Can physician judgment enhance model trustworthiness? A case study on predicting pathological lymph nodes in rectal cancer.

Explainability is key to enhancing the trustworthiness of artificial intelligence in medicine. However, there exists a significant gap between physicians' expectations for model explainability and the actual behavior of these models. This gap arises from the absence of a consensus on a physician-centered evaluation framework, which is needed to quantitatively assess the practical benefits that effective explainability should offer practitioners. Here, we hypothesize that superior attention maps, as a mechanism of model explanation, should align with the information that physicians focus on, potentially reducing prediction uncertainty and increasing model reliability. We employed a multimodal transformer to predict lymph node metastasis of rectal cancer using clinical data and magnetic resonance imaging. We explored how well attention maps, visualized through a state-of-the-art technique, can achieve agreement with physician understanding. Subsequently, we compared two distinct approaches for estimating uncertainty: a standalone estimation using only the variance of prediction probability, and a human-in-the-loop estimation that considers both the variance of prediction probability and the quantified agreement. Our findings revealed no significant advantage of the human-in-the-loop approach over the standalone one. In conclusion, this case study did not confirm the anticipated benefit of the explanation in enhancing model reliability. Superficial explanations could do more harm than good by misleading physicians into relying on uncertain predictions, suggesting that the current state of attention mechanisms should not be overestimated in the context of model explainability.

Real-world evidence of 18F-fluciclovine Positron emission tomography/computed tomography performance for recurrent prostate cancer in the Veterans Affairs Health System.

BACKGROUND: There are no population-level studies assessing 18F-fluciclovine (fluciclovine) utilization of Positron emission tomography/computed tomography (PET/CT) for biochemically recurrent prostate cancer (PC). We assessed fluciclovine PET/CT in the Veterans Affairs Health Care System. METHODS: Of 1153 men with claims suggesting receipt of fluciclovine PET/CT, we randomly reviewed charts of 300 who indeed underwent fluciclovine PET/CT. The primary outcome was fluciclovine PET/CT result (positive or negative). Comparison among groups stratified by androgen deprivation therapy (ADT) (yes vs. no) and prostate-specific antigen (PSA) (≤1 vs. >1 ng/mL) at imaging were performed. Logistic regression tested associations between PSA, ADT receipt, and race with fluciclovine PET/CT positive imaging. RESULTS: Fluciclovine PET/CT positivity rate was 33% for patients with PSA 0-0.5 ng/mL, 21% for >0.5-1.0, 54% for >1.0-2.0, and 66% for >2.0 (p < 0.01). A 59% positivity rate ocurred in patients treated with concurrent ADT versus 37% in those not on ADT (p < 0.01). White were more likely to have a positive scan versus Black patients (55% vs. 38%; p = 0.02). Patients whose primary treatment was radical prostatectomy had a lower positivity rate (33%) versus those treated with radiotherapy (55%) (p < 0.001). On multivariable logistic regression, PSA > 1 ng/mL (all men odds ratio [OR]: 4.06, 95% confidence interval [CI]: 2.07-7.96; men on ADT only OR: 4.42, 95% CI: 1.73-11.26) and use of ADT (OR: 3.94, 95% CI: 1.32-11.75), and White (all men OR: 2.22, 95% CI: 1.20-4.17) predicted positive fluciclovine PET/CT. CONCLUSION: This real-world study assessing 18F-fluciclovine PET/CT performance in an equal access health care system confirms higher detection rates than traditional imaging methods, but positivity is highly influenced by PSA at time of imaging. Additionally, patients currently receiving ADT have at least four times higher likelihood of a positive scan, showing that scan positivity isn't negatively affected by ADT status in this study. Finally, White men were more likely to have a positive scan, the reasons for which should be explored in future studies.

Risk prediction of cholangitis after stent implantation based on machine learning.

