term tocilizumab (TCZ) treatment.MethodsRetrospective analysis of GCA patients treated with TCZ at a single centre (2010–2022). Time to relapse and annualised relapse rate during and after TCZ treatment, prednisone use, and safety were assessed. Relapse was defined as reappearance of any GCA clinical manifestation that required treatment intensification, regardless of C reactive protein levels and erythrocyte sedimentation rate.ResultsSixty-five GCA patients were followed for a mean (SD) of 3.1 (1.6) years. The mean duration of the initial TCZ course was 1.9 (1.1) years. The Kaplan-Meier (KM)-estimated relapse rate at 18 months on TCZ was 15.5%. The first TCZ course was discontinued due to satisfactory remission achievement in 45 (69.2%) patients and adverse events in 6 (9.2%) patients. KM-estimated relapse rate at 18 months after TCZ discontinuation was 47.3%. Compared with patients stopping TCZ at or before 12 months of treatment, the multivariable adjusted HR (95% CI) for relapse in patients on TCZ beyond 12 months was 0.01 (0.00 to 0.28; p=0.005). Thirteen patients received >1 TCZ course. Multivariable adjusted annualised relapse rates (95% CI) in all periods on and off TCZ aggregated were 0.1 (0.1 to 0.2) and 0.4 (0.3 to 0.7), respectively (p=0.0004). Prednisone was discontinued in 76.9% of patients. During the study, 13 serious adverse events occurred in 11 (16.9%) patients.ConclusionLong-term TCZ treatment was associated with remission maintenance in most patients with GCA. The estimated relapse rate by 18 months after TCZ discontinuation was 47.3%.

Background Irritable bowel syndrome (IBS) is a disorder of gut-brain axis that manifests with chronic abdominal pain, altered bowel habits, and frequent psychiatric comorbidities. Despite mounting evidence showing gut microbiota composition and associated metabolites being altered in IBS, the mechanisms by which they drive the symptoms are unclear. We have previously shown that several IBS symptoms co-occur, that their severity vary among IBS subtypes (10.1093/jcag/gwab049.050), and that several bacterial taxa are differentially modulated during periods of symptom flares and remission. Here we investigate whether the changes in gut microbiome and bacterial metabolites are linked to symptom occurrence and severity. Purpose To investigate temporal associations of IBS symptoms with gut microbiota profiles and metabolites. Method 16S rRNA gene sequencing was performed on stool samples of 28 IBS patients (IBS-D n=20, IBS-C n=8) and 10 healthy controls (HC), collected weekly over a period of 25 weeks, during which gut and mood symptoms were recorded (total of 950 samples). Correlations between principal ordinates obtained from symptom scores and microbiota beta diversity were studied using Procrustes analysis in R. Metabolomics was performed by Mass Spectrometry and analysed using MetaboAnalyst 5.0. Statistical significance was set at p Result(s) Significant correlation was found between the symptom scores and microbiota beta diversity ordinates over time in 7 patients (5 IBS-D and 2 IBS-C subjects) out of 28 IBS patients. Metabolomics performed on samples selected based on Procrustes analysis and symptom severity scores of individual subjects showed that several pathways are altered in IBS patients (both subtypes) compared to HC, including primary bile acid biosynthesis, beta alanine metabolism, pyrimidine and histidine metabolism. Furthermore, during symptom flares, ornithine, citrulline and gluconic acid vary in IBS-D, while amino acids cysteine, methionine, threonine, and glycine vary in IBS-C subjects. Conclusion(s) Our results suggest that IBS symptoms and changes in gut microbiota composition and metabolites must be studied in conjunction, in order to understand the mechanisms underlying IBS pathophysiology. We found that same pathways are altered in IBS subjects irrespective of their subtype, suggestive of a basal metabolic shift in IBS patients. This shift may make them sensitive to further gut microbial modulation of carbohydrate and protein metabolism in IBS-D and IBS-C subjects, respectively, leading to symptom flares. Further analyses are needed to investigate these metabolites and associated bacteria, as they can help identifying subsets of patients with specific disease mechanisms. This will be a steppingstone in moving away from symptom-based subtyping towards mechanism-based grouping and developing effective treatment strategies accordingly. Disclosure of Interest None Declared

Altered environments in urban areas are known to impact and change animal behaviour. In particular, artificial light at night (ALAN) affects behaviour across taxonomic groups, including reptiles. Geckos in the genus Phelsuma are predominantly diurnal, but some have been documented to alter their foraging behaviour from a diurnal to nocturnal activity period when they have access to artificial light sources. Herein, we report new observations of six Phelsuma spp. (Andaman day geckos, P. andamanensis; blue‐tailed day geckos, P. cepediana; Madagascar giant day geckos, P. grandis; Reunion ornate day geckos, P. inexpectata; gold dust day geckos, P. laticauda; Mahe day geckos, P. sundbergi longinsulae) using artificial lights to engage in nocturnal activity that includes foraging, courtship, and agonistic behaviour. Artificial light at night augments the amount of time predators, especially visual predators, can spend foraging. This can increase their overall daily activity period (i.e. the amount of time spent active within 24 h), and research is yet to fully understand the cost–benefit trade‐offs this altered behaviour has on individual fitness. Overall, our novel accounts of six Phelsuma spp. contribute to knowledge regarding the diversity of animals that have altered their behaviour in response to ALAN and highlight the behavioural flexibility of this group of geckos.

