Differential signalling requirements for RIPK1-dependent pyroptosis in neutrophils and macrophages.

TLR4 and TNFR1 signalling promotes potent proinflammatory signal transduction events, thus, are often hijacked by pathogenic microorganisms. We recently reported that myeloid cells retaliate Yersinia blockade of TAK1/IKK signalling by triggering RIPK1-dependent caspase-8 activation that promotes downstream GSDMD and GSDME-mediated pyroptosis in macrophages and neutrophils respectively. However, the upstream signalling events for RIPK1 activation in these cells are not well defined. Here, we demonstrate that unlike in macrophages, RIPK1-driven pyroptosis and cytokine priming in neutrophils are driven through TNFR1 signalling, while TLR4-TRIF signalling is dispensable. Furthermore, we demonstrate that activation of RIPK1-dependent pyroptosis in neutrophils during Yersinia infection requires IFN-γ priming, which serves to induce surface TNFR1 expression and amplify soluble TNF secretion. In contrast, macrophages utilise both TNFR1 and TLR4-TRIF signalling to trigger cell death, but only require TRIF but not autocrine TNFR1 for cytokine production. Together, these data highlight the emerging theme of cell type-specific regulation in cell death and immune signalling in myeloid cells.

Adapting an Intervention to Address Barriers to Pain Management in Hospice: Formative Research to Inform EMPOWER-D for Dementia Caregivers.

Background: Nearly half of more than 1.7 million older Americans who receive hospice care each year have a primary or comorbid diagnosis of dementia. Pain is often undertreated in this patient population owing to myriad factors, including unmet informational needs among family caregivers. Objective: We sought to inform the adaptation of a pain education intervention for hospice family caregivers to the context of dementia by eliciting feedback on the educational content covered in adapted intervention materials. Design: We conducted a multimethod, formative research study to inform the adaptation of an existing, evidence-based intervention. Setting/Subjects: The study included a purposively recruited sample (n = 33) of hospice professionals (n = 18) and family caregivers (n = 15) from across the United States. Measurements: Participants quantitatively rated the importance of each of the eight pain concerns presented in the adapted intervention materials (1 = not important to 3 = very important) and provided qualitative feedback via Zoom interview on the acceptability, clinical accuracy, and potential benefits of the adapted content. We analyzed quantitative data via descriptive statistics and qualitative data via content analysis. Results: Participants rated the adapted educational content as highly important (rangemean = 2.56-3.00), particularly regarding concerns about caregivers' pain assessment, communicating with the hospice team about pain, and addressing misinformation regarding pain medication outcomes. Participants also provided suggestions to strengthen specific educational messages to improve comprehension and uptake. Conclusions: Findings support the continued development and testing of the adapted intervention.

Accuracy of glomerular filtration rate estimation using creatinine and cystatin C for identifying and monitoring moderate chronic kidney disease: the eGFR-C study.

