Is There an Added Value of Quantitative DCE-MRI by Magnetic Resonance Dispersion Imaging for Prostate Cancer Diagnosis?

In this multicenter, retrospective study, we evaluated the added value of magnetic resonance dispersion imaging (MRDI) to standard multiparametric MRI (mpMRI) for PCa detection. The study included 76 patients, including 51 with clinically significant prostate cancer (csPCa), who underwent radical prostatectomy and had an mpMRI including dynamic contrast-enhanced MRI. Two radiologists performed three separate randomized scorings based on mpMRI, MRDI and mpMRI+MRDI. Radical prostatectomy histopathology was used as the reference standard. Imaging and histopathology were both scored according to the Prostate Imaging-Reporting and Data System V2.0 sector map. Sensitivity and specificity for PCa detection were evaluated for mpMRI, MRDI and mpMRI+MRDI. Inter- and intra-observer variability for both radiologists was evaluated using Cohen's Kappa. On a per-patient level, sensitivity for csPCa for radiologist 1 (R1) for mpMRI, MRDI and mpMRI+MRDI was 0.94, 0.82 and 0.94, respectively. For the second radiologist (R2), these were 0.78, 0.94 and 0.96. R1 detected 4% additional csPCa cases using MRDI compared to mpMRI, and R2 detected 20% extra csPCa cases using MRDI. Inter-observer agreement was significant only for MRDI (Cohen's Kappa = 0.4250, p = 0.004). The results of this study show the potential of MRDI to improve inter-observer variability and the detection of csPCa.

Diagnostic performance of ADC and ADCratio in MRI-based prostate cancer assessment: A systematic review and meta-analysis.

OBJECTIVES: To identify factors influencing the diagnostic performance of the quantitative imaging biomarkers ADC and ADCratio in prostate cancer (PCa) detection. MATERIALS AND METHODS: A systematic literature search was conducted in Embase, Medline and Web of Science, for studies evaluating ADC values and ADCratio for PCa diagnosis, using the same patient cohorts and using histopathological references as ground truth. Pooled sensitivities, specificities, summary ROC curves and AUCs were calculated from constructed contingency data tables. Diagnostic performance (AUC) was quantitatively pooled using a bivariate mixed effects model. For identifying influencing factors, subgroup analysis, publication bias and heterogeneity assessment were investigated. RESULTS: Thirteen studies, involving 1038 patients and 1441 lesions, were included. For ADC, the pooled sensitivity and specificity was 80% (95% CI: 74-85%) and 78% (95% CI: 70-85%), respectively. For ADCratio pooled sensitivity and specificity was 80% (95% CI: 74-84%) and 80% (95% CI: 71-87%). Summary ROC analysis revealed AUCs of 0.86 (95% CI: 0.83-0.89) and 0.86 (95% CI: 0.83-0.89), respectively. Meta-regression showed heterogeneity between both imaging biomarkers. Subgroup analysis showed that ADCratio improved diagnostic performance in comparison to ADC when including both peripheral and transitional zone lesions (AUC: 0.87 [95% CI: 0.84-0.90] and 0.82 [95% CI: 0.79-0.85], respectively). CONCLUSION: Both ADC and ADCratio imaging biomarkers showed good and comparable diagnostic performance in PCa diagnosis. However, ADCratio shows better diagnostic performance than ADC in diagnosing transition zone cancers. CLINICAL RELEVANCE STATEMENT: In quantitative MRI-based PCa diagnosis, the imaging biomarker ADCratio is useful in challenging MRI readings of lesions. Understanding the performance of quantitative imaging biomarkers better can aid diagnostic MRI protocols, enhancing the precision of PCa assessments. KEY POINTS: MRI diffusion-weighted imaging-based ADC and ADCratio have comparable diagnostic performance in PCa assessment. In contrast to ADC, the ADCratio improves diagnostic performance, when assessing whole gland lesions. Compared to ADCratio, the ADC demonstrates enhanced diagnostic performance when evaluating peripheral zone lesions.

PI-QUAL version 2: an update of a standardised scoring system for the assessment of image quality of prostate MRI.