Background Coronavirus disease 2019 (Covid-19) pneumonia is often associated with hyperinflammation. Despite the disproportionate incidence of Covid-19 among underserved and racial and ethnic minority populations, the safety and efficacy of the anti–interleukin-6 receptor antibody tocilizumab in patients from these populations who are hospitalized with Covid-19 pneumonia are unclear. Methods We randomly assigned (in a 2:1 ratio) patients hospitalized with Covid-19 pneumonia who were not receiving mechanical ventilation to receive standard care plus one or two doses of either tocilizumab (8 mg per kilogram of body weight intravenously) or placebo. Site selection was focused on the inclusion of sites enrolling high-risk and minority populations. The primary outcome was mechanical ventilation or death by day 28. Results A total of 389 patients underwent randomization, and the modified intention-to-treat population included 249 patients in the tocilizumab group and 128 patients in the placebo group; 56.0% were Hispanic or Latino, 14.9% were Black, 12.7% were American Indian or Alaska Native, 12.7% were non-Hispanic White, and 3.7% were of other or unknown race or ethnic group. The cumulative percentage of patients who had received mechanical ventilation or who had died by day 28 was 12.0% (95% confidence interval [CI], 8.5 to 16.9) in the tocilizumab group and 19.3% (95% CI, 13.3 to 27.4) in the placebo group (hazard ratio for mechanical ventilation or death, 0.56; 95% CI, 0.33 to 0.97; P=0.04 by the log-rank test). Clinical failure as assessed in a time-to-event analysis favored tocilizumab over placebo (hazard ratio, 0.55; 95% CI, 0.33 to 0.93). Death from any cause by day 28 occurred in 10.4% of the patients in the tocilizumab group and 8.6% of those in the placebo group (weighted difference, 2.0 percentage points; 95% CI, – 5.2 to 7.8). In the safety population, serious adverse events occurred in 38 of 250 patients (15.2%) in the tocilizumab group and 25 of 127 patients (19.7%) in the placebo group. Conclusions In hospitalized patients with Covid-19 pneumonia who were not receiving mechanical ventilation, tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or death, but it did not improve survival. No new safety signals were identified. (Funded by Genentech; EMPACTA ClinicalTrials.gov number, NCT04372186.)

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Introduction Coronavirus disease 2019 (COVID-19) can present as a range of symptoms, from mild to critical; lower pulmonary involvement, including pneumonia, is often associated with severe and critical cases. Understanding the baseline characteristics of patients hospitalized with COVID-19 illness is essential for effectively targeting clinical care and allocating resources. This study aimed to describe baseline demographics and clinical characteristics of US patients hospitalized with COVID-19 and pulmonary involvement. Methods US patients with COVID-19 and pulmonary involvement during an inpatient admission from December 1, 2019, to May 20, 2020, were identified using the IBM Explorys® electronic health records database. Baseline (up to 12 months prior to first COVID-19 hospitalization) demographics and clinical characteristics and preadmission (14 days to 1 day prior to admission) pulmonary diagnoses were assessed. Patients were stratified by sex, age, race, and geographic region. Results Overall, 3471 US patients hospitalized with COVID-19 and pulmonary involvement were included. The mean (SD) age was 63.5 (16.3) years; 51.2% of patients were female, 55.0% African American, 81.6% from the South, and 16.8% from the Midwest. The most common comorbidities included hypertension (27.7%), diabetes (17.3%), hyperlipidemia (16.3%), and obesity (9.7%). Cough (27.3%) and dyspnea (15.2%) were the most common preadmission pulmonary symptoms. African American patients were younger (mean [SD], 62.5 [15.4] vs. 67.8 [6.2]) with higher mean (SD) body mass index (33.66 [9.46] vs. 30.42 [7.86]) and prevalence of diabetes (19.8% vs. 16.7%) and lower prevalence of chronic obstructive pulmonary disease (5.6% vs. 8.2%) and smoking/tobacco use (28.1% vs. 37.2%) than White patients. Conclusions Among US patients primarily from the South and Midwest hospitalized with COVID-19 and pulmonary involvement, the most common comorbidities were hypertension, diabetes, hyperlipidemia, and obesity. Differences observed between African American and White patients should be considered in the context of the complex factors underlying racial disparities in COVID-19. Electronic supplementary material The online version of this article (10.1007/s12325-020-01510-y) contains supplementary material, which is available to authorized users.

Summary Glyphosate is a popular, systemic, broad‐spectrum herbicide used in modern agriculture. Being a structural analog of phosphoenolpyruvate (PEP), it inhibits 5‐enolpyruvylshikimate 3‐phosphate synthase (EPSPS) which is responsible for the biosynthesis of aromatic amino acids and various aromatic secondary metabolites. Taking a lead from glyphosate‐resistant weeds, two mutant variants of the rice EPSPS gene were developed by amino acid substitution (T173I + P177S; TIPS‐OsEPSPS and G172A + T173I + P177S; GATIPS‐OsEPSPS). These mutated EPSPS genes were overexpressed in rice under the control of either native EPSPS or constitutive promoters (maize ubiquitin [ZmUbi] promoter). The overexpression of TIPS‐OsEPSPS under the control of the ZmUbi promoter resulted in higher tolerance to glyphosate (up to threefold of the recommended dose) without affecting the fitness and related agronomic traits of plants in both controlled and field conditions. Furthermore, such rice lines produced 17%–19% more grains compared to the wild type (WT) in the absence of glyphosate application and the phenylalanine and tryptophan contents in the transgenic seeds were found to be significantly higher in comparison with WT seeds. Our results also revealed that the native promoter guided expression of modified EPSPS genes did not significantly improve the glyphosate tolerance. The present study describing the introduction of a crop‐specific TIPS mutation in class I aroA gene of rice and its overexpression have potential to substantially improve the yield and field level glyphosate tolerance in rice. This is the first report to observe that the EPSPS has role to play in improving grain yield of rice.