Population pharmacokinetic modeling and target attainment analyses of rezafungin for the treatment of candidemia and invasive candidiasis.

Rezafungin is a chemically and metabolically stable echinocandin with a longer half-life than other echinocandins, allowing for a once-weekly intravenous infusion versus a daily infusion. Rezafungin is approved in the US for the treatment of candidemia and/or invasive candidiasis and is in development for the prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp. in immunosuppressed patients. A population pharmacokinetic (PPK) model was developed using data from five Phase 1, one Phase 2, and one Phase 3 study. The model found to best describe the available data was a three-compartment PPK model with first-order elimination characterized by the parameters clearance (CL), central volume (V1), peripheral volume (V23), intercompartmental clearance 1, and intercompartmental clearance 2. The variability model included correlated interindividual variability in CL, V1, and V23 and a proportional residual variability model. The following statistically significant covariates were identified: albumin concentrations on V23; body surface area (BSA) on CL, V1, and V23; and disease state on CL and V1. Disease states were defined as patients from the Phase 2 and Phase 3 studies and hepatically impaired subjects. Covariates of BSA, disease state, or albumin, included in the final model, were not associated with clinically meaningful changes in PK, nor were any other patient factors, indicating that a common dose regimen is adequate for all adult patients. Target attainment simulations were performed to estimate the probability of achieving PK/pharmacodynamic targets across the range of minimum inhibitory concentration values for six species of Candida.

Dynamics in the ordered and disordered phases of barocaloric adamantane.

High-entropy order-disorder phase transitions can be used for efficient and eco-friendly barocaloric solid-state cooling. Here the barocaloric effect is reported in an archetypal plastic crystal, adamantane. Adamantane has a colossal isothermally reversible entropy change of 106 J K-1 kg-1. Extremely low hysteresis means that this can be accessed at pressure differences less than 200 bar. Configurational entropy can only account for about 40% of the total entropy change; the remainder is due to vibrational effects. Using neutron spectroscopy and supercell lattice dynamics calculations, it is found that this vibrational entropy change is mainly caused by softening in the high-entropy phase of acoustic modes that correspond to molecular rotations. We attribute this difference in the dynamics to the contrast between an 'interlocked' state in the low-entropy phase and sphere-like behaviour in the high-entropy phase. Although adamantane is a simple van der Waals solid with near-spherical molecules, this approach can be leveraged for the design of more complex barocaloric molecular crystals. Moreover, this study shows that supercell lattice dynamics calculations can accurately map the effect of orientational disorder on the phonon spectrum, paving the way for studying the vibrational entropy, thermal conductivity, and other thermodynamic effects in more complex materials.

Neutron Scattering Studies of the Breathing Pyrochlore Antiferromagnet LiGaCr_{4}O_{8}.

We report neutron scattering measurements of the spinel oxide LiGaCr_{4}O_{8}, in which magnetic ions Cr^{3+} form a breathing pyrochlore lattice. Our experiments reveal the coexistence of a nearly dispersionless resonance mode and dispersive spin-wave excitations in the magnetically ordered state, which can be quantitatively described by a quantum spin model of hexagonal loops and linear spin-wave theory with the same set of exchange parameters, respectively. Comparison to other Cr spinel oxides reveals a linear relationship between the resonance energy and lattice constant across all these materials, which is in agreement with our hexagonal loop calculations. Our results suggest a unified picture for spin resonances in Cr spinel oxides.

A cluster-randomized crossover trial of Montessori activities delivered by family carers to nursing home residents with behavioral and psychological symptoms of dementia.