Multiparametric MRI is the optimal primary investigation when prostate cancer is suspected, and its ability to rule in and rule out clinically significant disease relies on high-quality anatomical and functional images. Avenues for achieving consistent high-quality acquisitions include meticulous patient preparation, scanner setup, optimised pulse sequences, personnel training, and artificial intelligence systems. The impact of these interventions on the final images needs to be quantified. The prostate imaging quality (PI-QUAL) scoring system was the first standardised quantification method that demonstrated the potential for clinical benefit by relating image quality to cancer detection ability by MRI. We present the updated version of PI-QUAL (PI-QUAL v2) which applies to prostate MRI performed with or without intravenous contrast medium using a simplified 3-point scale focused on critical technical and qualitative image parameters. CLINICAL RELEVANCE STATEMENT: High image quality is crucial for prostate MRI, and the updated version of the PI-QUAL score (PI-QUAL v2) aims to address the limitations of version 1. It is now applicable to both multiparametric MRI and MRI without intravenous contrast medium. KEY POINTS: High-quality images are essential for prostate cancer diagnosis and management using MRI. PI-QUAL v2 simplifies image assessment and expands its applicability to prostate MRI without contrast medium. PI-QUAL v2 focuses on critical technical and qualitative image parameters and emphasises T2-WI and DWI.

EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines on Prostate Cancer. Part II-2024 Update: Treatment of Relapsing and Metastatic Prostate Cancer.

BACKGROUND AND OBJECTIVE: The European Association of Urology (EAU)-European Association of Nuclear Medicine (EANM)-European Society for Radiotherapy and Oncology (ESTRO)-European Society of Urogenital Radiology (ESUR)-International Society of Urological Pathology (ISUP)-International Society of Geriatric Oncology (SIOG) guidelines on the treatment of relapsing, metastatic, and castration-resistant prostate cancer (PCa) have been updated. Here we provide a summary of the 2024 guidelines. METHODS: The panel performed a literature review of new data, covering the time frame between 2020 and 2023. The guidelines were updated and a strength rating for each recommendation was added on the basis of a systematic review of the evidence. KEY FINDINGS AND LIMITATIONS: Risk stratification for relapsing PCa after primary therapy may guide salvage therapy decisions. New treatment options, such as androgen receptor-targeted agents (ARTAs), ARTA + chemotherapy combinations, PARP inhibitors and their combinations, and prostate-specific membrane antigen-based therapy have become available for men with metastatic PCa. CONCLUSIONS AND CLINICAL IMPLICATIONS: Evidence for relapsing, metastatic, and castration-resistant PCa is evolving rapidly. These guidelines reflect the multidisciplinary nature of PCa management. The full version is available online (http://uroweb.org/guideline/ prostate-cancer/). PATIENT SUMMARY: This article summarises the 2024 guidelines for the treatment of relapsing, metastatic, and castration-resistant prostate cancer. These guidelines are based on evidence and guide doctors in discussing treatment decisions with their patients. The guidelines are updated every year.

EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines on Prostate Cancer-2024 Update. Part I: Screening, Diagnosis, and Local Treatment with Curative Intent.

BACKGROUND AND OBJECTIVE: The European Association of Urology (EAU)-European Association of Nuclear Medicine (EANM)-European Society for Radiotherapy and Oncology (ESTRO)-European Society of Urogenital Radiology (ESUR)-International Society of Urological Pathology (ISUP)-International Society of Geriatric Oncology (SIOG) guidelines provide recommendations for the management of clinically localised prostate cancer (PCa). This paper aims to present a summary of the 2024 version of the EAU-EANM-ESTRO-ESUR-ISUP-SIOG guidelines on the screening, diagnosis, and treatment of clinically localised PCa. METHODS: The panel performed a literature review of all new data published in English, covering the time frame between May 2020 and 2023. The guidelines were updated, and a strength rating for each recommendation was added based on a systematic review of the evidence. KEY FINDINGS AND LIMITATIONS: A risk-adapted strategy for identifying men who may develop PCa is advised, generally commencing at 50 yr of age and based on individualised life expectancy. The use of multiparametric magnetic resonance imaging in order to avoid unnecessary biopsies is recommended. When a biopsy is considered, a combination of targeted and regional biopsies should be performed. Prostate-specific membrane antigen positron emission tomography imaging is the most sensitive technique for identifying metastatic spread. Active surveillance is the appropriate management for men with low-risk PCa, as well as for selected favourable intermediate-risk patients with International Society of Urological Pathology grade group 2 lesions. Local therapies are addressed, as well as the management of persistent prostate-specific antigen after surgery. A recommendation to consider hypofractionation in intermediate-risk patients is provided. Patients with cN1 PCa should be offered a local treatment combined with long-term intensified hormonal treatment. CONCLUSIONS AND CLINICAL IMPLICATIONS: The evidence in the field of diagnosis, staging, and treatment of localised PCa is evolving rapidly. These PCa guidelines reflect the multidisciplinary nature of PCa management. PATIENT SUMMARY: This article is the summary of the guidelines for "curable" prostate cancer. Prostate cancer is "found" through a multistep risk-based screening process. The objective is to find as many men as possible with a curable cancer. Prostate cancer is curable if it resides in the prostate; it is then classified into low-, intermediary-, and high-risk localised and locally advanced prostate cancer. These risk classes are the basis of the treatments. Low-risk prostate cancer is treated with "active surveillance", a treatment with excellent prognosis. For low-intermediary-risk active surveillance should also be discussed as an option. In other cases, active treatments, surgery, or radiation treatment should be discussed along with the potential side effects to allow shared decision-making.

