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\"How should America wield its enormous power beyond its borders? Should it adhere to grand principles or act on narrow self-interest? Should it partner with other nations or avoid entangling alliances? Americans have been grappling with questions like these throughout the nation's history, and especially since the emergence of the United States as a major world power in the late nineteenth century. America in the World illuminates this history by capturing the diverse voices and viewpoints of some of the most colorful and eloquent people who participated in these momentous debates.Spanning the era from the Gilded Age to the Obama years, this unique reader collects more than two hundred documents--everything from presidential addresses and diplomatic cables to political cartoons and song lyrics. It encompasses various phases of American diplomatic history that are typically treated separately, such as the First World War, the Cold War, and 9/11. The book presents the perspectives of elite policymakers--presidents, secretaries of state, generals, and diplomats--alongside those of other kinds of Americans, such as newspaper columnists, clergymen, songwriters, poets, and novelists. It also features numerous documents from other countries, illustrating how foreigners viewed America's role in the world.Ideal for classroom use, America in the World sheds light on the complex interplay of political, economic, ideological, and cultural factors underlying the exercise of American power on the global stage\"-- Provided by publisher.

Clostridium difficile is a Gram-positive spore-forming anaerobe and a major cause of antibiotic-associated diarrhoea. Disruption of the commensal microbiota, such as through treatment with broad-spectrum antibiotics, is a critical precursor for colonisation by C. difficile and subsequent disease. Furthermore, failure of the gut microbiota to recover colonisation resistance can result in recurrence of infection. An unusual characteristic of C. difficile among gut bacteria is its ability to produce the bacteriostatic compound para-cresol (p-cresol) through fermentation of tyrosine. Here, we demonstrate that the ability of C. difficile to produce p-cresol in vitro provides a competitive advantage over gut bacteria including Escherichia coli, Klebsiella oxytoca and Bacteroides thetaiotaomicron. Metabolic profiling of competitive co-cultures revealed that acetate, alanine, butyrate, isobutyrate, p-cresol and p-hydroxyphenylacetate were the main metabolites responsible for differentiating the parent strain C. difficile (630Δerm) from a defined mutant deficient in p-cresol production. Moreover, we show that the p-cresol mutant displays a fitness defect in a mouse relapse model of C. difficile infection (CDI). Analysis of the microbiome from this mouse model of CDI demonstrates that colonisation by the p-cresol mutant results in a distinctly altered intestinal microbiota, and metabolic profile, with a greater representation of Gammaproteobacteria, including the Pseudomonales and Enterobacteriales. We demonstrate that Gammaproteobacteria are susceptible to exogenous p-cresol in vitro and that there is a clear divide between bacterial Phyla and their susceptibility to p-cresol. In general, Gram-negative species were relatively sensitive to p-cresol, whereas Gram-positive species were more tolerant. This study demonstrates that production of p-cresol by C. difficile has an effect on the viability of intestinal bacteria as well as the major metabolites produced in vitro. These observations are upheld in a mouse model of CDI, in which p-cresol production affects the biodiversity of gut microbiota and faecal metabolite profiles, suggesting that p-cresol production contributes to C. difficile survival and pathogenesis.

Background In metastatic urothelial carcinoma (mUC), predictive biomarkers that correlate with response to immune checkpoint inhibitors (ICIs) are lacking. Here, we interrogated genomic and clinical features associated with response to ICIs in mUC. Methods Sixty two mUC patients treated with ICI who had targeted tumour sequencing were studied. We examined associations between candidate biomarkers and clinical benefit (CB, any objective reduction in tumour size) versus no clinical benefit (NCB, no change or objective increase in tumour size). Both univariable and multivariable analyses for associations were conducted. A comparator cohort of 39 mUC patients treated with taxanes was analysed by using the same methodology. Results Nine clinical and seven genomic factors correlated with clinical outcomes in univariable analysis in the ICI cohort. Among the 16 factors, neutrophil-to-lymphocyte ratio (NLR) ≥5 (OR = 0.12, 95% CI, 0.01–1.15), visceral metastasis (OR = 0.05, 95% CI, 0.01–0.43) and single-nucleotide variant (SNV) count < 10 (OR = 0.04, 95% CI, 0.006–0.27) were identified as independent predictors of NCB to ICI in multivariable analysis (c-statistic = 0.90). None of the 16 variables were associated with clinical benefit in the taxane cohort. Conclusions This three-factor model includes genomic (SNV count >9) and clinical (NLR <5, lack of visceral metastasis) variables predictive for benefit to ICI but not taxane therapy for mUC. External validation of these hypothesis-generating results is warranted to enable use in routine clinical care.

