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Julie-Anne Tanner,1,2 Lisa C Brown,3 Kunbo Yu,3 James Li,3 Bryan M Dechairo4 1Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Department of Psychiatry, Toronto, ON, Canada; 2Assurex Health Ltd., Toronto, ON, Canada; 3Assurex Health, Inc., Mason, OH, USA; 4Myriad Genetics, Inc., Salt Lake City, UT, USACorrespondence: Julie-Anne TannerNeurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Department of Psychiatry, Assurex Health, Ltd., 250 College, Room R38, Toronto, ON M5T 1L8, CanadaTel +1 416 813-2745Email julie-anne.tanner@myriad.comObjective: To estimate Canadian pharmacy cost savings associated with psychiatric medication prescribing that is guided by combinatorial pharmacogenomic testing in patients switching or augmenting their psychiatric medication.Methods: Pharmacy claims data from a United States (US) pharmacy benefit manager were analyzed for 1662 patients who recently augmented or switched to a different antidepressant or antipsychotic medication and underwent combinatorial pharmacogenomic testing. Costs of prescription medications were translated to the Canadian healthcare system by matching drug names and doses using the Ontario Drug Benefit Formulary. One-year costs (2017 CAD) were compared between patients whose clinician prescribed antidepressants or antipsychotics that were consistent (congruent) or inconsistent (incongruent) with the combinatorial pharmacogenomic test recommendations.Results: Patients whose psychiatric medication treatment was congruent with the combinatorial pharmacogenomic test report saved $1061 CAD per member per year (PMPY) on prescription medication costs relative to patients whose medications were incongruent with their test report (p

Lindsay C Brown,1 Robert W Mutter,1 Michele Y Halyard2 1Department of Radiation Oncology, Mayo Clinic, Rochester, MN, 2Department of Radiation Oncology, Mayo Clinic, Scottsdale, AZ, USA Abstract: Breast cancer is a common and complex disease often necessitating multimodality care. Breast cancer may be treated with surgical resection, radiotherapy (RT), and systemic therapy, including chemotherapy, hormonal therapy, and targeted therapies, or a combination thereof. In the past 50 years, RT has played an increasingly significant role in the treatment of breast cancer, resulting in improvements in locoregional control and survival for women undergoing mastectomy who are at high risk of recurrence, and allowing for breast conservation in certain settings. Although radiation provides significant benefit to many women with breast cancer, it is also associated with risks of toxicity, including cardiac and pulmonary toxicity, lymphedema, and secondary malignancy. RT techniques have advanced and continue to evolve dramatically, offering increased precision and reproducibility of treatment delivery and flexibility of treatment schedule. This increased sophistication of RT offers promise of improved outcomes by maintaining or improving efficacy, reducing toxicity, and increasing patient access and convenience. A review of the role of radiation therapy in breast cancer, its associated toxicities and efforts in toxicity reduction is presented. Keywords: breast malignancy, radiotherapy, toxicity, outcomes

BackgroundThe erosion of the early mortality advantage of elective endovascular aneurysm repair (EVAR) compared with open repair of abdominal aortic aneurysm remains without a satisfactory explanation.MethodsAn individual-patient data meta-analysis of four multicentre randomized trials of EVAR versus open repair was conducted to a prespecified analysis plan, reporting on mortality, aneurysm-related mortality and reintervention.ResultsThe analysis included 2783 patients, with 14 245 person-years of follow-up (median 5·5 years). Early (0-6 months after randomization) mortality was lower in the EVAR groups (46 of 1393 versus 73 of 1390 deaths; pooled hazard ratio 0·61, 95 per cent c.i. 0·42 to 0·89; P = 0·010), primarily because 30-day operative mortality was lower in the EVAR groups (16 deaths versus 40 for open repair; pooled odds ratio 0·40, 95 per cent c.i. 0·22 to 0·74). Later (within 3 years) the survival curves converged, remaining converged to 8 years. Beyond 3 years, aneurysm-related mortality was significantly higher in the EVAR groups (19 deaths versus 3 for open repair; pooled hazard ratio 5·16, 1·49 to 17·89; P = 0·010). Patients with moderate renal dysfunction or previous coronary artery disease had no early survival advantage under EVAR. Those with peripheral artery disease had lower mortality under open repair (39 deaths versus 62 for EVAR; P = 0·022) in the period from 6 months to 4 years after randomization.ConclusionThe early survival advantage in the EVAR group, and its subsequent erosion, were confirmed. Over 5 years, patients of marginal fitness had no early survival advantage from EVAR compared with open repair. Aneurysm-related mortality and patients with low ankle : brachial pressure index contributed to the erosion of the early survival advantage for the EVAR group. Trial registration numbers: EVAR-1, ISRCTN55703451; DREAM (Dutch Randomized Endovascular Aneurysm Management), NCT00421330; ACE (Anévrysme de l'aorte abdominale, Chirurgie versus Endoprothèse), NCT00224718; OVER (Open Versus Endovascular Repair Trial for Abdominal Aortic Aneurysms), NCT00094575.