The Impact of Omitting Contralateral Systematic Biopsy on the Surgical Planning of Patients with a Unilateral Suspicious Lesion on Magnetic Resonance Imaging Undergoing Robot-assisted Radical Prostatectomy for Prostate Cancer.

Background and objective: A combined approach of magnetic resonance imaging (MRI)-targeted biopsy (TBx) and bilateral systematic biopsy (SBx) is advised in patients who have an increased risk of prostate cancer (PCa). The diagnostic gain of SBx in detecting PCa for treatment planning of patients undergoing robot-assisted radical prostatectomy (RARP) is unknown. This study aims to determine the impact of omitting contralateral SBx on the surgical planning of patients undergoing RARP in terms of nerve-sparing surgery (NSS) and extended pelvic lymph node dissection (ePLND). Methods: Case files from 80 men with biopsy-proven PCa were studied. All men had a unilateral suspicious lesion on MRI, and underwent TBx and bilateral SBx. Case files were presented to five urologists for the surgical planning of RARP. Each case file was presented randomly using two different sets of information: (1) results of TBx + bilateral SBx, and (2) results of TBx + ipsilateral SBx. The urologists assessed whether they would perform NSS and/or ePLND. Key findings and limitations: A change in the surgical plan concerning NSS on the contralateral side was observed in 9.0% (95% confidence interval [CI] 6.4-12.2) of cases. Additionally, the indication for ePLND changed in 5.3% (95% CI 3.3-7.9) of cases. Interobserver agreement based on Fleiss' kappa changed from 0.44 to 0.15 for the indication of NSS and from 0.84 to 0.83 for the indication of ePLND. Conclusions and clinical implications: In our series, the diagnostic information obtained from contralateral SBx has limited impact on the surgical planning of patients with a unilateral suspicious lesion on MRI scheduled to undergo RARP. Patient summary: In patients with one-sided prostate cancer on magnetic resonance imaging, omitting biopsies on the other side rarely changed the surgical plan with respect to nerve-sparing surgery and the indication to perform extended lymph node dissection.

Impact of long-term transmural plastic stents on recurrence after endoscopic treatment of walled-off pancreatic necrosis.

BACKGROUND: Endoscopic transmural drainage (ETD) using double-pigtail stents (DPSs) is a well-established treatment for walled-off pancreatic necrosis (WON). This study aimed to compare outcomes in patients undergoing ETD with DPSs left indwelling versus those where stents were removed or migrated. METHODS: This retrospective multicenter cohort study included patients with WON who underwent ETD using DPSs between July 2001 and December 2019. The primary outcome was recurrence of a pancreatic fluid collection (PFC). Secondary outcomes were long-term complications and recurrence-associated factors. Competing risk regression analysis considered DPS removal or migration as time-varying covariates. RESULTS: Among 320 patients (median age 58; 36% women), DPSs were removed in 153 (47.8%), migrated spontaneously in 27 (8.4%), and remained indwelling in 140 (43.8%). PFC recurrence was observed in 57 patients (17.8%): after removal (n = 39; 25.5%); after migration (n = 4; 14.8%); in patients with indwelling DPSs (n = 14; 10.0%). In 25 patients (7.8%), drainage of recurrent PFC was indicated. Risk factors for recurrence were DPS removal or migration (hazard ratio [HR] 3.45, 95%CI 1.37-8.70) and presence of a disconnected pancreatic duct (HR 5.08, 95%CI 1.84-14.0). CONCLUSIONS: Among patients who undergo ETD of WON, leaving DPSs in situ seems to lower the risk of recurrent fluid collections, without any long-term DPS-related complications. These results suggest that DPSs should not be routinely removed and can be safely left indwelling indefinitely.

Magnetic Resonance Imaging in Prostate Cancer Screening: A Systematic Review and Meta-Analysis.