The authors want to acknowledge the funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 869192 (NEGEM). The authors also acknowledge the work and support of all the NEGEM-project partners.

Effective treatments are needed for patients with muscle-invasive bladder cancer scheduled for radical cystectomy who are ineligible for or decline to receive neoadjuvant cisplatin-based chemotherapy. We aimed to evaluate neoadjuvant TAR-200 plus cetrelimab (anti-PD-1) versus cetrelimab monotherapy in this setting. SunRISe-4 is a randomised, open-label, phase 2 trial being conducted at 109 investigative centres in ten countries worldwide. Eligible patients were aged 18 years or older, were newly diagnosed with histologically confirmed muscle-invasive bladder cancer (stage cT2–cT4 N0M0), had an Eastern Cooperative Oncology Group performance status of 0–1, were scheduled to undergo radical cystectomy, and were deemed ineligible for or declined platinum-based neoadjuvant chemotherapy. Patients were randomly assigned (5:3) in blocks of eight using an interactive web response system to receive four cycles of intravesical TAR-200 (225 mg gemcitabine) plus intravenous cetrelimab (360 mg) every 21 days or four cycles of intravenous cetrelimab (360 mg) monotherapy every 21 days. Randomisation was stratified by results of transurethral resection of bladder tumour (visibly complete vs incomplete and ≤3 cm) and tumour stage (cT2 vs cT3–4a at initial diagnosis). The primary endpoint was centrally confirmed pathological complete response in the efficacy-evaluable set. As this was a prespecified interim analysis and all patients had not completed treatment, efficacy-evaluable set was defined as all patients who had radical cystectomy or progressive disease or death before radical cystectomy. Safety was analysed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04919512, and is ongoing. From July 7, 2022, to May 31, 2024, 196 patients were assessed for eligibility and 122 were randomly assigned (TAR-200 plus cetrelimab n=80, cetrelimab monotherapy n=42). 120 patients received at least one dose of study drug. Mean age was 70·7 years (SD 7·9); 102 (85%) participants were male, 18 (15%) were female, 81 (68%) were White, 28 (23%) were Asian, and 11 (9%) were other races. In the efficacy-evaluable set (TAR-200 plus cetrelimab n=53, cetrelimab monotherapy n=31), at a median follow up of 23·5 weeks (IQR 8·6–42·0), pathological complete response rates were 42% (22 of 53 patients; 95% CI 28–56) in the TAR-200 plus cetrelimab cohort and 23% (seven of 31 patients; 10–41) in the cetrelimab monotherapy cohort. In the safety set, at a median follow-up of 10·2 weeks (IQR 1·1–36·9), treatment-related adverse events occurred in 57 (72%) of 79 patients in the TAR-200 plus cetrelimab cohort and in 18 (44%) of 41 patients in the cetrelimab monotherapy cohort. Grade 3 or worse treatment-related adverse events occurred in nine (11%) patients in the TAR-200 plus cetrelimab cohort and two (5%) in the cetrelimab monotherapy cohort, the most common being haematuria (two [3%] in the TAR-200 plus cetrelimab cohort). Serious treatment-related adverse events occurred in nine (11%) patients in the TAR-200 plus cetrelimab cohort and one (2%) patient in the cetrelimab monotherapy cohort. In the TAR-200 plus cetrelimab cohort, seven (9%) patients had treatment-related adverse events leading to discontinuation of TAR-200 and six (8%) had treatment-related adverse events leading to discontinuation of cetrelimab; there were no treatment related deaths. In the cetrelimab monotherapy cohort, no patients discontinued due to treatment-related adverse events; there was one death from a treatment-related adverse event due to hyperglycaemic, hyperosmolar, non-ketotic syndrome. Neoadjuvant TAR-200 plus cetrelimab showed a high pathological complete response rate with a manageable safety profile. These results support continued investigation of TAR-200 in patients with muscle-invasive bladder cancer planned for radical cystectomy. Johnson & Johnson.