Background: Estimation of glomerular filtration rate using equations based on creatinine is widely used to manage chronic kidney disease. In the UK, the Chronic Kidney Disease Epidemiology Collaboration creatinine equation is recommended. Other published equations using cystatin C, an alternative marker of kidney function, have not gained widespread clinical acceptance. Given higher cost of cystatin C, its clinical utility should be validated before widespread introduction into the NHS. Objectives: Primary objectives were to: (1) compare accuracy of glomerular filtration rate equations at baseline and longitudinally in people with stage 3 chronic kidney disease, and test whether accuracy is affected by ethnicity, diabetes, albuminuria and other characteristics; (2) establish the reference change value for significant glomerular filtration rate changes; (3) model disease progression; and (4) explore comparative cost-effectiveness of kidney disease monitoring strategies. Design: A longitudinal, prospective study was designed to: (1) assess accuracy of glomerular filtration rate equations at baseline (n = 1167) and their ability to detect change over 3 years (n = 875); (2) model disease progression predictors in 278 individuals who received additional measurements; (3) quantify glomerular filtration rate variability components (n = 20); and (4) develop a measurement model analysis to compare different monitoring strategy costs (n = 875). Setting: Primary, secondary and tertiary care. Participants: Adults (≥ 18 years) with stage 3 chronic kidney disease. Interventions: Estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration and Modification of Diet in Renal Disease equations. Main outcome measures: Measured glomerular filtration rate was the reference against which estimating equations were compared with accuracy being expressed as P30 (percentage of values within 30% of reference) and progression (variously defined) studied as sensitivity/specificity. A regression model of disease progression was developed and differences for risk factors estimated. Biological variation components were measured and the reference change value calculated. Comparative costs of monitoring with different estimating equations modelled over 10 years were calculated. Results: Accuracy (P30) of all equations was ≥ 89.5%: the combined creatinine-cystatin equation (94.9%) was superior (p < 0.001) to other equations. Within each equation, no differences in P30 were seen across categories of age, gender, diabetes, albuminuria, body mass index, kidney function level and ethnicity. All equations showed poor (< 63%) sensitivity for detecting patients showing kidney function decline crossing clinically significant thresholds (e.g. a 25% decline in function). Consequently, the additional cost of monitoring kidney function annually using a cystatin C-based equation could not be justified (incremental cost per patient over 10 years = £43.32). Modelling data showed association between higher albuminuria and faster decline in measured and creatinine-estimated glomerular filtration rate. Reference change values for measured glomerular filtration rate (%, positive/negative) were 21.5/-17.7, with lower reference change values for estimated glomerular filtration rate. Limitations: Recruitment of people from South Asian and African-Caribbean backgrounds was below the study target. Future work: Prospective studies of the value of cystatin C as a risk marker in chronic kidney disease should be undertaken. Conclusions: Inclusion of cystatin C in glomerular filtration rate-estimating equations marginally improved accuracy but not detection of disease progression. Our data do not support cystatin C use for monitoring of glomerular filtration rate in stage 3 chronic kidney disease. Trial registration: This trial is registered as ISRCTN42955626. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/103/01) and is published in full in Health Technology Assessment; Vol. 28, No. 35. See the NIHR Funding and Awards website for further award information.

Chronic kidney disease, which affects approximately 14% of the adult population, often has no symptoms but, in some people, may later develop into kidney failure. Kidney disease is most often detected using a blood test called creatinine. Creatinine does not identify everyone with kidney disease, or those most likely to develop more serious kidney disease. An alternative blood test called cystatin C may be more accurate, but it is more expensive than the creatinine test. We compared the accuracy of these two tests in more than 1000 people with moderate kidney disease. Participants were tested over 3 years to see if the tests differed in their ability to detect worsening kidney function. We also wanted to identify risk factors associated with loss of kidney function, and how much the tests normally vary to better understand what results mean. We compared the accuracy and costs of monitoring people with the two markers. Cystatin C was found slightly more accurate than the creatinine test at estimating kidney function when comparing the baseline single measurements (95% accurate compared to 90%), but not at detecting worsening function over time. This means that the additional cost of monitoring people over time with cystatin C to detect kidney disease progression could not be justified. Kidney test results could vary by up to 20% between tests without necessarily implying changes in underlying kidney function ­ this is the normal level of individual variation. Cystatin C marginally improved accuracy of kidney function testing but not ability to detect worsening kidney function. Cystatin C improves identification of moderate chronic kidney disease, but our results do not support its use for routine monitoring of kidney function in such patients.

Microbe Profile: Bacteriophage ϕ6: a model for segmented RNA viruses and the evolutionary consequences of viral 'sex'.

Bacteriophage ϕ6 is a segmented dsRNA virus with a lipid envelope, which are unusual traits in bacterial viruses but common in eukaryotic viruses. This uniqueness allowed ϕ6 and its Pseudomonad hosts to serve as a molecular model for RNA genetics, mutation, replication, packaging, and reassortment in both bacterial and eukaryotic viruses. However, an additional uniqueness of ϕ6, created by its high mutation rate, was its use as an experimental system to study key questions such as the evolution of sex (segment reassortment), host-pathogen interactions, mutational load, rates of adaptation, genetic and phenotypic complexity, and game theory.

Double testing with lateral flow antigen test devices for COVID-19: does a second test in quick succession add value?