Importance: Prostate magnetic resonance imaging (MRI) is increasingly integrated within the prostate cancer (PCa) early detection pathway. Objective: To systematically evaluate the existing evidence regarding screening pathways incorporating MRI with targeted biopsy and assess their diagnostic value compared with prostate-specific antigen (PSA)-based screening with systematic biopsy strategies. Data Sources: PubMed/MEDLINE, Embase, Cochrane/Central, Scopus, and Web of Science (through May 2023). Study Selection: Randomized clinical trials and prospective cohort studies were eligible if they reported data on the diagnostic utility of prostate MRI in the setting of PCa screening. Data Extraction: Number of screened individuals, biopsy indications, biopsies performed, clinically significant PCa (csPCa) defined as International Society of Urological Pathology (ISUP) grade 2 or higher, and insignificant (ISUP1) PCas detected were extracted. Main Outcomes and Measures: The primary outcome was csPCa detection rate. Secondary outcomes included clinical insignificant PCa detection rate, biopsy indication rates, and the positive predictive value for the detection of csPCa. Data Synthesis: The generalized mixed-effect approach with pooled odds ratios (ORs) and random-effect models was used to compare the MRI-based and PSA-only screening strategies. Separate analyses were performed based on the timing of MRI (primary/sequential after a PSA test) and cutoff (Prostate Imaging Reporting and Data System [PI-RADS] score ≥3 or ≥4) for biopsy indication. Results: Data were synthesized from 80 114 men from 12 studies. Compared with standard PSA-based screening, the MRI pathway (sequential screening, PI-RADS score ≥3 cutoff for biopsy) was associated with higher odds of csPCa when tests results were positive (OR, 4.15; 95% CI, 2.93-5.88; P ≤ .001), decreased odds of biopsies (OR, 0.28; 95% CI, 0.22-0.36; P ≤ .001), and insignificant cancers detected (OR, 0.34; 95% CI, 0.23-0.49; P = .002) without significant differences in the detection of csPCa (OR, 1.02; 95% CI, 0.75-1.37; P = .86). Implementing a PI-RADS score of 4 or greater threshold for biopsy selection was associated with a further reduction in the odds of detecting insignificant PCa (OR, 0.23; 95% CI, 0.05-0.97; P = .048) and biopsies performed (OR, 0.19; 95% CI, 0.09-0.38; P = .01) without differences in csPCa detection (OR, 0.85; 95% CI, 0.49-1.45; P = .22). Conclusion and relevance: The results of this systematic review and meta-analysis suggest that integrating MRI in PCa screening pathways is associated with a reduced number of unnecessary biopsies and overdiagnosis of insignificant PCa while maintaining csPCa detection as compared with PSA-only screening.

The Transatlantic Recommendations for Prostate Gland Evaluation with Magnetic Resonance Imaging After Focal Therapy (TARGET): A Systematic Review and International Consensus Recommendations.

BACKGROUND AND OBJECTIVE: Magnetic resonance imaging (MRI) can detect recurrences after focal therapy for prostate cancer but there is no robust guidance regarding its use. Our objective was to produce consensus recommendations on MRI acquisition, interpretation, and reporting after focal therapy. METHODS: A systematic review was performed in July 2022 to develop consensus statements. A two-round consensus exercise was then performed, with a consensus meeting in January 2023, during which 329 statements were scored by 23 panellists from Europe and North America spanning urology, radiology, and pathology with experience across eight focal therapy modalities. Using RAND Corporation/University of California-Los Angeles methodology, the Transatlantic Recommendations for Prostate Gland Evaluation with MRI after Focal Therapy (TARGET) were based on consensus for statements scored with agreement or disagreement. KEY FINDINGS AND LIMITATIONS: In total, 73 studies were included in the review. All 20 studies (100%) reporting suspicious imaging features cited focal contrast enhancement as suspicious for cancer recurrence. Of 31 studies reporting MRI assessment criteria, the Prostate Imaging-Reporting and Data System (PI-RADS) score was the scheme used most often (20 studies; 65%), followed by a 5-point Likert score (six studies; 19%). For the consensus exercise, consensus for statements scored with agreement or disagreement increased from 227 of 295 statements (76.9%) in round one to 270 of 329 statements (82.1%) in round two. Key recommendations include performing routine MRI at 12 mo using a multiparametric protocol compliant with PI-RADS version 2.1 standards. PI-RADS category scores for assessing recurrence within the ablation zone should be avoided. An alternative 5-point scoring system is presented that includes a major dynamic contrast enhancement (DCE) sequence and joint minor diffusion-weighted imaging and T2-weighted sequences. For the DCE sequence, focal nodular strong early enhancement was the most suspicious imaging finding. A structured minimum reporting data set and minimum reporting standards for studies detailing MRI data after focal therapy are presented. CONCLUSIONS AND CLINICAL IMPLICATIONS: The TARGET consensus recommendations may improve MRI acquisition, interpretation, and reporting after focal therapy for prostate cancer and provide minimum standards for study reporting. PATIENT SUMMARY: Magnetic resonance imaging (MRI) scans can detect recurrent of prostate cancer after focal treatments, but there is a lack of guidance on MRI use for this purpose. We report new expert recommendations that may improve practice.