OBJECTIVE: Medical educators have used Jeopardy! game to teach medical knowledge. None has reported using it to teach psychosocial aspects of medicine. METHODS: As part of a cross-cultural communication curriculum for residents in an urban, medically underserved area, we piloted 'Bronx Jeopardy!to teach psychosocial aspects of the surrounding community. We applied the same rules used in the popular game show. Participants were asked to complete a survey to rate the content and format of the training. RESULTS: Thirty-four residents participated; 30 (88%) completed the survey. Most reported that the information was new. Almost all reported increased understanding of community diversity, desire to learn more about it, and raised awareness of its challenges and resources. All believed that the session helped dispel negative stereotypes. Regarding format, all participants reported that it built collegiality, stimulated interest, was a fun and effective way to learn, and helped retain information. CONCLUSION: Bronx Jeopardy! was a fun and effective way to learn about psychosocial aspects of pediatrics. PRACTICE IMPLICATIONS: Using a gaming format, Bronx Jeopardy! demonstrated an application of Adult Learning Theory. With an expanding questions bank, the tool can be adapted for teaching this topic in other residency programs. [ABSTRACT FROM AUTHOR]

Potential exposures among repair technicians engaged in vehicle resurfacing operations prior to spray painting have not been thoroughly characterized. Environmental and personal air monitoring conducted in the State of Rhode Island have shown that automotive repair technicians may be exposed to metal particulates in sanding dust and methylene chloride vapors during vehicle paint removal operations. Hand wipe samples demonstrated that metals in sanding dust adhered to the hands of workers throughout the duration of the work day and were available for incidental ingestion from the handling of food/nonfood items and hand-to-mouth contact. A blood lead (PbB) screening effort among 21 workers at 2 facilities showed that 4 non-/less-exposed workers had mean PbB levels at the U.S. geometric mean of 2.8 microg/dL, while 2 out of 9 (22%) dedicated vehicle repair technicians had PbB levels at or above 30 microg Pb/dL whole blood--the level for potential adverse reproductive effects. Methylene chloride exposures were also found to exceed the Occupational Safety and Health Administrations (OSHA) 8-hr time-weighted average (TWA) action level and permissible exposure limit (PEL) in a limited number of samples (120 and 26 ppm, integrated work shift samples). Our findings suggest that thousands of professional technicians and vocational high school students may be at increased risk of adverse reproductive and/or other systemic effects. [ABSTRACT FROM AUTHOR]

Pharmacogenomic testing has emerged as an aid in clinical decision making for psychiatric providers, but more data is needed regarding its utility in clinical practice and potential impact on patient care. In this cross-sectional study, we determined the real-world prevalence of pharmacogenomic actionability in patients receiving psychiatric care. Potential actionability was based on the prevalence of CYP2C19 and CYP2D6 phenotypes, including CYP2D6 allele-specific copy number variations (CNVs). Combined actionability additionally incorporated CYP2D6 phenoconversion and the novel CYP2C-TG haplotype in patients with available medication data. Across 15,000 patients receiving clinical pharmacogenomic testing, 65% had potentially actionable CYP2D6 and CYP2C19 phenotypes, and phenotype assignment was impacted by CYP2D6 allele-specific CNVs in 2% of all patients. Of 4114 patients with medication data, 42% had CYP2D6 phenoconversion from drug interactions and 20% carried a novel CYP2C haplotype potentially altering actionability. A total of 87% had some form of potential actionability from genetic findings and/or phenoconversion. Genetic variation detected via next-generation sequencing led to phenotype reassignment in 22% of individuals overall (2% in CYP2D6 and 20% in CYP2C19). Ultimately, pharmacogenomic testing using next-generation sequencing identified potential actionability in most patients receiving psychiatric care. Early pharmacogenomic testing may provide actionable insights to aid clinicians in drug prescribing to optimize psychiatric care., (© 2024. The Author(s).)