BACKGROUND/OBJECTIVES: We investigated if performing two lateral flow device (LFD) tests, LFD2 immediately after LFD1, could improve diagnostic sensitivity or specificity for detecting severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) antigen. STUDY DESIGN: Individuals aged ≥16 years attending UK community testing sites (February-May 2021) performed two successive LFD tests and provided a nose-and-throat sample for a polymerase chain reaction (PCR) test. Using the PCR result as the reference diagnosis, we assessed whether improvements could be achieved in sensitivity (by counting a positive result in either LFD as a positive overall test result) or specificity (by using LFD2 as confirmatory test). RESULTS: Overall, 2231 participants were included with 159 (7 %) having a positive PCR test. Of 2223 participants who completed both LFD tests, LFD results were highly concordant both with each other and with PCR tests (>97 %). The proportion of discord LFD results decreased significantly over the study period. Combined LFD usage achieved a sensitivity of 68.6 %, versus 67.1 % for either LFD individually. The specificity increased from 99.5 % to 99.8 % when using LFD2 as confirmatory test. Observed increases in sensitivity and specificity were not statistically significant. Void results were recorded for 31 (1.4 %) LFD1s, 19 (0.9 %) LFD2s and 6 (0.3 %) combined LFD tests. CONCLUSIONS: LFD tests were highly reproducible even when they were performed by untrained users following only written instructions and without supervision. While performing two LFD tests of the same type in quick succession marginally increased sensitivity or specificity, statistically significant improvements were not detected in our study.

Effect of Menstrual Cycle and Hormonal Contraception on Musculoskeletal Health and Performance: Protocol for a Prospective Cohort Design and Cross-Sectional Comparison.

BACKGROUND: Women of reproductive age experience cyclical variation in the female sex steroid hormones 17ß-estradiol and progesterone during the menstrual cycle that is attenuated by some hormonal contraceptives. Estrogens perform a primary function in sexual development and reproduction but have nonreproductive effects on bone, muscle, and sinew tissues (ie, ligaments and tendons), which may influence injury risk and physical performance. OBJECTIVE: The purpose of the study is to understand the effect of the menstrual cycle and hormonal contraceptive use on bone and calcium metabolism, and musculoskeletal health and performance. METHODS: A total of 5 cohorts of physically active women (aged 18-40 years) will be recruited to participate: eumenorrheic, nonhormonal contraceptive users (n=20); combined oral contraceptive pill (COCP) users (n=20); hormonal implant users (n=20); hormonal intrauterine system users (n=20); and hormonal injection users (n=20). Participants must have been using the COCP and implant for at least 1 year and the intrauterine system and injection for at least 2 years. First-void urine samples and fasted blood samples will be collected for biochemical analysis of calcium and bone metabolism, hormones, and metabolic markers. Knee extensor and flexor strength will be measured using an isometric dynamometer, and lower limb tendon and stiffness, tone, and elasticity will be measured using a Myoton device. Functional movement will be assessed using a single-leg drop to assess the frontal plane projection angle and the qualitative assessment of single leg loading. Bone density and macro- and microstructure will be measured using ultrasound, dual-energy x-ray absorptiometry, and high-resolution peripheral quantitative computed tomography. Skeletal material properties will be estimated from reference point indentation, performed on the flat surface of the medial tibia diaphysis. Body composition will be assessed by dual-energy x-ray absorptiometry. The differences in outcome measures between the hormonal contraceptive groups will be analyzed in a one-way between-group analysis of covariance. Within the eumenorrheic group, the influence of the menstrual cycle on outcome measures will be assessed using a linear mixed effects model. Within the COCP group, differences across 2 time points will be analyzed using the paired-samples 2-tailed t test. RESULTS: The research was funded in January 2020, and data collection started in January 2022, with a projected data collection completion date of August 2024. The number of participants who have consented at the point of manuscript submission is 66. It is expected that all data analysis will be completed and results published by the end of 2024. CONCLUSIONS: Understanding the effects of the menstrual cycle and hormonal contraception on musculoskeletal health and performance will inform contraceptive choices for physically active women to manage injury risk. TRIAL REGISTRATION: ClinicalTrials.gov NCT05587920; https://classic.clinicaltrials.gov/ct2/show/NCT05587920. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/50542.