Multi-organ single-cell transcriptomics of immune cells uncovered organ-specific gene expression and functions.

Despite the wealth of publicly available single-cell datasets, our understanding of distinct resident immune cells and their unique features in diverse human organs remains limited. To address this, we compiled a meta-analysis dataset of 114,275 CD45+ immune cells sourced from 14 organs in healthy donors. While the transcriptome of immune cells remains relatively consistent across organs, our analysis has unveiled organ-specific gene expression differences (GTPX3 in kidney, DNTT and ACVR2B in thymus). These alterations are linked to different transcriptional factor activities and pathways including metabolism. TNF-α signaling through the NFkB pathway was found in several organs and immune compartments. The presence of distinct expression profiles for NFkB family genes and their target genes, including cytokines, underscores their pivotal role in cell positioning. Taken together, immune cells serve a dual role: safeguarding the organs and dynamically adjusting to the intricacies of the host organ environment, thereby actively contributing to its functionality and overall homeostasis.

PRECISE Version 2: Updated Recommendations for Reporting Prostate Magnetic Resonance Imaging in Patients on Active Surveillance for Prostate Cancer.

BACKGROUND AND OBJECTIVE: The Prostate Cancer Radiological Estimation of Change in Sequential Evaluation (PRECISE) recommendations standardise the reporting of prostate magnetic resonance imaging (MRI) in patients on active surveillance (AS) for prostate cancer. An international consensus group recently updated these recommendations and identified the areas of uncertainty. METHODS: A panel of 38 experts used the formal RAND/UCLA Appropriateness Method consensus methodology. Panellists scored 193 statements using a 1-9 agreement scale, where 9 means full agreement. A summary of agreement, uncertainty, or disagreement (derived from the group median score) and consensus (determined using the Interpercentile Range Adjusted for Symmetry method) was calculated for each statement and presented for discussion before individual rescoring. KEY FINDINGS AND LIMITATIONS: Participants agreed that MRI scans must meet a minimum image quality standard (median 9) or be given a score of 'X' for insufficient quality. The current scan should be compared with both baseline and previous scans (median 9), with the PRECISE score being the maximum from any lesion (median 8). PRECISE 3 (stable MRI) was subdivided into 3-V (visible) and 3-NonV (nonvisible) disease (median 9). Prostate Imaging Reporting and Data System/Likert ≥3 lesions should be measured on T2-weighted imaging, using other sequences to aid in the identification (median 8), and whenever possible, reported pictorially (diagrams, screenshots, or contours; median 9). There was no consensus on how to measure tumour size. More research is needed to determine a significant size increase (median 9). PRECISE 5 was clarified as progression to stage ≥T3a (median 9). CONCLUSIONS AND CLINICAL IMPLICATIONS: The updated PRECISE recommendations reflect expert consensus opinion on minimal standards and reporting criteria for prostate MRI in AS. PATIENT SUMMARY: The Prostate Cancer Radiological Estimation of Change in Sequential Evaluation (PRECISE) recommendations are used in clinical practice and research to guide the interpretation and reporting of magnetic resonance imaging for patients on active surveillance for prostate cancer. An international panel has updated these recommendations, clarified the areas of uncertainty, and highlighted the areas for further research.

Key learning on the promise and limitations of MRI in prostate cancer screening.

MRI retains its ability to reduce the harm of prostate biopsies by decreasing biopsy rates and the detection of indolent cancers in population-based screening studies aiming to find clinically significant prostate cancers. Limitations of low positive predictive values and high reader variability in diagnostic performance require optimisations in patient selection, imaging protocols, interpretation standards, diagnostic thresholds, and biopsy methods. Improvements in diagnostic accuracy could come about through emerging technologies like risk calculators and polygenic risk scores to select men for MRI. Furthermore, artificial intelligence and workflow optimisations focused on streamlining the diagnostic pathway, quality control, and assurance measures will improve MRI variability. CLINICAL RELEVANCE STATEMENT: MRI significantly reduces harm in prostate cancer screening, lowering unnecessary biopsies and minimizing the overdiagnosis of indolent cancers. MRI maintains the effective detection of high-grade cancers, thus improving the overall benefit-to-harm ratio in population-based screenings with or without using serum prostate-specific antigen (PSA) for patient selection. KEY POINTS: • The use of MRI enables the harm reduction benefits seen in individual early cancer detection to be extended to both risk-stratified and non-stratified prostate cancer screening populations. • MRI limitations include a low positive predictive value and imperfect reader variability, which require standardising interpretations, biopsy methods, and integration into a quality diagnostic pathway. • Current evidence is based on one-time point use of MRI in screening; MRI effectiveness in multiple rounds of screening is not well-documented.