OBJECTIVES: One-on-one structured Montessori-based activities conducted with people with dementia can improve agitation and enhance engagement. These activities may however not always be implemented by nursing home staff. Family members may present an untapped resource for enabling these activities. This study aimed to evaluate the impact of the Montessori activities implemented by family members on visitation experiences with people who have dementia. DESIGN: Cluster-randomized crossover design. SETTING: General and psychogeriatric nursing homes in the state of Victoria, Australia. PARTICIPANTS: Forty participants (20 residents and 20 carers) were recruited. INTERVENTION: During visits, family members interacted with their relative either through engaging in Montessori-based activities or reading a newspaper (the control condition) for four 30-minute sessions over 2 weeks. MEASUREMENTS: Residents' predominant affect and engagement were rated for each 30-second interval using the Philadelphia Geriatric Center Affect Rating Scale and the Menorah Park Engagement Scale. The Pearlin Mastery Scale was used to rate carers satisfaction with visits. The 15-item Mutuality Scale measured the carers quality of their relationship with the resident. Carers' mood and overall quality of life were measured using the Center for Epidemiological Studies Depression Scale and Carer-QoL questionnaires, respectively. RESULTS: Linear regressions within the generalized estimating equations approach assessed residents' and carers' outcomes. Relative to the control condition, the Montessori condition resulted in more positive engagement (b = 13.0, 95%CI 6.3-19.7, p < 0.001) and affect (b = 0.4, 95%CI 0.2-0.6, p < 0.001) for the residents and higher satisfaction with visits for carers (b = 1.7, 95%CI 0.45-3.00, p = 0.008). No correction was applied to p-values for multiple comparisons. CONCLUSION: This study strengthens the evidence base for the use of the Montessori programs in increasing well-being in nursing home residents. The findings also provide evidence that family members are an additional valuable resource in implementing structured activities such as the Montessori program with residents.

The effect of previous shoulder pain on supraspinatus tendon thickness changes following swimming practice.

OBJECTIVES: To assess if swimming practice results in changes in supraspinatus tendon thickness, acromiohumeral distance, and occupational ratio in shoulders of elite swimmers with and without a history of shoulder pain. DESIGN: Case-Control study. METHODS: A convenience sample of fifty elite swimmers (14-22 years) were recruited for this study. Groups were defined by the presence (history of pain, N = 37) or absence (pain free, N = 63) of significant interfering shoulder pain within the previous 6 months. The current study analyzed supraspinatus tendon thickness, acromiohumeral distance, and the occupational ratio, through the use of ultrasound. Measures were taken prior to swim practice; immediately after practice; and 6 hours post-practice. RESULTS: No statistically significant difference in supraspinatus tendon thickness, acromiohumeral distance or ratio between shoulders with and without a history of pain were found at rest. Following a swimming practice, both shoulders with and without a history of pain had a significant increase in tendon thickness (0.27 & 0.17 mm; P ≤ .001 & <.001). The increase in thickness was significantly greater in the history of pain shoulders compared to pain-free shoulders (P = .003). At 6-hour post-practice, the history of pain shoulders was still significantly thicker than their pre-practice (rested) levels (P = .007). Despite changes in tendon thickness, the occupational ratio remained non-significant between groups. CONCLUSION: Shoulders with a history of pain show an altered response to swimming practice. The results of the current study have implications for training load and injury management. It should prompt investigation into how the tendon reacts under varying load conditions.

Absence of Pharmacokinetic Interactions between the Bruton's Tyrosine Kinase Inhibitor Fenebrutinib and Methotrexate.

Fenebrutinib (GDC-0853) is an orally administered small molecule inhibitor of Bruton's tyrosine kinase being investigated for treatment of rheumatoid arthritis in patients with inadequate responses to methotrexate (MTX). This study interrogated the potential for pharmacokinetic drug interactions between fenebrutinib and MTX. Eighteen healthy male subjects were enrolled in the study. They received a single oral dose of MTX (7.5 mg) on day 1 followed by a 13-day washout period. Subsequently, on days 15-20 the participants received 200 mg of fenebrutinib twice daily. On day 21, they received a 7.5 mg dose of MTX and a 200 mg dose of fenebrutinib under fasting conditions. The geometric mean ratios of MTX area under the plasma concentration-time curve (AUC) and C max on day 21 relative to day 1 (90% confidence interval [CI]) were 0.96 (0.88-1.04) and 1.05 (0.94-1.18), respectively. The geometric mean ratios of fenebrutinib AUC and C max for day 21 relative to day 20 (90% CI) were 1.03 (0.95-1.11) and 1.02 (0.90-1.15), respectively. The combination treatment was well tolerated, with an adverse event profile similar to that reported in other MTX trials. These results indicate that there is no clinically significant pharmacokinetic interaction between fenebrutinib and MTX.