Influenza-associated and COVID-19-associated pulmonary aspergillosis in critically ill patients.

Influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA) are increasingly recognised as important complications in patients requiring intensive care for severe viral pneumonia. The diagnosis can typically be made in 10-20% of patients with severe influenza or COVID-19, but only when appropriate diagnostic tools are used. Bronchoalveolar lavage sampling for culture, galactomannan testing, and PCR forms the cornerstone of diagnosis, whereas visual examination of the tracheobronchial tract during bronchoscopy is required to detect invasive Aspergillus tracheobronchitis. Azoles are the first-choice antifungal drugs, with liposomal amphotericin B as an alternative in settings where azole resistance is prevalent. Despite antifungal therapy, IAPA and CAPA are associated with poor outcomes, with fatality rates often exceeding 50%. In this Review, we discuss the mechanistic and clinical aspects of IAPA and CAPA. Moreover, we identify crucial knowledge gaps and formulate directions for future research.

Pitfalls in definitions on respiratory viruses and particularities of Adenovirus infection in hematopoietic cell transplantation patients: Recommendations from the EBMT practice harmonization and guidelines committee.

In 2023, the EBMT Practice harmonization and Guidelines Committee partnered with the EBMT Infection Diseases Working Party (IDWP) to undertake the task of delivering best practice recommendations, aiming to harmonize by expert consensus, the already existing definitions and future epidemiological and clinical studies among centers of the EBMT network. To attain this objective, a group of experts in the field was convened. The workgroup identified and discussed some critical aspects in definitions of community-acquired respiratory viruses (CARV) and adenovirus (ADV) infections in recipient of hematopoietic cell transplant (HCT). The methodology involved literature review and expert consensus. For CARV, expert consensus focused on defining infection severity, infection duration, and establishing criteria for lower respiratory tract disease (LRTD). For ADV, the expert consensus focused on surveillance methods and the definitions of ADV infection, certainty levels of disease, response to treatment, and attributable mortality. This consensus workshop provided indications to EBMT community aimed at facilitating data collection and consistency in the EBMT registry for respiratory viral infectious complications.

How Is Variability in Femoral and Acetabular Version Associated With Presentation Among Young Adults With Hip Pain?