Descending control and regulation of spontaneous flight turns in Drosophila.

The clumped distribution of resources in the world has influenced the pattern of foraging behavior since the origins of locomotion, selecting for a common search motif in which straight movements through resource-poor regions alternate with zig-zag exploration in resource-rich domains. For example, during local search, flying flies spontaneously execute rapid flight turns, called body saccades, but suppress these maneuvers during long-distance dispersal or when surging upstream toward an attractive odor. Here, we describe the key cellular components of a neural network in flies that generate spontaneous turns as well as a specialized pair of neurons that inhibits the network and suppresses turning. Using 2-photon imaging, optogenetic activation, and genetic ablation, we show that only four descending neurons appear sufficient to generate the descending commands to execute flight saccades. The network is organized into two functional units-one for right turns and one for left-with each unit consisting of an excitatory (DNae014) and an inhibitory (DNb01) neuron that project to the flight motor neuropil within the ventral nerve cord. Using resources from recently published connectomes of the fly, we identified a pair of large, distinct interneurons (VES041) that form inhibitory connections to all four saccade command neurons and created specific genetic driver lines for this cell. As predicted by its connectivity, activation of VES041 strongly suppresses saccades, suggesting that it promotes straight flight to regulate the transition between local search and long-distance dispersal. These results thus identify the key elements of a network that may play a crucial role in foraging ecology.

Leptospiral lipopolysaccharide dampens inflammation through upregulation of autophagy adaptor p62 and NRF2 signaling in macrophages.

Leptospira interrogans are pathogenic bacteria responsible for leptospirosis, a worldwide zoonosis. All vertebrates can be infected, and some species like humans are susceptible to the disease whereas rodents such as mice are resistant and become asymptomatic renal carriers. Leptospires are stealth bacteria that are known to escape several immune recognition pathways and resist killing mechanisms. We recently published that leptospires may survive intracellularly in and exit macrophages, avoiding xenophagy, a pathogen-targeting form of autophagy. Interestingly, the latter is one of the antimicrobial mechanisms often highjacked by bacteria to evade the host immune response. In this study we explored whether leptospires subvert the key molecular players of autophagy to facilitate infection. We showed in macrophages that leptospires triggered a specific accumulation of autophagy-adaptor p62 in puncta-like structures, without altering autophagic flux. We demonstrated that Leptospira-induced p62 accumulation is a passive mechanism depending on the leptospiral virulence factor LPS signaling via TLR4/TLR2. p62 is a central pleiotropic protein, also mediating cell stress and death, via the translocation of transcription factors. We demonstrated that Leptospira-driven accumulation of p62 induced the translocation of transcription factor NRF2, a key player in the anti-oxidant response. However, NRF2 translocation upon Leptospira infection did not result as expected in antioxydant response, but dampened the production of inflammatory mediators such as iNOS/NO, TNF and IL6. Overall, these findings highlight a novel passive bacterial mechanism linked to LPS and p62/NRF2 signaling that decreases inflammation and contributes to the stealthiness of leptospires.

Convert-Pheno: A software toolkit for the interconversion of standard data models for phenotypic data.

Efficient sharing and integration of phenotypic data is crucial for advancing biomedical research and enhancing patient outcomes in precision medicine and public health. To achieve this, the health data community has developed standards to promote the harmonization of variable names and values. However, the use of diverse standards across different research centers can hinder progress. Here we present Convert-Pheno, an open-source software toolkit that enables the interconversion of common data models for phenotypic data such as Beacon v2 Models, CDISC-ODM, OMOP-CDM, Phenopackets v2, and REDCap. Along with the software, we have created a detailed documentation that includes information on deployment and installation.

Membranous urethral length measurement on preoperative MRI to predict incontinence after radical prostatectomy: a literature review towards a proposal for measurement standardization.