IntroductionNon-muscle-invasive bladder cancer (NMIBC) is a biologically heterogeneous disease and is one of the most expensive malignancies to treat on a per patient basis. In part, this high cost is attributed to the need for long-term surveillance. We sought to perform an economic analysis of surveillance strategies to elucidate cumulative costs for the management of NMIBC.MethodsA Markov model was constructed to determine the average 5-year costs for the surveillance of patients with NMIBC. Patients were stratified into low, intermediate, and high-risk groups based on the EORTC risk calculator to determine recurrence and progression rates according to each category. The index patient was a compliant 65-year-old male. A total of four health states were utilized in the Markov model: no evidence of disease, recurrence, progression and cystectomy, and death.ResultsCumulative costs of care over a 5-year period were $52,125 for low-risk, $146,250 for intermediate-risk, and $366,143 for high-risk NMIBC. The primary driver of cost was progression to muscle-invasive disease requiring definitive therapy, contributing to 81% and 92% of overall cost for intermediate- and high-risk disease. Although low-risk tumors have a high likelihood of 5-year recurrence, the overall cost contribution of recurrence was 8%, whereas disease progression accounted for 71%.ConclusionAlthough protracted surveillance cystoscopy contributes to the expenditures associated with NMIBC, progression increases the overall cost of care across all three patient risk groups and most notably for intermediate- and high-risk disease patients.

Background To prospectively examine the association between diabetes and risk of prostate cancer defined by clinical and molecular features. Methods A total of 49,392 men from the Health Professionals Follow-up Study (HPFS) were followed from 1986 to 2014. Data on self-reported diabetes were collected at baseline and updated biennially. Clinical features of prostate cancer included localised, advanced, lethal, low-grade, intermediate-grade, and high-grade. Molecular features included TMPRSS2: ERG and PTEN subtypes. Cox proportional hazards regression models were used to evaluate the association between diabetes and incidence of subtype-specific prostate cancer. Results During 28 years of follow-up, we documented 6733 incident prostate cancer cases. Relative to men free from diabetes, men with diabetes had lower risks of total (HR: 0.82, 95% CI: 0.75–0.90), localised (HR: 0.82, 95% CI: 0.74–0.92), low-and intermediate-grade prostate cancer (HR: 0.77, 95% CI: 0.66–0.90; HR: 0.77, 95% CI: 0.65–0.91, respectively). For molecular subtypes, the HRs for ERG-negative and ERG-positive cases were 0.63 (0.42–0.95) and 0.72 (0.46–1.12); and for PTEN-intact and PTEN-loss cases were 0.69 (0.48–0.98) and 0.52 (0.19–1.41), respectively. Conclusion Besides providing advanced evidence for the inverse association between diabetes and prostate cancer, this study is the first to report associations between diabetes and ERG/PTEN defined prostate cancers.

Mycobacterium tuberculosis drug resistance (DR) challenges effective tuberculosis disease control. Current molecular tests examine limited numbers of mutations, and although whole genome sequencing approaches could fully characterise DR, data complexity has restricted their clinical application. A library (1,325 mutations) predictive of DR for 15 anti-tuberculosis drugs was compiled and validated for 11 of them using genomic-phenotypic data from 792 strains. A rapid online ‘TB-Profiler’ tool was developed to report DR and strain-type profiles directly from raw sequences. Using our DR mutation library, in silico diagnostic accuracy was superior to some commercial diagnostics and alternative databases. The library will facilitate sequence-based drug-susceptibility testing.