Introduction: Men with advanced germ cell tumors (GCT) treated with chemotherapy are at high risk of venous thromboembolism (VTE). Predictors of VTE may identify patients who would benefit from prophylactic anticoagulation., Patients and Methods: Men with advanced GCT (Stage IS, II, III) treated with chemotherapy were identified at 2 centers. High genomic risk was defined from a 5 single nucleotide polymorphism (SNP) germline panel. Logistic regression was used to evaluate the impact of genomic risk on VTE within 6 months of chemotherapy initiation. Orthogonal Projection to Latent Structures Discriminant Analysis (OPLS-DA) was used to build models to predict VTE based on clinical variables and an 86 SNP panel., Results: This 123-patient cohort experienced a VTE rate of 26% with an incidence of high genomic risk of 21%. Men with high genomic risk did not have a significantly higher VTE rate (31%, 8/26) than men with low genomic risk (25%, 24/97), unadjusted OR 1.4 (95% CI 0.5-3.5, P = .54). Incorporation of clinical variables (Khorana score, N3 status and elevated LDH) resulted in adjusted OR 2.1 (95% CI 0.7-6.5, P = .18). A combined model using clinical variables and 86 SNPs performed similarly (AUC 0.77) compared to clinical variables alone (AUC 0.72)., Conclusions: A previously established 5-SNP panel was not associated with VTE among patients with GCT receiving chemotherapy. However, multivariable models based on clinical variables alone warrant further validation to inform prophylactic anticoagulation strategies., Competing Interests: Disclosure LCB declares the following relationships: Consulting with Seattle Genetics and Pfizer. MR, MM, NS, JS, WS, RP, BN, TA, CL, WL, NH, AH, MH, and PEC report no conflicts of interest pertaining to this project. JP declares the following relationships: Research funding from Bristol Myer Squibb. EFB declares the following relationships: Stock/ownership with Exelixis, Becton Dickson, Gilead Sciences, Medtronic; Honoraria from Exelixis, Janssen Oncology, Novartis, Pfizer, Merck, Consulting for Johnson & Johnson; Speakers Bureau for AstraZenica and Exelixis, Research funding from Pfizer and Astellas Pharma., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Approximately, 5.5 million dental implants are estimated to be surgically placed in the United States yearly, with an anticipated long-term failure rate ranging from 3% to 10%. At the Salt Lake City Dental Clinic within the Department of Veterans Affairs (VHA), specific protocols have been established to mandate that clinicians present every dental implant case for review by a committee. To understand the effectiveness of this approach, a comparative data analysis was undertaken to compare local dental implant failure data against national VHA data., Methods: Leveraging electronic health records of veterans spanning from 2000 to 2021, we gathered procedural records related to dental implant placement or failure, demographic information, and medical history for individuals who received dental care at various dental clinics within the nationwide VHA network. Subsequently, statistical analyses were conducted using mixed-effects Poisson regression models with cluster-robust standard errors. Incident rate ratios (IRRs) for Utah-specific and nationwide cohorts were ascertained., Results: The Utah VHA dental clinical data showed that there was a slightly lower prevalence of implant failure at 6.7% compared to the national cohort, which had a rate of 6.9%. The implant level failure rates were also low, with 4.20 (confidence interval [CI]: 3.68, 4.81) per 1000 implant placements per year for Utah cohorts. The adjusted IRR indicated a relative 16% reduction in risk among Utah Veterans (IRR 0.84, 95% CI [0.76-0.92]; p < 0.001)., Conclusions: The stringent protocols in place at Salt Lake City, which integrate evidence-based practices and expert opinion for evaluating patient suitability for dental implant placement and subsequent care, contributed to the reduced risk among Utah Dental Clinic veterans pool compared to veterans of other states., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA.)

Bacteria detect local population numbers using quorum sensing, a method of cell-cell communication broadly utilized to control bacterial behaviors. In Vibrio species, the master quorum sensing regulators LuxR/HapR control hundreds of quorum sensing genes, many of which influence virulence, metabolism, motility, and more. Thiophenesulfonamides are potent inhibitors of LuxR/HapR that bind the ligand pocket in these transcription factors and block downstream quorum sensing gene expression. This class of compounds served as the basis for the development of a set of simple, robust, and educational procedures for college students to assimilate their chemistry and biology skills using a CURE model: course-based undergraduate research experience. Optimized protocols are described that comprise three learning stages in an iterative and multi-disciplinary platform to engage students in a year-long CURE: (1) design and synthesize new small molecule inhibitors based on the thiophenesulfonamide core, (2) use structural modeling to predict binding affinity to the target, and (3) assay the compounds for efficacy in microbiological assays against specific Vibrio LuxR/HapR proteins. The described reporter assay performed in E. coli successfully predicts the efficacy of the compounds against target proteins in the native Vibrio species.

