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Background and Objective: Multiparametric magnetic resonance imaging (mpMRI) of the prostate is used for prostate cancer diagnosis. However, mpMRI has lower sensitivity for small tumours. Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT) offers increased sensitivity over conventional imaging. This study aims to determine whether the diagnostic accuracy of 18F-DCFPyL PSMA-PET/CT was superior to that of mpMRI for detecting prostate cancer (PCa) at biopsy., Methods: Between 2020 and 2021, a prospective multicentre single-arm phase 3 imaging trial enrolled patients with clinical suspicion for PCa to have both mpMRI and PSMA-PET/CT (thorax to thigh), with reviewers blinded to the results of other imaging. Multiparametric MRI was considered positive for Prostate Imaging Reporting and Data System (PIRADS) 3-5. PSMA-PET/CT was assessed quantitatively (positive maximum standardised uptake value [SUVmax] >7) and qualitatively (five-point lexicon of certainty). Patients underwent targeted and systematic biopsy, with the technique at the discretion of the treating urologist. Clinically significant PCa (csPCa) was defined as International Society of Urological Pathology grade group (GG) ≥2. The primary outcome was the diagnostic accuracy for detecting PCa, reported as sensitivity, specificity, negative predictive value (NPV), and area under the curve (AUC) of the receiver operating curve. The secondary endpoints included a comparison of the diagnostic accuracy for detecting csPCa, assessing gains in combining PMSA-PET/CT with mpMRI to mpMRI alone., Key Findings and Limitations: Of the 236 patients completing both mpMRI and PSMA-PET/CT, 184 (76.7%) had biopsy. Biopsy histology was benign (n = 73), GG 1 (n = 27), and GG ≥2 (n = 84). The diagnostic accuracy of mpMRI for detecting PCa (AUC 0.76; 95% confidence interval [CI] 0.69, 0.82) was higher than that of PSMA-PET/CT (AUC 0.63; 95% CI 0.56, 0.70, p = 0.03). The diagnostic accuracy of mpMRI for detecting csPCa (AUC 0.72; 95% CI 0.67, 0.78) was higher than that of PSMA-PET/CT (AUC 0.62; 95% CI 0.55, 0.69) but not statistically significant (p = 0.27). A combination of PSMA-PET/CT and mpMRI showed excellent sensitivity (98.8%, 95% CI 93.5%, 100%) and NPV (96%, 95% CI 79.6%, 99.9%) over mpMRI alone (86.9% and 80.7%, respectively, p = 0.01). Thirty-two patients (13.6%) had metastatic disease. They tended to be older (68.4 vs 65.1 yr, p = 0.023), and have higher prostate-specific antigen (PSA; median PSA 9.6 vs 6.2ng/ml, p < 0.001) and abnormal prostate on digital rectal examination (78.2% vs 44.1%, p < 0.001)., Conclusions and Clinical Implications: Multiparametric MRI had superior diagnostic accuracy to PSMA-PET/CT for detecting PCa, though the difference is not significant in case of csPCa detection. A combination of mpMRI and PSMA-PET/CT showed improved sensitivity and NPV. PSMA-PET/CT could be considered for diagnostic use in patients unable to have mpMRI or those with concerning clinical features but negative mpMRI., Patient Summary: In this trial, we compared the ability of 18F-labelled prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT) with that of multiparametric magnetic resonance imaging (mpMRI) to diagnose prostate cancer by biopsy in a prostate-specific antigen screening population. We found that MRI was superior to PSMA to diagnose prostate cancer, though there was no difference in ability to diagnose clinically significant prostate cancer. PSMA-PET/CT could be considered for diagnostic use in patients unable to have mpMRI or those with concerning clinical features but negative mpMRI. Combining MRI with PSMA-PET increases the negative predictive value over MRI alone and may help men avoid invasive prostate biopsy., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aim: The aim of the third Asia-Pacific Advanced Prostate Cancer Consensus Conference (APAC APCCC 2023) was to discuss the application in the Asia-Pacific (APAC) region of consensus statements from the 4th Advanced Prostate Cancer Consensus Conference (APCCC 2022)., Methods: The one-day meeting in July 2023 brought together 27 experts from 14 APAC countries. The meeting covered five topics: (1) Intermediate- and high-risk and locally advanced prostate cancer; (2) Management of newly diagnosed metastatic hormone-sensitive prostate cancer; (3) Management of non-metastatic castration-resistant prostate cancer; (4) Homologous recombination repair mutation testing; (5) Management of metastatic castration-resistant prostate cancer. Pre- and post-symposium polling gathered APAC-specific responses to APCCC consensus questions and insights on current practices and challenges in the APAC region., Results: APAC APCCC highlights APAC-specific considerations in an evolving landscape of diagnostic technologies and treatment innovations for advanced prostate cancer. While new technologies are available in the region, cost and reimbursement continue to influence practice significantly. Individual patient considerations, including the impact of chemophobia on Asian patients, also influence decision-making., Conclusion: The use of next-generation imaging, genetic testing, and new treatment combinations is increasing the complexity and duration of prostate cancer management. Familiarity with new diagnostic and treatment options is growing in the APAC region. Insights highlight the continued importance of a multidisciplinary approach that includes nuclear medicine, genetic counseling, and quality-of-life expertise. The APAC APCCC meeting provides an important opportunity to share practice and identify APAC-specific issues and considerations in areas of low evidence where clinical experience is growing., (© 2024 The Authors. Asia‐Pacific Journal of Clinical Oncology published by John Wiley & Sons Australia, Ltd.)