A four-group urine risk classifier for predicting outcomes in patients with prostate cancer.

OBJECTIVES: To develop a risk classifier using urine-derived extracellular vesicle (EV)-RNA capable of providing diagnostic information on disease status prior to biopsy, and prognostic information for men on active surveillance (AS). PATIENTS AND METHODS: Post-digital rectal examination urine-derived EV-RNA expression profiles (n = 535, multiple centres) were interrogated with a curated NanoString panel. A LASSO-based continuation ratio model was built to generate four prostate urine risk (PUR) signatures for predicting the probability of normal tissue (PUR-1), D'Amico low-risk (PUR-2), intermediate-risk (PUR-3), and high-risk (PUR-4) prostate cancer. This model was applied to a test cohort (n = 177) for diagnostic evaluation, and to an AS sub-cohort (n = 87) for prognostic evaluation. RESULTS: Each PUR signature was significantly associated with its corresponding clinical category (P < 0.001). PUR-4 status predicted the presence of clinically significant intermediate- or high-risk disease (area under the curve = 0.77, 95% confidence interval [CI] 0.70-0.84). Application of PUR provided a net benefit over current clinical practice. In an AS sub-cohort (n = 87), groups defined by PUR status and proportion of PUR-4 had a significant association with time to progression (interquartile range hazard ratio [HR] 2.86, 95% CI 1.83-4.47; P < 0.001). PUR-4, when used continuously, dichotomized patient groups with differential progression rates of 10% and 60% 5 years after urine collection (HR 8.23, 95% CI 3.26-20.81; P < 0.001). CONCLUSION: Urine-derived EV-RNA can provide diagnostic information on aggressive prostate cancer prior to biopsy, and prognostic information for men on AS. PUR represents a new and versatile biomarker that could result in substantial alterations to current treatment of patients with prostate cancer.

Correction to: Application of a Novel 'Make and Test in Parallel' Strategy to Investigate the Effect of Formulation on the Pharmacokinetics of GDC-0810 in Healthy Subjects.

The Publisher regrets the typesetting mistake of retaining incorrect text in the Figure 1 caption. The correct text for the caption is "Molecular Structure of GDC-0810 NMG Salt". The original article has been corrected.

Application of a Novel 'Make and Test in Parallel' Strategy to Investigate the Effect of Formulation on the Pharmacokinetics of GDC-0810 in Healthy Subjects.

PURPOSE: GDC-0810, administered orally, was used in Phase I and II clinical studies to treat estrogen receptor positive breast cancers. It contains N-methyl-D-glucamine (NMG) salt of GDC-0810 with 10% sodium lauryl sulfate (SLS) as a surfactant and 15% sodium bicarbonate (NaHCO3) as an alkalizing agent to aid dissolution. To improve the processability of the formulation and reduce potential mucosal irritation in future Phase III clinical studies, the salt form and the amount of excipient required further optimization. To achieve this, we employed a novel "Make and Test in Parallel" strategy that facilitated selecting formulation in a rapid timeframe. METHODS: RapidFACT®, a streamlined, data-driven drug product optimization platform was used to bridge Phase I/II and Phase III formulations of GDC-0810. Five prototype formulations, varying in either the form of active pharmaceutical ingredient and/or the levels of the excipients SLS and NaHCO3 were assessed. Uniquely, the specific compositions of formulations manufactured and dosed were selected in real-time from emerging clinical data. RESULTS: The study successfully identified a Phase III formulation with a reduced SLS content, which when administered following a low-fat meal, gave comparable pharmacokinetic exposure to the Phase I/II formulation administered under the same conditions. CONCLUSIONS: Our novel 'Make and Test in Parallel' approach enabled optimization of GDC-0810 formulation in a time- and cost-efficient fashion.