Background: Almost 80% of individuals with functional dyspepsia experience meal-related symptoms and are diagnosed with postprandial distress syndrome (PDS). However, studies evaluating dietary modifications in PDS are sparse. We performed a single-center randomized trial comparing reassurance and diagnostic explanation (RADE) with or without traditional dietary advice (TDA) in PDS., Methods: Following a normal upper gastrointestinal endoscopy, individuals with PDS were randomized to a leaflet providing RADE ± TDA; the latter recommending small, regular meals and reducing the intake of caffeine/alcohol/fizzy drinks and high-fat/processed/spicy foods. Questionnaires were completed over 4 weeks, including self-reported adequate relief of dyspeptic symptoms, and the validated Leuven Postprandial Distress Scale (LPDS), Gastrointestinal Symptom Rating Scale, and Nepean Dyspepsia Index for quality of life. The primary endpoint(s) to define clinical response were (i) ≥50% adequate relief of dyspeptic symptoms and (ii) >0.5-point reduction in the PDS subscale of the LPDS (calculated as the mean scores for early satiety, postprandial fullness, and upper abdominal bloating)., Key Results: Of the 53 patients with PDS, 27 were assigned RADE-alone and 26 to additional TDA. Baseline characteristics were similar between groups, with a mean age of 39 years, 70% female, 83% white British, and coexistent irritable bowel syndrome in 66%. The primary endpoints of (i) adequate relief of dyspeptic symptoms were met by 33% (n = 9) assigned RADE-alone versus 39% (n = 10) with TDA; p-value = 0.70, while (ii) a reduction of >0.5 points in the PDS subscale was met by 37% (n = 10) assigned RADE-alone versus 27% (n = 7) with TDA; p-value = 0.43. Response rates did not differ according to irritable bowel syndrome status. There were no significant between-group changes in the gastrointestinal symptom rating scale and dyspepsia quality of life., Conclusions & Inferences: This study of predominantly white British patients with PDS found the addition of TDA did not lead to significantly greater symptom reduction compared with RADE alone. Alternate dietary strategies should be explored in this cohort., (© 2024 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Urinary prostaglandin (PG) E metabolite (PGE-M) and 11-dehydro (d)-thromboxane (TX) B 2 are biomarkers of cyclooxygenase-dependent prostanoid synthesis. We investigated (1) the effect of aspirin 300 mg daily and eicosapentaenoic acid (EPA) 2000 mg daily, alone and in combination, on urinary biomarker levels and, (2) whether urinary biomarker levels predicted colorectal polyp risk, during participation in the seAFOod polyp prevention trial. Urinary PGE-M and 11-d-TXB 2 were measured by liquid chromatography-tandem mass spectrometry. The relationship between urinary biomarker levels and colorectal polyp outcomes was investigated using negative binomial (polyp number) and logistic (% with one or more polyps) regression models. Despite wide temporal variability in PGE-M and 11-d-TXB 2 levels within individuals, both aspirin and, to a lesser extent, EPA decreased levels of both biomarkers (74% [P ≤ .001] and 8% [P ≤ .05] reduction in median 11-d-TXB 2 values, respectively). In the placebo group, a high (quartile [Q] 2-4) baseline 11-d-TXB 2 level predicted increased polyp number (incidence rate ratio [IRR] [95% CI] 2.26 [1.11,4.58]) and risk (odds ratio [95% CI] 3.56 [1.09,11.63]). A low (Q1) on-treatment 11-d-TXB 2 level predicted reduced colorectal polyp number compared to placebo (IRR 0.34 [0.12,0.93] for combination aspirin and EPA treatment) compared to high on-treatment 11-d-TXB 2 values (0.61 [0.34,1.11]). Aspirin and EPA both inhibit PGE-M and 11-d-TXB 2 synthesis in keeping with shared in vivo cyclooxygenase inhibition. Colorectal polyp risk and treatment response prediction by 11-d-TXB 2 is consistent with a role for platelet activation during early colorectal carcinogenesis. The use of urinary 11-d-TXB 2 measurement for a precision approach to colorectal cancer risk prediction and chemoprevention requires prospective evaluation., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Assembled genome sequences are being generated at an exponential rate. Here we present FCS-GX, part of NCBI's Foreign Contamination Screen (FCS) tool suite, optimized to identify and remove contaminant sequences in new genomes. FCS-GX screens most genomes in 0.1-10 min. Testing FCS-GX on artificially fragmented genomes demonstrates high sensitivity and specificity for diverse contaminant species. We used FCS-GX to screen 1.6 million GenBank assemblies and identified 36.8 Gbp of contamination, comprising 0.16% of total bases, with half from 161 assemblies. We updated assemblies in NCBI RefSeq to reduce detected contamination to 0.01% of bases. FCS-GX is available at https://github.com/ncbi/fcs/ or https://doi.org/10.5281/zenodo.10651084 ., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The gut microbiome consists of trillions of bacteria, fungi, and viruses that inhabit the digestive tract. These communities are sensitive to disruption from environmental exposures ranging from diet changes to illness. Disruption of the community of lactic acid producing bacteria, Lactobaccillacea, has been well documented in mood disorders and stress exposure. In fact, oral supplement with many Lactobacillus species can ameliorate these effects, preventing depression- and anxiety-like behavior. Here, we utilize a gnotobiotic mouse colonized with the Altered Schaedler Flora to remove the two native species of Lactobaccillacea: L. intestinalis and L. murinus. Using this microbial community, we found that the Lactobacillus species themselves, and not the disrupted microbial communities are protective from environmental stressors. Further, we determine that Lactobaccillacea are maintaining homeostatic IFNγ levels which are mediating these behavioral and circuit level responses. By utilizing the Altered Schaedler Flora, we have gained new insight into how probiotics influence behavior and provide novel methods to study potential therapies to treat mood disorders., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Authors declare that they have no competing interests. A.G. is a consultant for Novoron Bioscience., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Psychotropic medication efficacy and tolerability are critical treatment issues faced by individuals with psychiatric disorders and their healthcare providers. For some people, it can take months to years of a trial-and-error process to identify a medication with the ideal efficacy and tolerability profile. Current strategies (e.g. clinical practice guidelines, treatment algorithms) for addressing this issue can be useful at the population level, but often fall short at the individual level. This is, in part, attributed to interindividual variation in genes that are involved in pharmacokinetic (i.e. absorption, distribution, metabolism, elimination) and pharmacodynamic (e.g. receptors, signaling pathways) processes that in large part, determine whether a medication will be efficacious or tolerable. A precision prescribing strategy know as pharmacogenomics (PGx) assesses these genomic variations, and uses it to inform selection and dosing of certain psychotropic medications. In this review, we describe the path that led to the emergence of PGx in psychiatry, the current evidence base and implementation status of PGx in the psychiatric clinic, and finally, the future growth potential of precision psychiatry via the convergence of the PGx-guided strategy with emerging technologies and approaches (i.e. pharmacoepigenomics, pharmacomicrobiomics, pharmacotranscriptomics, pharmacoproteomics, pharmacometabolomics) to personalize treatment of psychiatric disorders.