Objective: To determine whether the addition of inhaled methoxyflurane to periprostatic infiltration of local anaesthetic (PILA) during transrectal ultrasonography-guided prostate biopsies (TRUSBs) improved pain and other aspects of the experience., Patients and Methods: We conducted a multicentre, placebo-controlled, double-blind, randomized phase 3 trial, involving 420 men undergoing their first TRUSB. The intervention was PILA plus a patient-controlled device containing either 3 mL methoxyflurane, or 3 mL 0.9% saline plus one drop of methoxyflurane to preserve blinding. The primary outcome was the pain score (0-10) reported by the participant after 15 min. Secondary outcomes included ratings of other aspects of the biopsy experience, willingness to undergo future biopsies, urologists' ratings, biopsy completion, and adverse events., Results: The mean (SE) pain scores 15 min after TRUSB were 2.51 (0.22) in those assigned methoxyflurane vs 2.82 (0.22) for placebo (difference 0.31, 95% confidence interval [CI] -0.75 to 0.14; P = 0.18). Methoxyflurane was associated with better scores for discomfort (difference -0.48, 95% CI -0.92 to -0.03; P = 0.035, adjusted [adj.] P = 0.076), whole experience (difference -0.50, 95% CI -0.92 to -0.08; P = 0.021, adj. P = 0.053), and willingness to undergo repeat biopsies (odds ratio 1.67, 95% CI 1.12-2.49; P = 0.01) than placebo. Methoxyflurane resulted in higher scores for drowsiness (difference +1.64, 95% CI 1.21-2.07; P < 0.001, adj. P < 0.001) and dizziness (difference +1.78, 95% CI 1.31-2.24; P < 0.001, adj. P < 0.001) than placebo. There was no significant difference in the number of ≥ grade 3 adverse events., Conclusions: We found no evidence that methoxyflurane improved pain scores at 15 min, however, improvements were seen in patient-reported discomfort, overall experience, and willingness to undergo repeat biopsies., (© 2021 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