The risk of cholangitis after ERCP implantation in malignant obstructive jaundice patients remains unknown. To develop models based on artificial intelligence methods to predict cholangitis risk more accurately, according to patients after stent implantation in patients' MOJ clinical data. This retrospective study included 218 patients with MOJ undergoing ERCP surgery. A total of 27 clinical variables were collected as input variables. Seven models (including univariate analysis and six machine learning models) were trained and tested for classified prediction. The model' performance was measured by AUROC. The RFT model demonstrated excellent performances with accuracies up to 0.86 and AUROC up to 0.87. Feature selection in RF and SHAP was similar, and the choice of the best variable subset produced a high performance with an AUROC up to 0.89. We have developed a hybrid machine learning model with better predictive performance than traditional LR prediction models, as well as other machine learning models for cholangitis based on simple clinical data. The model can assist doctors in clinical diagnosis, adopt reasonable treatment plans, and improve the survival rate of patients.

Atomically Resolved Transition Pathways of Iron Redox.

The redox transition between iron and its oxides is of the utmost importance in heterogeneous catalysis, biological metabolism, and geological evolution. The structural characteristics of this reaction may vary based on surrounding environmental conditions, giving rise to diverse physical scenarios. In this study, we explore the atomic-scale transformation of nanosized Fe3O4 under ambient-pressure H2 gas using in-situ environmental transmission electron microscopy. Our results reveal that the internal solid-state reactions dominated by iron diffusion are coupled with the surface reactions involving gaseous O or H species. During reduction, we observe two competitive reduction pathways, namely Fe3O4 → FeO → Fe and Fe3O4 → Fe. An intermediate phase with vacancy ordering is observed during the disproportionation reaction of Fe2+ → Fe0 + Fe3+, which potentially alleviates stress and facilitates ion migration. As the temperature decreases, an oxidation process occurs in the presence of environmental H2O and trace amounts of O2. A direct oxidation of Fe to Fe3O4 occurs in the absence of the FeO phase, likely corresponding to a change in the water vapor content in the atmosphere. This work elucidates a full dynamical scenario of iron redox under realistic conditions, which is critical for unraveling the intricate mechanisms governing the solid-solid and solid-gas reactions.

Advanced application of tea residue extracts rich in polyphenols for enhancing sludge dewaterability: Unraveling the role of pH regulation.

Tea polyphenols (TPs), as a kind of derivatives from tea waste, were employed as a novel environmentally friendly bio-based sludge conditioner in this study. The findings showed that when TPs were applied at a dosage of 300 mg g-1 DS, the sludge CST0/CST ratio significantly increased to 1.90. pH regulation was found to markedly affect the dewatering efficiency of sludge. At pH 4, the CST0/CST rose to 2.86, coupled with a reduction in the specific resistance to filtration (SRF) from 6.69 × 1013 m kg-1 to 1.43 × 1013 m kg-1 and a decrease in the moisture content (MC) from 90.57% to 68.75%. TPs formed complexes and precipitated sludge proteins, as demonstrated by changes in the extracellular polymeric substances (EPS), viscosity, zeta potential, and particles size distribution. The optimization significance of acidification treatment on sludge structure disintegration, the interaction of TPs with EPS, and the removal of sludge proteins were elucidated. The research provided an ideal approach for the integrated utilization of biomass resources from tea waste and highlighted the potential application of TPs as an environmentally friendly conditioner in sludge dewatering.

Addressing racial disparities in prostate cancer pathology prediction models: external validation and comparison of four models of pathological outcome prediction before radical prostatectomy in the multiethnic SEARCH cohort.