Experience Focussed Counselling with Voice Hearers: Towards a Trans-diagnostic Key to Understanding Past and Current Distress-A Thematic Enquiry.

As it is increasingly evident that distressing voices can be linked to traumatic events across diagnoses, there is a need for new transdiagnostic interventions for persons with voice hearing related distress. Twenty-five interviews with voice hearers and mental health professionals explored the trans-diagnostic suitability of Experience Focussed Counselling (EFC) compared to Treatment As Usual. An Applied Thematic Analysis was used. Themes identified were: intervention applicability; impact of regular treatment before study; impact of EFC process; process of working with voices; impact of regular treatment during study; views on treatment or approach. The EFC focus was considered helpful across diagnoses. The findings support EFC as a transdiagnostic intervention.

Tri-focal Model of Care Implementation: Perspectives of Residents and Family.

PURPOSE: To explore residents' and family members' perceptions of partnership-centered long-term care (LTC) associated with implementation of the Tri-focal Model of Care. The Model promotes partnership-centered care, evidence-based practice, and a positive environment. Its implementation is supported by a specifically designed education program. METHODS: The Model was implemented over approximately 12 months in seven LTC facilities in Victoria, Australia. A qualitative exploratory-descriptive approach was used. Data were collected using individual and focus group interviews with residents and family members prior to and following implementation of the Model. Data were analyzed thematically. FINDINGS: Prior to implementation of the Model, residents described experiencing a sense of disempowerment, and emphasized the importance of communication, engagement, and being a partner in the staff-resident care relationship. Following implementation, residents reported experiencing improved partnership approaches to care, although there were factors that impacted on having a good experience. Family members described a desire to remain involved in the resident's life by establishing good communication and rapport with staff. They acknowledged this was important for partnership-centered care. Following implementation, they described experiencing a partnership with staff, giving them confidence to assist staff and be included in decisions about the resident. CONCLUSIONS: The Tri-focal Model of Care can enable residents, family members, and staff to be partners in resident care in LTC settings. CLINICAL RELEVANCE: With an ageing population, an increasing demand for complex, individualized LTC exists. Delivery of high-quality LTC requires a strategy to implement a partnership-centered approach, involving residents, family members, and staff.

Introducing a model incorporating early integration of specialist palliative care: A qualitative research study of staff's perspectives.

BACKGROUND: Palliative care has evolved to encompass early integration, with evaluation of patient and organisational outcomes. However, little is known of staff's experiences and adaptations when change occurs within palliative care services. AIM: To explore staff experiences of a transition from a service predominantly focused on end-of-life care to a specialist service encompassing early integration. DESIGN: Qualitative research incorporating interviews, focus groups and anonymous semi-structured questionnaires. Data were analysed using a comparative approach. Service activity data were also aggregated. SETTING/PARTICIPANTS: A total of 32 medical, nursing, allied health and administrative staff serving a 22-bed palliative care unit and community palliative service, within a large health service. RESULTS: Patients cared for within the new model were significantly more likely to be discharged home (7.9% increase, p = 0.003) and less likely to die in the inpatient unit (10.4% decrease, p < 0.001). While early symptom management was considered valuable, nurses particularly found additional skill expectations challenging, and perceived patients' acute care needs as detracting from emotional and end-of-life care demands. Staff views varied on whether they regarded the new model's faster-paced work-life as consistent with fundamental palliative care principles. Less certainty about care goals, needing to prioritise care tasks, reduced shared support rituals and other losses could intensify stress, leading staff to develop personalised coping strategies. CONCLUSION: Services introducing and researching innovative models of palliative care need to ensure adequate preparation, maintenance of holistic care principles in faster work-paced contexts and assist staff dealing with demands associated with caring for patients at different stages of illness trajectories.