Genome sequence analysis reveals that the zoonotic malaria parasite Plasmodium knowlesi consists of three highly divergent subpopulations. Two, commonly seen in sympatric human clinical infections in Malaysian Borneo, were identified in a previous study as corresponding to parasites seen in long-tailed and pig-tailed macaque hosts, respectively. A third type has been detected in a few laboratory-maintained isolates originally derived in the 1960s elsewhere in Southeast Asia. Divergence between the subpopulations varies significantly across the genome but overall is at a level indicating different subspecies. Analysis of the diversity within the most common type in human infections shows strong signatures of natural selection, including balancing selection and directional selection, on loci distinct from those under selection in endemic human malaria parasites. Malaria cases caused by the zoonotic parasite Plasmodium knowlesi are being increasingly reported throughout Southeast Asia and in travelers returning from the region. To test for evidence of signatures of selection or unusual population structure in this parasite, we surveyed genome sequence diversity in 48 clinical isolates recently sampled from Malaysian Borneo and in five lines maintained in laboratory rhesus macaques after isolation in the 1960s from Peninsular Malaysia and the Philippines. Overall genomewide nucleotide diversity (π = 6.03 × 10 −3 ) was much higher than has been seen in worldwide samples of either of the major endemic malaria parasite species Plasmodium falciparum and Plasmodium vivax . A remarkable substructure is revealed within P . knowlesi , consisting of two major sympatric clusters of the clinical isolates and a third cluster comprising the laboratory isolates. There was deep differentiation between the two clusters of clinical isolates [mean genomewide fixation index ( F ST ) = 0.21, with 9,293 SNPs having fixed differences of F ST = 1.0]. This differentiation showed marked heterogeneity across the genome, with mean F ST values of different chromosomes ranging from 0.08 to 0.34 and with further significant variation across regions within several chromosomes. Analysis of the largest cluster (cluster 1, 38 isolates) indicated long-term population growth, with negatively skewed allele frequency distributions (genomewide average Tajima’s D = −1.35). Against this background there was evidence of balancing selection on particular genes, including the circumsporozoite protein ( csp ) gene, which had the top Tajima’s D value (1.57), and scans of haplotype homozygosity implicate several genomic regions as being under recent positive selection.

Whole-genome sequencing technologies are being increasingly applied to Plasmodium falciparum clinical isolates to identify genetic determinants of malaria pathogenesis. However, genome-wide discovery methods, such as haplotype scans for signatures of natural selection, are hindered by missing genotypes in sequence data. Poor correlation between single nucleotide polymorphisms (SNPs) in the P. falciparum genome complicates efforts to apply established missing-genotype imputation methods that leverage off patterns of linkage disequilibrium (LD). The accuracy of state-of-the-art, LD-based imputation methods (IMPUTE, Beagle) was assessed by measuring allelic r2 for 459 P. falciparum samples from malaria patients in 4 countries: Thailand, Cambodia, Gambia, and Malawi. In restricting our analysis to 86 k high-quality SNPs across the populations, we found that the complete-case analysis was restricted to 21k SNPs (24.5%), despite no single SNP having more than 10% missing genotypes. The accuracy of Beagle in filling in missing genotypes was consistently high across all populations (allelic r2, 0.87-0.96), but the performance of IMPUTE was mixed (allelic r2, 0.34-0.99) depending on reference haplotypes and population. Positive selection analysis using Beagle-imputed haplotypes identified loci involved in resistance to chloroquine (crt) in Thailand, Cambodia, and Gambia, sulfadoxine-pyrimethamine (dhfr, dhps) in Cambodia, and artemisinin (kelch13) in Cambodia. Tajima's D-based analysis identified genes under balancing selection that encode well-characterized vaccine candidates: apical merozoite antigen 1 (ama1) and merozoite surface protein 1 (msp1). In contrast, the complete-case analysis failed to identify any well-validated drug resistance or candidate vaccine loci, except kelch13. In a setting of low LD and modest levels of missing genotypes, using Beagle to impute P. falciparum genotypes is a viable strategy for conducting accurate large-scale population genetics and association analyses, and supporting global surveillance for drug resistance markers and candidate vaccine antigens.