BACKGROUND: Certain widely used pathological outcome prediction models that were developed in tertiary centers tend to overpredict outcomes in the community setting; thus, the Michigan Urological-Surgery Improvement Collaborative (MUSIC) model was developed in general urology practice to address this issue. Additionally, the development of these models involved a relatively small proportion of Black men, potentially compromising the accuracy of predictions in this patient group. We tested the validity of the MUSIC and three widely used nomograms to compare their overall and race-stratified predictive performance. METHODS: We extracted data from 4139 (1138 Black) men from the Shared Equal Access Regional Cancer Hospital (SEARCH) database of the Veterans Affairs health system. The predictive performance of the MUSIC model was compared to the Memorial-Sloan Kettering (MSK), Briganti-2012, and Partin-2017 models for predicting lymph-node invasion (LNI), extra-prostatic extension (EPE), and seminal vesicle invasion (SVI). RESULTS: The median PSA of Black men was higher than White men (7.8 vs. 6.8 ng/ml), although they were younger by a median of three years and presented at a lower-stage disease. MUSIC model showed comparable discriminatory capacity (AUC:77.0%) compared to MSK (79.2%), Partin-2017 (74.6%), and Briganti-2012 (76.3%), with better calibration for LNI. AUCs for EPE and SVI were 72.7% and 76.9%, respectively, all comparable to the MSK and Partin models. LNI AUCs for Black and White men were 69.6% and 79.6%, respectively, while EPE and SVI AUCs were comparable between races. EPE and LNI had worse calibration in Black men. Decision curve analysis showed MUSIC superiority over the MSK model in predicting LNI, especially among Black men. CONCLUSION: Although the discriminatory performance of all models was comparable for each outcome, the MUSIC model exhibited superior net benefit to the MSK model in predicting LNI outcomes among Black men in the SEARCH population.

Research progress on metabolites of nitrofurazone in aquatic products.

The carcinogenic and teratogenic risks of nitrofurazone (NFZ) led to its restriction in aquatic products. Semicarbazide (SEM), one of its metabolites, is a primary focus of modern monitoring techniques. However, the SEM residue in aquatic products is believed to be formed through endogenous mechanisms, especially for aquatic crustaceans. In this article, we will discuss the source of SEM, including its usage as an antibiotic in aquatic products (nitrofurazone), its production during food processing (azodicarbonamide and hypochlorite treatment), its occurrence naturally in the body, and its intake from the environment. SEM detection techniques were divided into three groups: derivatization, extraction/purification, and analytical methods. Applications based on liquid chromatography and its tandem mass spectrometry, immunoassay, and electrochemical methods were outlined, as were the use of various derivatives and their assisted derivatization, as well as extraction and purification techniques based on liquid-liquid extraction and solid-phase extraction. The difficulties of implementing SEM for nitrofurazone monitoring in aquatic products from crustaceans are also discussed. Possible new markers and methods for detecting them are discussed. Finally, the present research on monitoring illicit nitrofurazone usage through its metabolites is summarised, and potential problems that need to be overcome by continuing research are proposed with an eye toward giving references for future studies.

SIMarker: Cellular similarity detection and its application to diagnosis and prognosis of liver cancer.

BACKGROUND: The emergence of single-cell technology offers a unique opportunity to explore cellular similarity and heterogeneity between precancerous diseases and solid tumors. However, there is lacking a systematic study for identifying and characterizing similarities at single-cell resolution. METHODS: We developed SIMarker, a computational framework to detect cellular similarities between precancerous diseases and solid tumors based on gene expression at single-cell resolution. Taking hepatocellular carcinoma (HCC) as a case study, we quantified the cellular and molecular connections between HCC and cirrhosis. Core analysis modules of SIMarker is publicly available at https://github.com/xmuhuanglab/SIMarker ("SIM" means "similarity" and "Marker" means "biomarkers). RESULTS: We found PGA5+ hepatocytes in HCC showed cirrhosis-like characteristics, including similar transcriptional programs and gene regulatory networks. Consequently, the genes constituting the gene expression program of these cirrhosis-like subpopulations were designated as cirrhosis-like signatures (CLS). Strikingly, our utilization of CLS enabled the development of diagnosis and prognosis biomarkers based on within-sample relative expression orderings of gene pairs. These biomarkers achieved high precision and concordance compared with previous studies. CONCLUSIONS: Our work provides a systematic method to investigate the clinical translational significance of cellular similarities between HCC and cirrhosis, which opens avenues for identifying similar paradigms in other categories of cancers and diseases.

Direct-coating of cellulose hydrogel on PVDF membranes with superhydrophilic and antifouling properties for high-efficiency oil/water emulsion separation.