Aspirin and eicosapentaenoic acid (EPA) reduce colorectal adenomatous polyp risk and affect synthesis of oxylipins including prostaglandin E2. We investigated whether 35 SNPs in oxylipin metabolism genes such as cyclooxygenase (PTGS) and lipoxygenase (ALOX), as well as 7 SNPs already associated with colorectal cancer risk reduction by aspirin (e.g., TP53; rs104522), modified the effects of aspirin and EPA on colorectal polyp recurrence in the randomized 2 × 2 factorial seAFOod trial. Treatment effects were reported as the incidence rate ratio (IRR) and 95% confidence interval (CI) by stratifying negative binomial and Poisson regression analyses of colorectal polyp risk on SNP genotype. Statistical significance was reported with adjustment for the false discovery rate as the P and q value. 542 (of 707) trial participants had both genotype and colonoscopy outcome data. Reduction in colorectal polyp risk in aspirin users compared with nonaspirin users was restricted to rs4837960 (PTGS1) common homozygotes [IRR, 0.69; 95% confidence interval (CI), 0.53-0.90); q = 0.06], rs2745557 (PTGS2) compound heterozygote-rare homozygotes [IRR, 0.60 (0.41-0.88); q = 0.06], rs7090328 (ALOX5) rare homozygotes [IRR 0.27 (0.11-0.64); q = 0.05], rs2073438 (ALOX12) common homozygotes [IRR, 0.57 (0.41-0.80); q = 0.05], and rs104522 (TP53) rare homozygotes [IRR, 0.37 (0.17-0.79); q = 0.06]. No modification of colorectal polyp risk in EPA users was observed. In conclusion, genetic variants relevant to the proposed mechanism of action on oxylipins are associated with differential colorectal polyp risk reduction by aspirin in individuals who develop multiple colorectal polyps. SNP genotypes should be considered during development of personalized, predictive models of colorectal cancer chemoprevention by aspirin., Prevention Relevance: Single-nucleotide polymorphisms in genes controlling lipid mediator signaling may modify the colorectal polyp prevention activity of aspirin. Further investigation is required to determine whether testing for genetic variants can be used to target cancer chemoprevention by aspirin to those who will benefit most., (©2023 The Authors; Published by the American Association for Cancer Research.)

Aims: The forthcoming STAMPEDE2 trial has three comparisons in metastatic hormone-sensitive prostate cancer. We aim to determine clinical practices among STAMPEDE trial investigators for access to imaging and therapeutic choices and explore their interest in participation in STAMPEDE2., Materials and Methods: The survey was developed and distributed online to 120 UK STAMPEDE trial sites. Recipients were invited to complete the survey between 16 and 30 May 2022. The survey consisted of 30 questions in five sections on access to stereotactic ablative body radiotherapy (SABR), 177lutetium-prostate-specific membrane antigen-617 ( 177 Lu-PSMA-617), choice of systemic therapies and use of positron emission tomography/computerised tomography and whole-body magnetic resonance imaging., Results: From 58/120 (48%) sites, 64 respondents completed the survey: 55/64 (86%) respondents were interested to participate in SABR, 44/64 (69%) in 177 Lu-PSMA-617 and 56/64 (87.5%) in niraparib with abiraterone comparisons; 45/64 (70%) respondents had access to bone, spine and lymph node metastases SABR delivery and 7/64 (11%) to 177 Lu-PSMA-617. In addition to androgen deprivation therapy, 60/64 (94%) respondents used androgen receptor signalling inhibitors and 46/64 (72%) used docetaxel; 29/64 (45%) respondents would consider triplet therapy with androgen deprivation therapy, androgen receptor signalling inhibitors and docetaxel. Positron emission tomography/computerised tomography was available to 62/64 (97%) respondents and requested by 45/64 (70%) respondents for disease uncertainty on conventional imaging and 39/64 (61%) at disease relapse. Whole-body magnetic resonance imaging was available to 24/64 (38%) respondents and requested by 13/64 (20%) respondents in highly selected patients. In low-volume disease, 38/64 (59%) respondents requested scans at baseline and disease relapse. In high-volume disease, 29/64 (45%) respondents requested scans at baseline, best response (at prostate-specific antigen nadir) and disease relapse; 54/64 (84%) respondents requested computerised tomography and bone scan for best response assessment., Conclusion: There is noteworthy disparity in clinical practice across current study sites, however most have expressed an interest in participation in the forthcoming STAMPEDE2 trial., (Copyright © 2023. Published by Elsevier Ltd.)