BACKGROUND: Acetabular and femoral version contribute to hip pain in patients with femoroacetabular impingement (FAI) or dysplasia. However, definitions and measurement methods of femoral version have varied in different studies, resulting in different "normal" values being used by clinicians for what should be the same anatomic measurement. This could result in discrepant or even inappropriate treatment recommendations. QUESTIONS/PURPOSES: In patients undergoing hip preservation surgery, (1) what is the range of acetabular and femoral version at presentation, and how much do two commonly used measurement techniques (those of Murphy and Reikerås) differ? (2) How are differences in acetabular and femoral version associated with clinical factors and outcomes scores at the time of presentation? METHODS: This was a retrospective analysis of data gathered in a longitudinally maintained database of patients undergoing hip preservation at a tertiary care referral center. Between June 2020 and December 2021, 282 hips in 258 patients were treated for an isolated labral tear (9% [26 hips]), hip dysplasia (21% [59 hips]), FAI (52% [147 hips]), mixed FAI and dysplasia (17% [47 hips]), or pediatric deformity (slipped capital femoral head epiphysis or Perthes disease; 1% [3 hips]) with hip arthroscopy (71% [200 hips]), periacetabular osteotomy (26% [74 hips]), surgical hip dislocation (2.5% [7 hips]), or femoral derotation osteotomy (0.5% [1 hip]). We considered those with complete radiographic data (CT including the pelvis and distal femur) and patient-reported outcome scores as potentially eligible. Exclusion criteria were age younger than 18 or older than 55 years (5 hips, 3 patients), signs of hip osteoarthritis (Tönnis grade ≥ 2; 0), pediatric deformity (slipped capital femoral head epiphysis or Perthes disease; 3 hips, 3 patients), previous femoral or acetabular osteotomy (2 hips, 2 patients), avascular necrosis of the femoral head (0), history of neuromuscular disorder (Ehlers-Danlos syndrome; 3 hips, 3 patients) or rheumatoid disease (ankylosing spondylitis; 1 hip, 1 patient), and when CT did not include the knees (19 hips, 19 patients). Based on these criteria, 249 hips in 227 patients were included. Of patients with bilateral symptomatic hips, one side was randomly selected for inclusion, leaving 227 hips in 227 patients for further analysis. The patients' median age (range) was 34 years (19 to 55 years), the median BMI (range) was 27 kg/m2 (16 to 55 kg/m2), and 63% (144) were female; they were treated with hip arthroscopy (in 74% [168]) or periacetabular osteotomy (in 23% [52]). Patients underwent a CT scan to measure acetabular version and femoral version using the Murphy (low < 10°; normal: 10° to 25°; high > 25°) or Reikerås (low < 5°; normal: 5° to 20°; high > 20°) technique. The McKibbin index was calculated (low: < 20°; normal: 20° to 50°; high > 50°). Based on the central acetabular version and femoral version as measured by Murphy, hips were grouped according to their rotational profile into four groups: unstable rotational profile: high (high acetabular version with high femoral version) or moderate (high acetabular version with normal femoral version or normal acetabular version with high femoral version); normal rotational profile (normal acetabular version with femoral version); compensatory rotational profile (low acetabular version with high femoral version or high acetabular version with low femoral version); and impingement rotational profile (low acetabular version with low femoral version): high (low acetabular version with low femoral version) or moderate (low acetabular version with normal femoral version or normal acetabular version with low femoral version). Radiographic assessments were manually performed on digitized images by two orthopaedic residents, and 25% of randomly selected measurements were repeated by the senior author, a fellowship-trained hip preservation and arthroplasty surgeon. Interobserver and intraobserver reliabilities were calculated using the correlation coefficient with a two-way mixed model, showing excellent agreement for Murphy technique measurements (intraclass correlation coefficient 0.908 [95% confidence interval 0.80 to 0.97]) and Reikerås technique measurements (ICC 0.938 [95% CI 0.81 to 0.97]). Patient-reported measures were recorded using the International Hip Outcome Tool (iHOT-33) (0 to 100; worse to best). RESULTS: The mean acetabular version was 18° ± 6°, and mean femoral version was 24° ± 12° using the Murphy technique and 12° ± 11° with the Reikerås method. Eighty percent (181 of 227) of hips had normal acetabular version, 42% (96 of 227) to 63% (142 to 227) had normal femoral version per Murphy and Reikerås, respectively, and 67% (152 to 227) had a normal McKibbin index. Patients with an impingement profile (low acetabular version or femoral version) were older (39 ± 9 years) than patients with an unstable (high acetabular version or femoral version; 33 ± 9 years; p = 0.004), normal (33 ± 9 years; p = 0.02), or compensatory (high acetabular version with low femoral version or vice versa; 33 ± 7 years; p = 0.08) rotational profile. Using the Murphy technique, femoral version was 12° greater than with the Reikerås method (R2 0.85; p < 0.001). There were no differences in iHOT-33 score between different groups (impingement: 32 ± 17 versus normal 35 ± 21 versus compensated: 34 ± 20 versus unstable: 31 ± 17; p = 0.40). CONCLUSION: Variability in femoral version is twice as large as acetabular version. Patients with an impingement rotational profile were older than patients with a normal, compensatory, or unstable profile, indicating there are other variables not yet fully accounted for that lead to earlier pain and presentation in these groups. Important differences exist between measurement methods. This study shows that different measurement methods for femoral anteversion result in different numbers; if other authors compare their results to those of other studies, they should use equations such as the one suggested in this study. LEVEL OF EVIDENCE: Level III, prognostic study.

SARS-CoV-2 Nucleocapsid Protein Induces Tau Pathological Changes That Can Be Counteracted by SUMO2.