As a well-known natural and innocuous plant constituent, cellulose consists of abundant hydroxyl groups and can tightly adsorb onto material surfaces hydrogen bonding, resulting in a superhydrophilic surface. In this work, the hydrophobic polyvinylidene fluoride (PVDF) membranes were modified by immersing them in cellulose hydrogel using a simple one-step process. The modified PVDF membrane exhibited excellent resistance to fouling and oil adhesion, making it highly effective in separating various oil-in-water emulsions. The cellulose-modified PVDF membranes achieved a high oil rejection rate (>99 %) and a maximum separation flux of 2675.2 L·m-2·h-1. Furthermore, even an oil-in-water emulsion containing bovine serum albumin maintained a steady permeation flux after four filtration cycles. Additionally, these cellulose-modified PVDF membranes demonstrated excellent underwater superoleophobicity across a wide range of pH levels and high saline conditions. Overall, these cellulose-modified superhydrophilic PVDF membranes are sustainable, environmentally friendly, easily scalable, and hold great promise for practical applications in oily wastewater treatment.

InstrumentNet: An integrated model for real-time segmentation of intracranial surgical instruments.

In robot-assisted surgery, precise surgical instrument segmentation technology can provide accurate location and pose data for surgeons, helping them perform a series of surgical operations efficiently and safely. However, there are still some interfering factors, such as surgical instruments being covered by tissue, multiple surgical instruments interlacing with each other, and instrument shaking during surgery. To better address these issues, an effective surgical instrument segmentation network called InstrumentNet is proposed, which adopts YOLOv7 as the object detection framework to achieve a real-time detection solution. Specifically, a multiscale feature fusion network is constructed, which aims to avoid problems such as feature redundancy and feature loss and enhance the generalization ability. Furthermore, an adaptive feature-weighted fusion mechanism is introduced to regulate network learning and convergence. Finally, a semantic segmentation head is introduced to integrate the detection and segmentation functions, and a multitask learning loss function is specifically designed to optimize the surgical instrument segmentation performance. The proposed segmentation model is validated on a dataset of intracranial surgical instruments provided by seven experts from Beijing Tiantan Hospital and achieved an mAP score of 93.5 %, Dice score of 82.49 %, and MIoU score of 85.48 %, demonstrating its universality and superiority. The experimental results demonstrate that the proposed model achieves good segmentation performance on surgical instruments compared to other advanced models and can provide a reference for developing intelligent medical robots.

Are associations between obesity and prostate cancer outcomes following radical prostatectomy the same in smokers and non-smokers? Results from the SEARCH Cohort.

PURPOSE: Obesity and smoking have been associated with poor prostate cancer (PC) outcomes. We investigated associations between obesity and biochemical recurrence (BCR), metastasis, castrate resistant-PC (CRPC), PC-specific mortality (PCSM), and all-cause mortality (ACM) and examined if smoking modified these associations. METHODS: We analyzed SEARCH Cohort data from men undergoing RP between 1990 and 2020. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between body mass index (BMI) as a continuous variable and weight status classifications (normal: 18.5 ≤ 25 kg/m2; overweight: 25-29.9 kg/m2; obese: ≥ 30 kg/m2) and PC outcomes. RESULTS: Among 6,241 men, 1,326 (21%) were normal weight, 2,756 (44%) overweight and 2159 (35%) obese; 1,841 (30%) were never-smokers, 2,768 (44%) former and 1,632 (26%) current-smokers. Among all men, obesity was associated with non-significant increased risk of PCSM, adj-HR = 1.71; 0.98-2.98, P = 0.057, while overweight and obesity were inversely associated with ACM, adj-HR = 0.75; 0.66-0.84, P < 0.001 and adj-HR = 0.86; 0.75-0.99, P = 0.033, respectively. Other associations were null. BCR and ACM were stratified for smoking status given evidence for interactions (P = 0.048 and P = 0.054, respectively). Among current-smokers, overweight was associated with an increase in BCR (adj-HR = 1.30; 1.07-1.60, P = 0.011) and a decrease in ACM (adj-HR = 0.70; 0.58-0.84, P < 0.001). Among never-smokers, BMI (continuous) was associated with an increase in ACM (adj-HR = 1.03; 1.00-1.06, P = 0.033). CONCLUSIONS: While our results are consistent with obesity as a risk factor for PCSM, we present evidence of effect modification by smoking for BCR and ACM highlighting the importance of stratifying by smoking status to better understand associations with body weight.