Purpose: Homologous recombination deficiency (HRD) is a well-described phenotype of some prostate cancers; however, current biomarkers for HRD are imperfect and rely on detection of single gene alterations in the homologous recombination repair (HRR) pathway, which may not capture the complexity of HRD biology. RNA signature-based methods of HRD identification present a potentially dynamic assessment of the HRD phenotype; however, its relationship with HRR gene alterations is not well characterized in prostate cancer., Methods: A HRD assay on the basis of an RNA signature associated with biallelic BRCA1/2 loss was applied to a retrospective cohort study of 985 men with prostate cancer analyzed on the Tempus xT platform. HRD status was defined by a binary threshold on a continuous scale., Results: In this cohort, of the 126 (13%) patients found to be HRD+ by RNA signature (HRD-RNA+), 100 (79%) had no coexisting HRR gene alteration. Among samples with biallelic BRCA1/2 loss, 78% (7/9) were classified as HRD-RNA+, while 8% (2/25) of samples with BRCA1/2 monoallelic loss were HRD-RNA+. Biallelic and monoallelic ATM loss exhibited HRD-RNA+ at a lower prevalence: 6.7% (1/15) and 7.1% (1/14), respectively, compared with HRD-RNA+ prevalence among samples without any HRR gene loss (13%; 100/782). HRD-RNA+ was associated with a significantly higher prevalence of TP53 and AR gene alterations relative to HRD-RNA- after correction for multiple comparisons, 59% versus 39% ( q = 0.003) and 23% versus 12% ( q = 0.024), respectively., Conclusion: Use of an RNA-based HRD signature significantly expands the fraction of patients with prostate cancer who may derive benefit from poly (ADP-ribose) polymerase inhibitors (PARPis) compared with using HRR gene mutations alone. Further studies are needed to evaluate functional HRD significance and inform future usage as a predictive biomarker for PARPi selection.

Background: The seAFOod polyp prevention trial was a randomised, placebo-controlled, 2 × 2 factorial trial of aspirin 300 mg and eicosapentaenoic acid (EPA) 2000 mg daily in individuals who had a screening colonoscopy in the English Bowel Cancer Screening Programme (BCSP). Aspirin treatment was associated with a 20% reduction in colorectal polyp number at BCSP surveillance colonoscopy 12 months later. It is unclear what happens to colorectal polyp risk after short-term aspirin use., Aim: To investigate colorectal polyp risk according to the original trial treatment allocation, up to 6 years after trial participation., Methods: All seAFOod trial participants were scheduled for further BCSP surveillance and provided informed consent for the collection of colonoscopy outcomes. We linked BCSP colonoscopy data to trial outcomes data., Results: In total, 507 individuals underwent one or more colonoscopies after trial participation. Individuals grouped by treatment allocation were well matched for clinical characteristics, follow-up duration and number of surveillance colonoscopies. The polyp detection rate (PDR; the number of individuals who had ≥1 colorectal polyp detected) after randomization to placebo aspirin was 71.1%. The PDR was 80.1% for individuals who had received aspirin (odds ratio [OR] 1.13 [95% confidence interval 1.02, 1.24]; p = 0.02). There was no difference in colorectal polyp outcomes between individuals who had been allocated to EPA compared with its placebo (OR for PDR 1.00 [0.91, 1.10]; p = 0.92)., Conclusion: Individuals who received aspirin in the seAFOod trial demonstrated increased colorectal polyp risk during post-trial surveillance. Rebound elevated neoplastic risk after short-term aspirin use has important implications for aspirin cessation driven by age-related bleeding risk. ISRCTN05926847., (© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