The signalling receptor for LPS, CD14, is a key marker of, and facilitator for, pro-inflammatory macrophage function. Pro-inflammatory macrophage differentiation remains a process facilitating a broad array of disease pathologies, and has recently emerged as a potential target against cytokine storm in COVID19. Here, we perform a whole-genome CRISPR screen to identify essential nodes regulating CD14 expression in myeloid cells, using the differentiation of THP-1 cells as a starting point. This strategy uncovers many known pathways required for CD14 expression and regulating macrophage differentiation while additionally providing a list of novel targets either promoting or limiting this process. To speed translation of these results, we have then taken the approach of independently validating hits from the screen using well-curated small molecules. In this manner, we identify pharmacologically tractable hits that can either increase CD14 expression on non-differentiated monocytes or prevent CD14 upregulation during macrophage differentiation. An inhibitor for one of these targets, MAP2K3, translates through to studies on primary human monocytes, where it prevents upregulation of CD14 following M-CSF induced differentiation, and pro-inflammatory cytokine production in response to LPS. Therefore, this screening cascade has rapidly identified pharmacologically tractable nodes regulating a critical disease-relevant process., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Osteoarthritis is the most common musculoskeletal disease and the leading cause of disability globally. Here, we performed a genome-wide association study for osteoarthritis (77,052 cases and 378,169 controls), analyzing four phenotypes: knee osteoarthritis, hip osteoarthritis, knee and/or hip osteoarthritis, and any osteoarthritis. We discovered 64 signals, 52 of them novel, more than doubling the number of established disease loci. Six signals fine-mapped to a single variant. We identified putative effector genes by integrating expression quantitative trait loci (eQTL) colocalization, fine-mapping, and human rare-disease, animal-model, and osteoarthritis tissue expression data. We found enrichment for genes underlying monogenic forms of bone development diseases, and for the collagen formation and extracellular matrix organization biological pathways. Ten of the likely effector genes, including TGFB1 (transforming growth factor beta 1), FGF18 (fibroblast growth factor 18), CTSK (cathepsin K), and IL11 (interleukin 11), have therapeutics approved or in clinical trials, with mechanisms of action supportive of evaluation for efficacy in osteoarthritis.

Globalization is defined for individuals as their connectivity in global networks. Social identity is conceptualized as attachment and identification with a group. We measure individual involvement with global networks and local, national, and global social identity through a questionnaire. Propensity to cooperate is measured in experiments involving local and global others. Firstly, we analyze possible determinants of global social identity. Overall, attachment to global identity is significantly lower than national and local identity, but there is a significant positive correlation between global social identity and an index of individual global connectivity. Secondly, we find a significant mediating effect of global social identity between individual global connectivity and propensity to cooperate at the global level. This is consistent with a cosmopolitan hypothesis of how participation in global networks reshapes social identity: Increased participation in global networks increases global social identity and this in turn increases propensity to cooperate with others. We also show that this model receives more support than alternative models substituting either propensity to associate with others or general generosity for individual global connectivity. We further demonstrate that more globalized individuals do not reduce contributions to local accounts while increasing contributions to global accounts, but rather are overall more generous. Finally, we find that the effect of global social identity on cooperation is significantly stronger in countries at a relatively low stage of globalization, compared to more globalized countries., Competing Interests: The authors have declared that no competing interests exist.

Background: Chronic obstructive pulmonary disease (COPD) has substantial economic and human costs; it is expected to be the third leading cause of death worldwide by 2030. To minimize these costs high quality guidelines have been developed. However, guidelines alone rarely result in meaningful change. One method of integrating guidelines into practice is the use of clinical pathways (CPWs). CPWs bring available evidence to a range of healthcare professionals by detailing the essential steps in care and adapting guidelines to the local context., Methods/design: We are working with local stakeholders to develop CPWs for COPD with the aims of improving care while reducing utilization. The CPWs will employ several steps including: standardizing diagnostic training, unifying components of chronic disease care, coordinating education and reconditioning programs, and ensuring care uses best practices. Further, we have worked to identify evidence-informed implementation strategies which will be tailored to the local context. We will conduct a three-year research project using an interrupted time series (ITS) design in the form of a multiple baseline approach with control groups. The CPW will be implemented in two health regions (experimental groups) and two health regions will act as controls (control groups). The experimental and control groups will each contain an urban and rural health region. Primary outcomes for the study will be quality of care operationalized using hospital readmission rates and emergency department (ED) presentation rates. Secondary outcomes will be healthcare utilization and guideline adherence, operationalized using hospital admission rates, hospital length of stay and general practitioner (GP) visits. Results will be analyzed using segmented regression analysis., Discussion: Funding has been procured from multiple stakeholders. The project has been deemed exempt from ethics review as it is a quality improvement project. Intervention implementation is expected to begin in summer of 2017. This project is expected to improve quality of care and reduce healthcare utilization. In addition it will provide evidence on the effects of CPWs in both urban and rural settings. If the CPWs are found effective we will work with all stakeholders to implement similar CPWs in surrounding health regions., Trial Registration: Clinicaltrials.gov ( NCT03075709 ). Registered 8 March 2017.