Diabetes and Prostate Cancer Outcomes in Men with Nonmetastatic Castration-Resistant Prostate Cancer: Results from the SEARCH Cohort.

BACKGROUND: The prognosis of diabetic men with advanced prostate cancer is poorly understood and understudied. Hence, we studied associations between diabetes and progression to metastases, prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) in men with nonmetastatic castration-resistant prostate cancer (nmCRPC). METHODS: Data from men diagnosed with nmCRPC between 2000 and 2017 at 8 Veterans Affairs Health Care Centers were analyzed using Cox regression to determine HRs and 95% confidence intervals (CI) for associations between diabetes and outcomes. Men with diabetes were classified according to: (i) ICD-9/10 codes only, (ii) two HbA1c values > 6.4% (missing ICD-9/10 codes), and (iii) all diabetic men [(i) and (ii) combined]. RESULTS: Of 976 men (median age: 76 years), 304 (31%) had diabetes at nmCRPC diagnosis, of whom 51% had ICD-9/10 codes. During a median follow-up of 6.5 years, 613 men were diagnosed with metastases, and 482 PCSM and 741 ACM events occurred. In multivariable-adjusted models, ICD-9/10 code-identified diabetes was inversely associated with PCSM (HR, 0.67; 95% CI, 0.48-0.92) while diabetes identified by high HbA1c values (no ICD-9/10 codes) was associated with an increase in ACM (HR, 1.41; 95% CI, 1.16-1.72). Duration of diabetes, prior to CRPC diagnosis was inversely associated with PCSM among men identified by ICD-9/10 codes and/or HbA1c values (HR, 0.93; 95% CI, 0.88-0.98). CONCLUSIONS: In men with late-stage prostate cancer, ICD-9/10 'code-identified' diabetes is associated with better overall survival than 'undiagnosed' diabetes identified by high HbA1c values only. IMPACT: Our data suggest that better diabetes detection and management may improve survival in late-stage prostate cancer.

Sex differences in the association of treatment-resistant schizophrenia and serum interleukin-6 levels.

BACKGROUND: Low-grade inflammation and altered inflammatory markers have been observed in treatment-resistant schizophrenia (TRS). Interleukin-6 (IL-6) is one of the pro-inflammatory cytokines linked with TRS and receives increasing attention. Previous studies showed that patients with TRS might have higher IL-6 levels compared with healthy individuals and treatment-responsive patients. Besides, emerging evidence has suggested that there are sex differences in the associations between IL-6 levels and various illnesses, including chronic hepatitis C, metabolic syndrome, etc.; however, there is limited study on TRS. In this present study, we aimed to compare the serum IL-6 levels of TRS and partially responsive schizophrenia (PRS) and explore potential sex differences in the association of TRS and IL-6 levels. METHODS: The study population consisted of a total of 90 patients with schizophrenia: 64 TRS patients (45.3% males and 54.7% females) and 26 PRS patients (46.2% males and 53.8% females). We measured serum IL-6 levels using enzyme-linked immunosorbent assay (ELISA) and analyzed them separately by gender, controlling for confounders (age, education, medication, body mass index, and PANSS scores) rigorously. RESULT: The results showed that patients with TRS had higher serum IL-6 levels than patients with PRS (p = 0.002). In females, IL-6 levels increased significantly in the TRS group compared with the PRS group (p = 0.005). And a positive correlation tendency was observed between IL-6 levels and PANSS general sub-scores (r = 0.31, p = 0.039), although this correlation was not significant after correcting for multiple comparisons. Whereas, there were no differences in IL-6 levels between the TRS and PRS (p = 0.124) in males. CONCLUSION: Our findings provided evidence supporting the hypothesis that the inflammatory response system (IRS) may play a role in the pathogenesis of TRS in a sex-dependent manner. In addition, sex differences in the immune dysfunction of individuals with schizophrenia cannot be neglected, and inflammation in male and female TRS should be discussed separately.

Quality-of-life impact of interstitial cystitis and other pelvic pain syndromes.