Neurologic manifestations are an immediate consequence of SARS-CoV-2 infection, the etiologic agent of COVID-19, which, however, may also trigger long-term neurological effects. Notably, COVID-19 patients with neurological symptoms show elevated levels of biomarkers associated with brain injury, including Tau proteins linked to Alzheimer's pathology. Studies in brain organoids revealed that SARS-CoV-2 alters the phosphorylation and distribution of Tau in infected neurons, but the mechanisms are currently unknown. We hypothesize that these pathological changes are due to the recruitment of Tau into stress granules (SGs) operated by the nucleocapsid protein (NCAP) of SARS-CoV-2. To test this hypothesis, we investigated whether NCAP interacts with Tau and localizes to SGs in hippocampal neurons in vitro and in vivo. Mechanistically, we tested whether SUMOylation, a posttranslational modification of NCAP and Tau, modulates their distribution in SGs and their pathological interaction. We found that NCAP and Tau colocalize and physically interact. We also found that NCAP induces hyperphosphorylation of Tau and causes cognitive impairment in mice infected with NCAP in their hippocampus. Finally, we found that SUMOylation modulates NCAP SG formation in vitro and cognitive performance in infected mice. Our data demonstrate that NCAP induces Tau pathological changes both in vitro and in vivo. Moreover, we demonstrate that SUMO2 ameliorates NCAP-induced Tau pathology, highlighting the importance of the SUMOylation pathway as a target of intervention against neurotoxic insults, such as Tau oligomers and viral infection.

Single-nucleus multiomics reveals the disrupted regulatory programs in three brain regions of sporadic early-onset Alzheimer's disease.

Sporadic early-onset Alzheimer's disease (sEOAD) represents a significant but less-studied subtype of Alzheimer's disease (AD). Here, we generated a single-nucleus multiome atlas derived from the postmortem prefrontal cortex, entorhinal cortex, and hippocampus of nine individuals with or without sEOAD. Comprehensive analyses were conducted to delineate cell type-specific transcriptomic changes and linked candidate cis- regulatory elements (cCREs) across brain regions. We prioritized seven conservative transcription factors in glial cells in multiple brain regions, including RFX4 in astrocytes and IKZF1 in microglia, which are implicated in regulating sEOAD-associated genes. Moreover, we identified the top 25 altered intercellular signaling between glial cells and neurons, highlighting their regulatory potential on gene expression in receiver cells. We reported 38 cCREs linked to sEOAD-associated genes overlapped with late-onset AD risk loci, and sEOAD cCREs enriched in neuropsychiatric disorder risk loci. This atlas helps dissect transcriptional and chromatin dynamics in sEOAD, providing a key resource for AD research.

Single nucleus transcriptomics supports a role for CCNA2-induced human adult cardiomyocyte cytokinesis.

Cyclin A2 (CCNA2) is a master regulatory gene of the cell cycle that is normally silenced in postnatal mammalian cardiomyocytes. We have previously demonstrated that it can induce significant cardiac repair in both small and large animals when delivered to the heart via a viral vector. To date, whether CCNA2 gene delivery can induce cytokinesis in isolated cardiomyocytes from adult human hearts has not been investigated. Therefore, we designed a human gene therapy vector featuring a replication-deficient, E1/E3-deleted human adenovirus five encoding human CCNA2 driven by the cardiac Troponin T promoter to enable the expression of CCNA2 in freshly isolated human cardiomyocytes. Utilizing time-lapse microscopy live imaging of cultured adult human cardiomyocytes isolated from a 21-year-old male, 41-year-old female, and 55-year-old male, we now report that human adult cardiomyocytes can be induced to undergo complete cytokinesis in response to CCNA2 gene delivery with preservation of sarcomere integrity in the resulting daughter cells. To elucidate the mechanistic underpinnings of CCNA2-dependent gene regulation in governing cardiomyocyte cytokinesis, we conducted single nucleus transcriptomics (snRNA-seq, 10X Genomics) analysis in hearts isolated from adult transgenic mice that constitutively express CCNA2 in cardiomyocytes (CCNA2-Tg) and non-transgenic mice (nTg). Remarkably, we identified a subpopulation of cardiomyocytes enriched with cytokinesis, proliferative, and reprogramming genes in hearts obtained from CCNA2-Tg mice as compared to hearts obtained from nTg mice. We also performed bulk RNA sequencing of human adult and fetal hearts, and we identified key reprogramming genes that are involved in CCNA2-induced cytokinesis. These results provide a compelling path forward for the clinical development of cardiac regenerative therapy based on strategic manipulation of the cardiomyocyte cell cycle.