Evaluating the Liverpool Care Pathway for care of the terminally ill in rural Australia.

PURPOSE: This study evaluates a pilot implementation of the Liverpool Care Pathway (LCP), a clinical tool used to guide the care of dying patients in the last days of life, on the end-of-life care for dying patients in three regions in rural Australia. METHODS: The LCP was implemented at 13 participating sites: nine hospitals (general wards), one community-based palliative care service, and three in-hospital palliative care units. To evaluate the implementation of the LCP, 415 eligible patient records were examined: 223 pre-implementation and 192 post-implementation (116 on the LCP and 76 receiving usual care). The primary analysis compared all patients pre-implementation of the LCP versus all patients post-implementation. RESULTS: Increases were found post-implementation for communication with other health professionals and with patients or family (pre-69 %, post-87 %; p ≤ 0.000), use of palliative medications (pre-87 %, post-98 %; p ≤ 0.000) and frequency of symptom assessments (pre-66 %, post-82 %; p ≤ 0.000). Fewer blood and radiological investigations were conducted and venous access devices used in the post-implementation groups than in the pre-implementation period. CONCLUSIONS: This study suggests that when rigorously implemented, the LCP improves important components of end-of-life care for dying patients and their families.

The feasibility of volunteers facilitating personalized activities for nursing home residents with dementia and agitation.

BACKGROUND: Nursing home residents' behavioral and psychological symptoms of dementia are often exacerbated by a lack of social contact and meaningful activity. Volunteers might assist in addressing this deficiency but they are often discouraged by staff from engaging with residents with challenging behaviors. As a result, some of the neediest residents receive the least social and psychological support. AIM: This project explored the implementation of personalized, one-to-one activities by nursing home volunteers to determine if volunteers were able and willing to complete a training program and undertake activities with residents with dementia and challenging behaviors. METHODS: 19 nursing home volunteers in Melbourne, Australia, were trained to apply Montessori-type personalized activities with a selected resident whose dementia was complicated by a frequent, non-aggressive agitated behavior. The volunteers were asked to attend a workshop and pay six 30-min visits to the resident over a three week period. They completed knowledge and attitude rating scales before and after the intervention and were interviewed afterward regarding their experiences and perceptions. RESULTS: 16 volunteers completed the program and eight met or exceeded every study requirement. Most of them derived satisfaction from engaging residents' interest and were pleased to learn new skills. The scores on the dementia knowledge and attitude rating scale of those who completed the visits were higher at the study's outset than the scores of those who failed to make any visits. CONCLUSIONS: It is certainly feasible to train volunteers to work with residents who might otherwise be isolated. It is important to demonstrate activities to volunteers at the outset and to provide them with careful, ongoing supervision and support. Notwithstanding some difficulties and challenges, volunteers represent a growing and hitherto untapped pool of support for people with dementia and complex needs.

Developing a web-based app for non-mental health nurses to assess the mental health needs and risks of children and young people.

There is high demand for specialist mental health services for children and young people in the UK. Non-mental health nurses are well-placed to assess the mental health needs and risks of children and young people to maximise opportunities for early intervention and relieve the pressure on child and adolescent mental health services. This article provides an overview of a service development project to develop a web-based application (app) to support non-mental health nurses when assessing the mental health needs and risks of children and young people. The article describes the development, testing and evaluation process, which involved consultation with children and young people as well as interviews, focus groups and an online survey with a range of professionals working with children and young people. Overall, the findings suggest that the app is appropriate for use by non-mental health nurses in terms of quality, functionality and acceptability.

Structure, Spin Correlations, and Magnetism of the S = 1/2 Square-Lattice Antiferromagnet Sr2CuTe1-xWxO6 (0 ≤ x ≤ 1).