OBJECTIVES: To investigate the membranous urethral length (MUL) measurement and its interobserver agreement, and propose literature-based recommendations to standardize MUL measurement for increasing interobserver agreement. MUL measurements based on prostate MRI scans, for urinary incontinence risk assessment before radical prostatectomy (RP), may influence treatment decision-making in men with localised prostate cancer. Before implementation in clinical practise, MRI-based MUL measurements need standardization to improve observer agreement. METHODS: Online libraries were searched up to August 5, 2022, on MUL measurements. Two reviewers performed article selection and critical appraisal. Papers reporting on preoperative MUL measurements and urinary continence correlation were selected. Extracted information included measuring procedures, MRI sequences, population mean/median values, and observer agreement. RESULTS: Fifty papers were included. Studies that specified the MRI sequence used T2-weighted images and used either coronal images (n = 13), sagittal images (n = 18), or both (n = 12) for MUL measurements. 'Prostatic apex' was the most common description of the proximal membranous urethra landmark and 'level/entry of the urethra into the penile bulb' was the most common description of the distal landmark. Population mean (median) MUL value range was 10.4-17.1 mm (7.3-17.3 mm), suggesting either population or measurement differences. Detailed measurement technique descriptions for reproducibility were lacking. Recommendations on MRI-based MUL measurement were formulated by using anatomical landmarks and detailed descriptions and illustrations. CONCLUSIONS: In order to improve on measurement variability, a literature-based measuring method of the MUL was proposed, supported by several illustrative case studies, in an attempt to standardize MRI-based MUL measurements for appropriate urinary incontinence risk preoperatively. CLINICAL RELEVANCE STATEMENT: Implementation of MUL measurements into clinical practise for personalized post-prostatectomy continence prediction is hampered by lack of standardization and suboptimal interobserver agreement. Our proposed standardized MUL measurement aims to facilitate standardization and to improve the interobserver agreement. KEY POINTS: • Variable approaches for membranous urethral length measurement are being used, without detailed description and with substantial differences in length of the membranous urethra, hampering standardization. • Limited interobserver agreement for membranous urethral length measurement was observed in several studies, while preoperative incontinence risk assessment necessitates high interobserver agreement. • Literature-based recommendations are proposed to standardize MRI-based membranous urethral length measurement for increasing interobserver agreement and improving preoperative incontinence risk assessment, using anatomical landmarks on sagittal T2-weighted images.

A Systematic Review of the Efficacy and Toxicity of Brachytherapy Boost Combined with External Beam Radiotherapy for Nonmetastatic Prostate Cancer.

CONTEXT: The optimum use of brachytherapy (BT) combined with external beam radiotherapy (EBRT) for localised/locally advanced prostate cancer (PCa) remains uncertain. OBJECTIVE: To perform a systematic review to determine the benefits and harms of EBRT-BT. EVIDENCE ACQUISITION: Ovid MEDLINE, Embase, and EBM Reviews-Cochrane Central Register of Controlled Trials databases were systematically searched for studies published between January 1, 2000 and June 7, 2022, according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. Eligible studies compared low- or high-dose-rate EBRT-BT against EBRT ± androgen deprivation therapy (ADT) and/or radical prostatectomy (RP) ± postoperative radiotherapy (RP ± EBRT). The main outcomes were biochemical progression-free survival (bPFS), severe late genitourinary (GU)/gastrointestinal toxicity, metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS), at/beyond 5 yr. Risk of bias was assessed and confounding assessment was performed. A meta-analysis was performed for randomised controlled trials (RCTs). EVIDENCE SYNTHESIS: Seventy-three studies were included (two RCTs, seven prospective studies, and 64 retrospective studies). Most studies included participants with intermediate-or high-risk PCa. Most studies, including both RCTs, used ADT with EBRT-BT. Generally, EBRT-BT was associated with improved bPFS compared with EBRT, but similar MFS, CSS, and OS. A meta-analysis of the two RCTs showed superior bPFS with EBRT-BT (estimated fixed-effect hazard ratio [HR] 0.54 [95% confidence interval {CI} 0.40-0.72], p < 0.001), with absolute improvements in bPFS at 5-6 yr of 4.9-16%. However, no difference was seen for MFS (HR 0.84 [95% CI 0.53-1.28], p = 0.4) or OS (HR 0.87 [95% CI 0.63-1.19], p = 0.4). Fewer studies examined RP ± EBRT. There is an increased risk of severe late GU toxicity, especially with low-dose-rate EBRT-BT, with some evidence of increased prevalence of severe GU toxicity at 5-6 yr of 6.4-7% across the two RCTs. CONCLUSIONS: EBRT-BT can be considered for unfavourable intermediate/high-risk localised/locally advanced PCa in patients with good urinary function, although the strength of this recommendation based on the European Association of Urology guideline methodology is weak given that it is based on improvements in biochemical control. PATIENT SUMMARY: We found good evidence that radiotherapy combined with brachytherapy keeps prostate cancer controlled for longer, but it could lead to worse urinary side effects than radiotherapy without brachytherapy, and its impact on cancer spread and patient survival is less clear.