This systematic review evaluated the animal and human evidence for pharmacomicrobiomics (PMx) interactions of antidepressant medications. Studies of gut microbiota effects on functional and behavioral effects of antidepressants in human and animal models were identified from PubMed up to December 2022. Risk of bias was assessed, and results are presented as a systematic review following PRISMA guidelines. A total of 28 (21 animal, 7 human) studies were included in the review. The reviewed papers converged on three themes: (1) Antidepressants can alter the composition and metabolites of gut microbiota, (2) gut microbiota can alter the bioavailability of certain antidepressants, and (3) gut microbiota may modulate the clinical or modeled mood modifying effects of antidepressants. The majority (n = 22) of studies had at least moderate levels of bias present. While strong evidence is still lacking to understand the clinical role of antidepressant PMx in human health, there is evidence for interactions among antidepressants, microbiota changes, microbiota metabolite changes, and behavior. Well-controlled studies of the mediating and moderating effects of baseline and treatment-emergent changes in microbiota on therapeutic and adverse responses to antidepressants are needed to better establish a potential role of PMx in personalizing antidepressant treatment selection and response prediction.

Amphiphilic copolymers of various-molecular-weight (MW) poly(ethylene glycol) (PEG) were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. The first PEG series, poly(ethylene glycol)monomethacrylate (PEGMA, average Mn 200 and 400 MW), contained an -OH terminal group, and the second series, poly(ethylene glycol) monomethyl ether monomethacrylate (PEGMMA, average Mn 200, 400, and 1000 MW), possessed an -OCH 3 terminal group. A total of five PEG-functionalized copolymers contained the same hydrophobic monomer, butyl acrylate (BA), and were successfully reproduced via a one-pot synthesis. The resulting PEG-functionalized copolymers provide a systematic trend of properties including surface tension, critical micelle concentration (CMC), cloud point (CP), and foam lifetime based on the average MW of the PEG monomer and final polymer properties. In general, the PEGMA series produced more stable foams with PEGMA200 demonstrating the least change in foam height with time over a 10 min period. The important exception is that at elevated temperatures, the PEGMMA1000 copolymer had longer foam lifetimes. The self-assembling copolymers were characterized by gel permeation chromatography (GPC), 1 H nuclear magnetic resonance (NMR), attenuated total reflection Fourier transform infrared (FTIR-ATR), CMC, surface tension, dynamic light scattering (DLS), as a foam using a dynamic foam analyzer (DFA), and foam lifetime at ambient and elevated temperatures. The copolymers described highlight the importance of the PEG monomer MW and terminal end group for surface interaction and final polymer properties for foam stabilization.