Quantum spin liquids are highly entangled magnetic states with exotic properties. The S = 1/2 square-lattice Heisenberg model is one of the foundational models in frustrated magnetism with a predicted, but never observed, quantum spin liquid state. Isostructural double perovskites Sr2CuTeO6 and Sr2CuWO6 are physical realizations of this model but have distinctly different types of magnetic order and interactions due to a d10/d0 effect. Long-range magnetic order is suppressed in the solid solution Sr2CuTe1-xWxO6 in a wide region of x = 0.05-0.6, where the ground state has been proposed to be a disorder-induced spin liquid. Here, we present a comprehensive neutron scattering study of this system. We show using polarized neutron scattering that the spin liquid-like x = 0.2 and x = 0.5 samples have distinctly different local spin correlations, which suggests that they have different ground states. Low-temperature neutron diffraction measurements of the magnetically ordered W-rich samples reveal magnetic phase separation, which suggests that the previously ignored interlayer coupling between the square planes plays a role in the suppression of magnetic order at x ≈ 0.6. These results highlight the complex magnetism of Sr2CuTe1-xWxO6 and hint at a new quantum critical point between 0.2 < x < 0.4.

Absence of Clinically Meaningful Drug-Drug Interactions with Rezafungin: Outcome of Investigations.

Rezafungin is a novel once-weekly echinocandin for intravenous injection currently in development for the treatment of Candida infections and the prevention of Candida, Aspergillus, and Pneumocystis infections in allogeneic blood and marrow transplant recipients. While in vitro data indicated that rezafungin exposure was unlikely to be affected by commonly prescribed medicines, interactions resulting in the altered systemic exposure of some drugs coadministered with rezafungin could not be excluded. Two phase 1 open label crossover studies, conducted in healthy subjects, examined drug interactions between rezafungin and multiple drug probe cytochrome P450 (CYP) substrates and/or transporter proteins, immunosuppressants, and cancer therapies. Statistical analysis compared the outcomes for drugs coadministered with rezafungin to those for the drugs administered alone. The geometric mean ratio was reported, and a default 90% confidence interval (CI) no-effect equivalence range of 80 to 125% was used for the maximal plasma concentration (Cmax), the area under the curve from time zero to the final sampling time point (AUC0-t), and the AUC from time zero to infinity (AUC0-∞). Most probes and concomitant drugs were within the equivalence range. For tacrolimus, ibrutinib, mycophenolic acid, and venetoclax, the AUC or Cmax was reduced (10 to 19%), with lower bounds of the 90% CI values falling outside the no-effect range. The rosuvastatin AUC and Cmax and the repaglinide AUC0-∞ were increased (12 to 16%), with the 90% CI being marginally above the upper bound. Overall, the in vitro and in vivo data demonstrated a low drug interaction potential with rezafungin via CYP substrate/transporter pathways and commonly prescribed comedications, suggesting that coadministration was unlikely to result in clinically significant effects. Treatment-emergent adverse events were typically mild, and rezafungin was generally well tolerated. IMPORTANCE Antifungal agents used to treat life-threatening infections are often associated with severe drug-drug interactions (DDIs) that may limit their usefulness. Rezafungin, a newly approved once-weekly echinocandin, has been shown to be free of DDIs based on extensive nonclinical and clinical testing described in this study.

Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials.