Development of a novel streamlined workflow (AACRE) and database (inCREDBle) for genomic analysis of carbapenem-resistant Enterobacterales.

In response to the threat of increasing antimicrobial resistance, we must increase the amount of available high-quality genomic data gathered on antibiotic-resistant bacteria. To this end, we developed an integrated pipeline for high-throughput long-read sequencing, assembly, annotation and analysis of bacterial isolates and used it to generate a large genomic data set of carbapenemase-producing Enterobacterales (CPE) isolates collected in Spain. The set of 461 isolates were sequenced with a combination of both Illumina and Oxford Nanopore Technologies (ONT) DNA sequencing technologies in order to provide genomic context for chromosomal loci and, most importantly, structural resolution of plasmids, important determinants for transmission of antimicrobial resistance. We developed an informatics pipeline called Assembly and Annotation of Carbapenem-Resistant Enterobacteriaceae (AACRE) for the full assembly and annotation of the bacterial genomes and their complement of plasmids. To explore the resulting genomic data set, we developed a new database called inCREDBle that not only stores the genomic data, but provides unique ways to filter and compare data, enabling comparative genomic analyses at the level of chromosomes, plasmids and individual genes. We identified a new sequence type, ST5000, and discovered a genomic locus unique to ST15 that may be linked to its increased spread in the population. In addition to our major objective of generating a large regional data set, we took the opportunity to compare the effects of sample quality and sequencing methods, including R9 versus R10 nanopore chemistry, on genome assembly and annotation quality. We conclude that converting short-read and hybrid microbial sequencing and assembly workflows to the latest nanopore chemistry will further reduce processing time and cost, truly enabling the routine monitoring of resistance transmission patterns at the resolution of complete chromosomes and plasmids.

A Machine Learning Framework Reduces the Manual Workload for Systematic Reviews of the Diagnostic Performance of Prostate Magnetic Resonance Imaging.

Prostate magnetic resonance imaging has become the imaging standard for prostate cancer in various clinical settings, with interpretation standardized according to the Prostate Imaging Reporting and Data System (PI-RADS). Each year, hundreds of scientific studies that report on the diagnostic performance of PI-RADS are published. To keep up with this ever-increasing evidence base, systematic reviews and meta-analyses are essential. As systematic reviews are highly resource-intensive, we investigated whether a machine learning framework can reduce the manual workload and speed up the screening process (title and abstract). We used search results from a living systematic review of the diagnostic performance of PI-RADS (1585 studies, of which 482 were potentially eligible after screening). A naïve Bayesian classifier was implemented in an active learning environment for classification of the titles and abstracts. Our outcome variable was the percentage of studies that can be excluded after 95% of relevant studies have been identified by the classifier (work saved over sampling: WSS@95%). In simulation runs of the entire screening process (controlling for classifier initiation and the frequency of classifier updating), we obtained a WSS@95% value of 28% (standard error of the mean ±0.1%). Applied prospectively, our classification framework would translate into a significant reduction in manual screening effort. Patient summary: Systematic reviews of scientific evidence are labor-intensive and take a lot of time. For example, many studies on prostate cancer diagnosis via MRI (magnetic resonance imaging) are published every year. We describe the use of machine learning to reduce the manual workload in screening search results. For a review of MRI for prostate cancer diagnosis, this approach reduced the screening workload by about 28%.

Descending control and regulation of spontaneous flight turns in Drosophila.

The clumped distribution of resources in the world has influenced the pattern of foraging behavior since the origins of life, selecting for a common locomotor search motif in which straight movements through resource-poor regions alternate with zig -zag exploration in resource-rich domains. For example, flies execute rapid changes in flight heading called body saccades during local search, but suppress these turns during long-distance dispersal or when surging upwind after encountering an attractive odor plume. Here, we describe the key cellular components of a neural network in flies that generates spontaneous turns as well as a specialized neuron that inhibits the network to promote straight flight. Using 2-photon imaging, optogenetic activation, and genetic ablation, we show that only four descending neurons appear sufficient to generate the descending commands to execute flight saccades. The network is organized into two functional couplets-one for right turns and one for left-with each couplet consisting of an excitatory (DNae014) and inhibitory (DNb01) neuron that project to the flight motor neuropil within the ventral nerve cord. Using resources from recently published connectomes of the fly brain, we identified a large, unique interneuron (VES041) that forms inhibitory connections to all four saccade command neurons and created specific genetic driver lines for this cell. As suggested by its connectivity, activation of VES041 strongly suppresses saccades, suggesting that it regulates the transition between local search and long-distance dispersal. These results thus identify the critical elements of a network that not only structures the locomotor behavior of flies, but may also play a crucial role in their natural foraging ecology.