Background and Objectives: Treatment with mepolizumab, a humanized monoclonal antibody to interleukin-5, reduces the rate of asthma exacerbations and the requirement for systemic glucocorticoids while maintaining asthma control. Treatment decisions are guided by predictors of response, including blood eosinophil thresholds in patients with frequent exacerbations despite intensive anti-inflammatory and controller treatment. Identification of additional predictors of response could aid treatment decisions. We investigated genetic associations that may predict response to mepolizumab-treatment., Methods: In this post hoc analysis of DREAM and MENSA, association of genetic markers was tested in patients with severe asthma treated with mepolizumab who provided consent for pharmacogenetic research. Association was tested in a tiered approach with alpha spend differing for candidate genetic markers selected for prior history of association with relevant traits or pathways and in a genome-wide analyses (p < 4.7 × 10 -4 and p < 5 × 10 -8 , respectively). Efficacy endpoints included: clinically significant exacerbation rate (tested using a negative binomial model), time to first exacerbation (tested with a Cox proportional hazards model), change in exacerbation rate, change in eosinophil count, and change in IgE level (tested by linear regression)., Results: No genetic marker was significantly associated with the primary endpoint, clinically significant exacerbation rate. One genetic marker was associated with time to first clinically significant exacerbation, but this association was driven by the DREAM data and was not supported in additional sensitivity analyses by treatment regimen/dose., Conclusion: No genetic effect on mepolizumab-treatment response was identified in this population on intensive asthma treatment, with history of frequent exacerbations and pre-selected for airway eosinophilia., (Copyright © 2017. Published by Elsevier Ltd.)

The growing body of transcriptomic, proteomic, metabolomic and genomic data generated from disease states provides a great opportunity to improve our current understanding of the molecular mechanisms driving diseases and shared between diseases. The use of both clinical and molecular phenotypes will lead to better disease understanding and classification. In this study, we set out to gain novel insights into diseases and their relationships by utilising knowledge gained from system-level molecular data. We integrated different types of biological data including genome-wide association studies data, disease-chemical associations, biological pathways and Gene Ontology annotations into an Integrated Disease Network (IDN), a heterogeneous network where nodes are bio-entities and edges between nodes represent their associations. We also introduced a novel disease similarity measure to infer disease-disease associations from the IDN. Our predicted associations were systemically evaluated against the Medical Subject Heading classification and a statistical measure of disease co-occurrence in PubMed. The strong correlation between our predictions and co-occurrence associations indicated the ability of our approach to recover known disease associations. Furthermore, we presented a case study of Crohn's disease. We demonstrated that our approach not only identified well-established connections between Crohn's disease and other diseases, but also revealed new, interesting connections consistent with emerging literature. Our approach also enabled ready access to the knowledge supporting these new connections, making this a powerful approach for exploring connections between diseases.

Background: Urosepsis is the most common complication requiring hospital admission after transrectal biopsy of the prostate. This study aims to assess the local incidence and causative organisms of hospital admissions with urosepsis after transrectal ultrasound-guided prostate (TRUS) biopsy. As morbidity is high, treatment must be commenced empirically prior to cultures. A review of bacterial antibiotic susceptibilities was undertaken to guide optimal treatment of post-biopsy urosepsis., Methods: A total of 1421 patients underwent TRUS biopsy in a single city over a 2-year period. All patients received prophylactic antibiotics prior to the procedure. A retrospective review of a prospectively collated database was performed in all patients admitted to Christchurch Hospital, the only acute admitting hospital in Christchurch, with infection within 30 days after biopsy. Hospital admission records were reviewed, including urine and blood culture results., Results: Forty patients (2.8%) were admitted with infection after the biopsy, the majority occurring within the first week after procedure and four required intensive care unit (ICU) admission (10%). The most common organism isolated on urine and blood cultures was Escherichia coli. Significant E. coli resistance was seen to fluoroquinolones, amoxicillin and trimethoprim., Conclusion: Rates of infection after TRUS biopsy and antibiotic resistance are increasing internationally. Treatment for urosepsis should be aggressive as 10% of those patients admitted required ICU admission. TRUS biopsy with ciprofloxacin prophylaxis led to infectious complications comparable with other international reports and appears to remain an appropriate prophylactic antibiotic of choice. Infections requiring hospital admission were all susceptible to a combination of ceftriaxone and gentamicin, and would be an effective initial antibiotic of choice., (© 2013 The Authors. ANZ Journal of Surgery © 2013 Royal Australasian College of Surgeons.)