Diagnostic karyotype provides the framework for risk-stratification schemes in acute myeloid leukemia (AML); however, the prognostic significance of many rare recurring cytogenetic abnormalities remains uncertain. We studied the outcomes of 5876 patients (16-59 years of age) who were classified into 54 cytogenetic subgroups and treated in the Medical Research Council trials. In multivariable analysis, t(15;17)(q22;q21), t(8;21)(q22;q22), and inv(16)(p13q22)/t(16;16)(p13;q22) were the only abnormalities found to predict a relatively favorable prognosis (P < .001). In patients with t(15;17) treated with extended all-trans retinoic acid and anthracycline-based chemotherapy, additional cytogenetic changes did not have an impact on prognosis. Similarly, additional abnormalities did not have a significant adverse effect in t(8;21) AML; whereas in patients with inv(16), the presence of additional changes, particularly +22, predicted a better outcome (P = .004). In multivariable analyses, various abnormalities predicted a significantly poorer outcome, namely abn(3q) (excluding t(3;5)(q25;q34)), inv(3)(q21q26)/t(3;3)(q21;q26), add(5q)/del(5q), -5, -7, add(7q)/del(7q), t(6;11)(q27;q23), t(10;11)(p11 approximately 13;q23), other t(11q23) (excluding t(9;11)(p21 approximately 22;q23) and t(11;19)(q23;p13)), t(9;22)(q34;q11), -17, and abn(17p). Patients lacking the aforementioned favorable or adverse aberrations but with 4 or more unrelated abnormalities also exhibited a significantly poorer prognosis (designated "complex" karyotype group). These data allow more reliable prediction of outcome for patients with rarer abnormalities and may facilitate the development of consensus in reporting of karyotypic information in clinical trials involving younger adults with AML. This study is registered at http://www.isrctn.org as ISRCTN55678797 and ISRCTN17161961.

Field-tuned quantum effects in a triangular-lattice Ising magnet.

We report thermodynamic and neutron scattering measurements of the triangular-lattice quantum Ising magnet TmMgGaO4 in longitudinal magnetic fields. Our experiments reveal a quasi-plateau state induced by quantum fluctuations. This state exhibits an unconventional non-monotonic field and temperature dependence of the magnetic order and excitation gap. In the high field regime where the quantum fluctuations are largely suppressed, we observed a disordered state with coherent magnon-like excitations despite the suppression of the spin excitation intensity. Through detailed semi-classical calculations, we are able to understand these behaviors quantitatively from the subtle competition between quantum fluctuations and frustrated Ising interactions.

Microbiomes of Urine and the Prostate Are Linked to Human Prostate Cancer Risk Groups.

BACKGROUND: Bacteria play a suspected role in the development of several cancer types, and associations between the presence of particular bacteria and prostate cancer have been reported. OBJECTIVE: To provide improved characterisation of the prostate and urine microbiome and to investigate the prognostic potential of the bacteria present. DESIGN, SETTING, AND PARTICIPANTS: Microbiome profiles were interrogated in sample collections of patient urine (sediment microscopy: n = 318, 16S ribosomal amplicon sequencing: n = 46; and extracellular vesicle RNA-seq: n = 40) and cancer tissue (n = 204). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Microbiomes were assessed using anaerobic culture, population-level 16S analysis, RNA-seq, and whole genome DNA sequencing. RESULTS AND LIMITATIONS: We demonstrate an association between the presence of bacteria in urine sediments and higher D'Amico risk prostate cancer (discovery, n = 215 patients, p < 0.001; validation, n = 103, p < 0.001, χ2 test for trend). Characterisation of the bacterial community led to the (1) identification of four novel bacteria (Porphyromonas sp. nov., Varibaculum sp. nov., Peptoniphilus sp. nov., and Fenollaria sp. nov.) that were frequently found in patient urine, and (2) definition of a patient subgroup associated with metastasis development (p = 0.015, log-rank test). The presence of five specific anaerobic genera, which includes three of the novel isolates, was associated with cancer risk group, in urine sediment (p = 0.045, log-rank test), urine extracellular vesicles (p = 0.039), and cancer tissue (p = 0.035), with a meta-analysis hazard ratio for disease progression of 2.60 (95% confidence interval: 1.39-4.85; p = 0.003; Cox regression). A limitation is that functional links to cancer development are not yet established. CONCLUSIONS: This study characterises prostate and urine microbiomes, and indicates that specific anaerobic bacteria genera have prognostic potential. PATIENT SUMMARY: In this study, we investigated the presence of bacteria in patient urine and the prostate. We identified four novel bacteria and suggest a potential prognostic utility for the microbiome in prostate cancer.