Association between mpMRI detected tumor apparent diffusion coefficient and 5-year biochemical recurrence risk after radical prostatectomy.

PURPOSE: To assess the ability of tumor apparent diffusion coefficient (ADC) values obtained from multiparametric magnetic resonance imaging (mpMRI) to predict the risk of 5-year biochemical recurrence (BCR) after radical prostatectomy (RP). MATERIALS AND METHODS: This retrospective analysis included 1207 peripheral and 232 non-peripheral zone prostate cancer (PCa) patients who underwent mpMRI before RP (2012-2015), with the outcome of interest being 5-year BCR. ADC was evaluated as a continuous variable and as categories: low (< 850 µm2/s), intermediate (850-1100 µm2/s), and high (> 1100 µm2/s). Kaplan-Meier curves with log-rank testing of BCR-free survival, multivariable Cox proportional hazard regression models were formed to estimate the risk of BCR. RESULTS: Among the 1439 males with median age 63 (± 7) years, the median follow-up was 59 months, and 306 (25%) patients experienced BCR. Peripheral zone PCa patients with BCR had lower tumor ADC values than those without BCR (874 versus 1025 µm2/s, p < 0.001). Five-year BCR-free survival rates were 52.3%, 74.4%, and 87% for patients in the low, intermediate, and high ADC value categories, respectively (p < 0.0001). Lower ADC was associated with BCR, both as continuously coded variable (HR: 5.35; p < 0.001) and as ADC categories (intermediate versus high ADC-HR: 1.56, p = 0.017; low vs. high ADC-HR; 2.36, p < 0.001). In the non-peripheral zone PCa patients, no association between ADC and BCR was observed. CONCLUSION: Tumor ADC values and categories were found to be predictive of the 5-year BCR risk after RP in patients with peripheral zone PCa and may serve as a prognostic biomarker.

Whole-body MRI in oncology: acquisition protocols, current guidelines, and beyond.

Acknowledging the increasing use of whole-body magnetic resonance imaging (WB-MRI) in the oncological setting, we conducted a narrative review focusing on practical aspects of the examination and providing a synthesis of various acquisition protocols described in the literature. Firstly, we addressed the topic of patient preparation, emphasizing methods to enhance examination acceptance. This included strategies for reducing anxiety and patient distress, improving staff-patient interactions, and increasing overall patient comfort. Secondly, we analysed WB-MRI acquisition protocols recommended in existing imaging guidelines, such as MET-RADS-P, MY-RADS, and ONCO-RADS, and provided an overview of acquisition protocols reported in the literature regarding other expanding applications of WB-MRI in oncology, in patients with breast cancer, ovarian cancer, melanoma, colorectal and lung cancer, lymphoma, and cancers of unknown primary. Finally, we suggested possible acquisition parameters for whole-body images across MR systems from three different vendors.

Blockade of IL-1ß and PD-1 with combination chemotherapy reduces systemic myeloid suppression in metastatic pancreatic cancer with heterogeneous effects in the tumor.

Innate inflammation promotes tumor development, although the role of innate inflammatory cytokines in established human tumors is unclear. Here we report clinical and translational results from a phase Ib trial testing whether IL-1ß blockade in human pancreatic cancer would alleviate myeloid immunosuppression and reveal antitumor T-cell responses to PD-1 blockade. Patients with treatment-naïve advanced pancreatic ductal adenocarcinoma (n=10) were treated with canakinumab, a high-affinity monoclonal human anti-interleukin-1ß (IL-1ß), the PD-1 blocking antibody spartalizumab, and gemcitabine/n(ab)paclitaxel. Analysis of paired peripheral blood from patients in the trial versus patients receiving multiagent chemotherapy showed a modest increase in HLA-DR+CD38+ activated CD8+ T cells and a decrease in circulating monocytic myeloid-derived suppressor cells (MDSCs) by flow cytometry for patients in the trial, but not in controls. Similarly, we used patient serum to differentiate monocytic MDSCs in vitro and showed that functional inhibition of T-cell proliferation was reduced when using on-treatment serum samples from patients in the trial but not when using serum from patients treated with chemotherapy alone. Within the tumor we observed few changes in suppressive myeloid-cell populations or activated T cells as assessed by single-cell transcriptional profiling or multiplex immunofluorescence, although increases in CD8+ T cells suggest that improvements in the tumor immune microenvironment might be revealed by a larger study. Overall, the data indicate that exposure to PD-1 and IL-1ß blockade induced a modest reactivation of peripheral CD8+ T cells and decreased circulating monocytic MDSCs; however, these changes did not lead to similarly uniform alterations in the tumor microenvironment.