Purpose: To develop an image-based technique capable of detection and grading of prostate cancer, which combines features extracted from multiparametric MRI into a single parameter map of cancer probability., Materials and Methods: A combination of features extracted from diffusion tensor MRI and dynamic contrast enhanced MRI was used to characterize biopsy samples from 29 patients. Support vector machines were used to separate the cancerous samples from normal biopsy samples and to compute a measure of cancer probability, presented in the form of a cancer colormap. The classification results were compared with the biopsy results and the classifier was tuned to provide the largest area under the receiver operating characteristic (ROC) curve. Based solely on the tuning of the classifier on the biopsy data, cancer colormaps were also created for whole-mount histopathology slices from four radical prostatectomy patients., Results: An area under ROC curve of 0.96 was obtained on the biopsy dataset and was validated by a "leave-one-patient-out" procedure. The proposed measure of cancer probability shows a positive correlation with Gleason score. The cancer colormaps created for the histopathology patients do display the dominant tumors. The colormap accuracy increases with measured tumor area and Gleason score., Conclusion: Dynamic contrast enhanced imaging and diffusion tensor imaging, when used within the framework of supervised classification, can play a role in characterizing prostate cancer., (Copyright © 2012 Wiley Periodicals, Inc.)

Objective: The objective of this paper is to report on the pathologic and biochemical progression-free outcomes of patients who underwent radical prostatectomy for high-risk localized prostate cancer., Methods: Data was collected prospectively from 299 patients who underwent radical prostatectomy for high-risk clinically localized prostate cancer by 2 surgeons at a single institution. High risk was defined as 1 or more of 3 adverse factors: prostate-specific antigen (PSA) >20, biopsy Gleason score 8 to 10 and clinical stage T3. PSA recurrence was defined as PSA >0.4 ng/mL or any salvage therapy., Results: Median age was 63.3 years (46.1-75.9). Median follow-up was 4.7 years (range 0.5-17.3 years). PSA at diagnosis was >20 ng/mL in 31.4%. Biopsy Gleason score was 8 to 10 in 66.9%. Clinical stage was T3 in 24.4%. 81.6% of patients had a single baseline risk factor, 15.7% had 2 risk factors and 2.7% had all 3 risk factors. Neoadjuvant therapy was administered to 184 patients (61.5%). Pathologic stage was organ-confined in 39.6%, specimen-confined in 26%, non-specimen-confined in 26.4%, and 8% had lymph node positive disease. Overall survival, cancer-specific survival and biochemical progression-free survival was 99%, 99.67% and 70.2%, respectively. Univariate analysis showed that PSA at diagnosis, percentage of cores positive and number of risk factors were predictors of PSA recurrence (p < 0.05). Multivariate analysis showed that PSA at diagnosis was an independent predictor of PSA recurrence (p < 0.05)., Conclusion: Radical prostatectomy is associated with favourable biochemical progression-free, clinical and overall survival in selected men with high-risk localized prostate cancer, and should therefore be considered an option in these patients. Baseline PSA >20 ng/mL is a significant independent predictor of PSA recurrence.

Objectives: To describe all terrain vehicle (ATV) ownership, access, use, and safety behaviours in rural Manitoba children., Methods: Questionnaire administered to a convenience sample of grade 6 students attending an agricultural fair., Results: 162 grade 6 children participated. The mean age was 11.4 years, and 46% were male. 125 students (77%) reported having access to ATVs, including 69 four wheeled, 24 three wheeled, and four both three and four wheeled ATVs. ATV experience was reported in 95 students, significantly more often in males and among those with a family owned ATV, with no difference between children living on a farm and in a town. Use of helmets and protective clothing was inadequate (10-40%), and dangerous riding habits common, with males and children living on a farm reporting significantly fewer desirable behaviours., Conclusions: ATVs are commonly used by children in rural Manitoba, with inadequate protective gear and dangerous riding habits. Mandatory rider training, consumer and dealer education, and legislation enforcement could improve ATV safety in this population.

A procedure is described for the automatic off-line analysis of amino acid chromatograms of protein hydrolysates, using a small computer. The data requirements are basic, and, unlike previous programs, the present system allows the separation and identification of bands, as well as the quantitative determination of composition. With minor modification, the program could be extended for use with most types of chromatographic data. The validity of the application of the program to experimental data is discussed.