Background: Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival., Methods: We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland. Eligible patients (no age restriction) had metastatic, histologically-confirmed prostate adenocarcinoma; a WHO performance status of 0-2; and adequate haematological, renal, and liver function. Patients were randomly assigned (1:1) using a computerised algorithm and a minimisation technique to either standard of care (androgen deprivation therapy; docetaxel 75 mg/m 2 intravenously for six cycles with prednisolone 10 mg orally once per day allowed from Dec 17, 2015) or standard of care plus abiraterone acetate 1000 mg and prednisolone 5 mg (in the abiraterone trial) orally or abiraterone acetate and prednisolone plus enzalutamide 160 mg orally once a day (in the abiraterone and enzalutamide trial). Patients were stratified by centre, age, WHO performance status, type of androgen deprivation therapy, use of aspirin or non-steroidal anti-inflammatory drugs, pelvic nodal status, planned radiotherapy, and planned docetaxel use. The primary outcome was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who started treatment. A fixed-effects meta-analysis of individual patient data was used to compare differences in survival between the two trials. STAMPEDE is registered with ClinicalTrials.gov (NCT00268476) and ISRCTN (ISRCTN78818544)., Findings: Between Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial. Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial. Median follow-up was 96 months (IQR 86-107) in the abiraterone trial and 72 months (61-74) in the abiraterone and enzalutamide trial. In the abiraterone trial, median overall survival was 76·6 months (95% CI 67·8-86·9) in the abiraterone group versus 45·7 months (41·6-52·0) in the standard of care group (hazard ratio [HR] 0·62 [95% CI 0·53-0·73]; p<0·0001). In the abiraterone and enzalutamide trial, median overall survival was 73·1 months (61·9-81·3) in the abiraterone and enzalutamide group versus 51·8 months (45·3-59·0) in the standard of care group (HR 0·65 [0·55-0·77]; p<0·0001). We found no difference in the treatment effect between these two trials (interaction HR 1·05 [0·83-1·32]; p interaction =0·71) or between-trial heterogeneity (I 2 p=0·70). In the first 5 years of treatment, grade 3-5 toxic effects were higher when abiraterone was added to standard of care (271 [54%] of 498 vs 192 [38%] of 502 with standard of care) and the highest toxic effects were seen when abiraterone and enzalutamide were added to standard of care (302 [68%] of 445 vs 204 [45%] of 454 with standard of care). Cardiac causes were the most common cause of death due to adverse events (five [1%] with standard of care plus abiraterone and enzalutamide [two attributed to treatment] and one (<1%) with standard of care in the abiraterone trial)., Interpretation: Enzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term androgen deprivation therapy. Clinically important improvements in survival from addition of abiraterone to androgen deprivation therapy are maintained for longer than 7 years., Funding: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas., Competing Interests: Declaration of interests GA reports personal fees, grants, and travel support from Janssen and Astellas; personal fees or travel support from Pfizer, Ipsen, Novartis (Advanced Accelerator Applications), Abbott Laboratories, Ferring, ESSA Pharmaceuticals, Bayer Healthcare Pharmaceuticals, BeiGene, Takeda, AstraZeneca, and Sanofi Aventis; grant support from AstraZeneca, Innocrin Pharma, and Arno Therapeutics; receives a share of the royalty income from The Institute of Cancer Research Rewards to Discoverers Scheme for abiraterone; and holds a patent on plasma methylation signatures as biomarkers for prostate cancer (GB1915469.9). LM, AC, CB, CG, HR, CLA, CM, NP, CP, CD-M, DG, MRS, LCB, REL, and MKBP report research grants for the STAMPEDE trial from Janssen, Astellas, Novartis, Sanofi, and Clovis. NWC reports personal fees from Janssen and Astellas. AS reports grants or contracts with the National Institute for Health Research, John Black Charitable Foundation, and Prostate Cancer Foundation. RJJ reports research grants from Astellas, Clovis, Exelixis, Bayer, and Roche; and advisory board participation and speaker's honoraria from Janssen, Astellas, Bayer, Novartis, Pfizer, Merck Serono, MSD, Roche, Ipsen, and Bristol Myers Squibb. CCP reports consulting fees from Advanced Accelerator Applications, ITM Radiopharma, Myovant, and Clarity Pharmaceuticals; and speaker's honoraria from Janssen and Bayer. SG reports consulting fees from Tolremo; payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, educational events, and honoraria from Silvio Grasso Consulting, WebMD (Medscape), European Society of Medical Oncology, Orikata, Swiss Group for Clinical Cancer Research, Beijing United Family Hospital and Clinics, Deutchland European School of Oncology, Swiss Academy of Multidisciplinary Oncology, PeerVoice, and Radiotelevisione Svizzera Italiana; travel support from Proteomedix and AstraZeneca; a patent for biomarker discovery (WO 2009138392 A1); advisory board participation for Janssen, MSD, Bayer, Roche, Astellas, Pfizer, Telixpharma, Bristol Myers Squibb, Advanced Accelerator Applications, Orion, Novartis, Modra Pharmaceuticals, AstraZeneca, Myriad Genetic, and Amgen; and a scientific committee role for Pfizer. CG reports institution funding from Astellas, Clovis Oncology, Janssen, Novartis, Pfizer, and Sanofi Genzyme; and charitable funding from Cancer Research UK and Medical Research Council. SC reports consulting fees from Telix, Novartis (Advanced Accelerator Applications), Huma, Remedy Bio, and Curesponse; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Bayer, Janssen, Astellas, Amgen, and Advanced Accelerator Applications; participation on a data safety monitoring board or advisory board for Amgen, Janssen, and Bayer; and stocks in Huma and Remedy Bio. JMO reports a grant from Prostate Cancer UK. AB reports speaker's fees from Janssen, Astellas, Bristol Myers Squibb, Roche, MSD, and Bayer; support for attending meetings and travel from Janssen and Bayer; and participation on a data safety monitoring board or advisory board for Janssen, Bristol Myers Squibb, and AstraZeneca. NS reports support for travel expenses from Janssen-Cilag. JT reports support from Janssen and Astellas for conference attendance; and participation in advisory boards for Janssen and Astellas. PD reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Pfizer, Bristol Myers Squibb, Ipsen, EUSA Pharma, and EISAI; support for attending meetings or travel from Janssen and Ipsen; and participation on a data safety monitoring board or advisory board for Pfizer and EUSA Pharma. OP reports support for educational meetings and conference attendance from Janssen and Astellas. AR reports sponsorships for attending a conference from Janssen. AHM reports sponsorship to attend an educational meeting from Astellas. RC reports consulting fees from Astellas, Bayer, Novartis, Janssen, Sanofi, Pfizer, MSD, Bristol Myers Squibb, Roche, Debiopharm, AstraZeneca, Ipsen, and Merck; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Ipsen, Astellas, Janssen, Roche, and Merck; and participation as a board member for the Swiss Group for Clinical Cancer Research. DPD reports consulting fees and participation on an advisory board for Janssen; and a patent for a localisation and stabilisation device (EP1933709B1). MRS reports speaker fees from Eisai and being a non-paid member of independent data monitoring committees for academic sponsors. NDJ reports research grants for the STAMPEDE trial from Janssen, Astellas, Novartis, Sanofi, Clovis, and Cancer Research UK; and consulting and lecture fees from Astellas and Janssen. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. 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