Quantifying error in effect size estimates in attention, executive function, and implicit learning.

Accurate quantification of effect sizes has the power to motivate theory and reduce misinvestment of scientific resources by informing power calculations during study planning. However, a combination of publication bias and small sample sizes (∼N = 25) hampers certainty in current effect size estimates. We sought to determine the extent to which sample sizes may produce errors in effect size estimates for four commonly used paradigms assessing attention, executive function, and implicit learning (attentional blink, multitasking, contextual cueing, and serial response task). We combined a large data set with a bootstrapping approach to simulate 1,000 experiments across a range of N (13-313). Beyond quantifying the effect size and statistical power that can be anticipated for each study design, we demonstrate that experiments with lower N may double or triple information loss. We also show that basing power calculations on effect sizes from similar studies yields a problematically imprecise estimate between 40% and 67% of the time, given commonly used sample sizes. Last, we show that skewness of intersubject behavioral effects may serve as a predictor of an erroneous estimate. We conclude with practical recommendations for researchers and demonstrate how our simulation approach can yield theoretical insights that are not readily achieved by other methods such as identifying the information gained from rejecting the null hypothesis and quantifying the contribution of individual variation to error in effect size estimates. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

A deep learning anthropomorphic model observer for a detection task in PET.

BACKGROUND: Lesion detection is one of the most important clinical tasks in positron emission tomography (PET) for oncology. An anthropomorphic model observer (MO) designed to replicate human observers (HOs) in a detection task is an important tool for assessing task-based image quality. The channelized Hotelling observer (CHO) has been the most popular anthropomorphic MO. Recently, deep learning MOs (DLMOs), mostly based on convolutional neural networks (CNNs), have been investigated for various imaging modalities. However, there have been few studies on DLMOs for PET. PURPOSE: The goal of the study is to investigate whether DLMOs can predict HOs better than conventional MOs such as CHO in a two-alternative forced-choice (2AFC) detection task using PET images with real anatomical variability. METHODS: Two types of DLMOs were implemented: (1) CNN DLMO, and (2) CNN-SwinT DLMO that combines CNN and Swin Transformer (SwinT) encoders. Lesion-absent PET images were reconstructed from clinical data, and lesion-present images were reconstructed with adding simulated lesion sinogram data. Lesion-present and lesion-absent PET image pairs were labeled by eight HOs consisting of four radiologists and four image scientists in a 2AFC detection task. In total, 2268 pairs of lesion-present and lesion-absent images were used for training, 324 pairs for validation, and 324 pairs for test. CNN DLMO, CNN-SwinT DLMO, CHO with internal noise, and non-prewhitening matched filter (NPWMF) were compared in the same train-test paradigm. For comparison, six quantitative metrics including prediction accuracy, mean squared errors (MSEs) and correlation coefficients, which measure how well a MO predicts HOs, were calculated in a 9-fold cross-validation experiment. RESULTS: In terms of the accuracy and MSE metrics, CNN DLMO and CNN-SwinT DLMO showed better performance than CHO and NPWMF, and CNN-SwinT DLMO showed the best performance among the MOs evaluated. CONCLUSIONS: DLMO can predict HOs more accurately than conventional MOs such as CHO in PET lesion detection. Combining SwinT and CNN encoders can improve the DLMO prediction performance compared to using CNN only.