Objective: To compare health-related quality of life (HRQOL) and pelvic pain levels over time in patients with interstitial cystitis/bladder pain syndrome (IC/BPS) and those with other pelvic pain conditions (OPPC) including chronic prostatitis, dyspareunia, vaginismus, vulvodynia, and vulvar vestibulitis. Methods: We prospectively enrolled male and female patients from any Veterans Health Administration (VHA) center in the US. They completed the Genitourinary Pain Index (GUPI) quantifying urologic HRQOL and the 12-Item Short Form Survey version 2 (SF-12) quantifying general HRQOL at enrollment and 1 year later. Participants were classified by ICD diagnosis codes and confirmed by chart review to be IC/BPS or OPPC (308 and 85 patients respectively). Results: At baseline and follow-up, IC/BPS patients, on average, had worse urologic and general HRQOL than OPPC patients. IC/BPS patients demonstrated improvement in urologic HRQOL measures over the study but demonstrated no significant change in any general HRQOL measure suggesting a condition-specific impact. Patients with OPPC demonstrated similar improvements in urologic HRQOL but had deteriorating mental health and general HRQOL at follow-up suggesting a wider general HRQOL impact for these diseases. Conclusions: We found that patients with IC/BPS had worse urologic HRQOL compared to other pelvic conditions. Despite this, IC/BPS showed stable general HRQOL over time, suggesting a more condition-specific impact on HRQOL. OPPC patients showed deteriorating general HRQOL, suggesting more widespread pain symptoms in these conditions.

The Impact of Blue Light Cystoscopy Use Among Nonmuscle Invasive Bladder Cancer Patients in an Equal Access Setting: Implications on Recurrence and Time to Recurrence.

INTRODUCTION: Prior studies suggest that white light cystoscopy (WLC) alone can fail to detect cases of non-muscle invasive bladder cancer (NMIBC) vs. blue light cystoscopy (BLC). We describe bladder cancer outcomes and the impact of BLC among NMIBC patients in an equal access setting. MATERIALS AND METHODS: We assessed 378 NMIBC patients within the Veterans Affairs system that had a CPT code for BLC from December 1, 2014 to December 31, 2020. We determined recurrence rates and time to recurrence prior to BLC (ie, after previous WLC if available) and following BLC. We used the Kaplan-Meier method to estimate event-free survival and Cox regression to determine association between BLC and recurrence, progression, and overall survival; and further, whether these outcomes differed by race. RESULTS: Of 378 patients with complete data, 43 (11%) were Black and 300 (79%) White. Median follow-up was 40.7 months from bladder cancer diagnosis. Median time to first recurrence following BLC was longer vs. WLC alone (40 [33-NE] vs. 26 [17-39] months). Recurrence risk was significantly lower following BLC (Hazard Ratio [HR] 0.70; 95% Confidence Interval [CI], 0.54-0.90). There was no significant difference in recurrence (HR 0.69; 95% CI, 0.39-1.20), progression (HR 1.13; 95% CI, 0.32-3.96), and overall survival (HR 0.74; 95% CI, 0.31-1.77) following BLC by Black vs. White race. CONCLUSION: In this study from an equal access setting in the VA, we observed significantly decreased recurrence risk and prolonged time interval to recurrence following BLC vs. WLC alone. There was no difference in bladder cancer outcomes by race.

Case report: Anterior mediastinal mass in a patient with pleural effusion and dyspnea.

Background: Compound lymphoma is an uncommon type of lymphoid malignancy, and those consisting of concurrent B- and T-cell tumors are relatively rare. Case Summary: A 41-year-old man was presented with a 1-month history of progressively worsening cough, chest tightness, and dyspnea after exercise, which could be relieved following rest. Contrast-enhanced computed tomography scan demonstrated a 7.4 × 4.9 cm2 heterogeneous mass in the anterior mediastinum, where a large area of cystic liquid existed, and multiple enlarged lymph nodes in the mediastinum. Since the biopsy failed to yield an exact diagnosis and there was no sign of metastasis, the tumor was surgically resectioned. Surgical findings included obscure boundaries and consistent tumor stiffness with pericardial and pleural invasion. Further pathological examination combined with immunophenotype and gene rearrangement test found the mass composite of angioimmunoblastic T-cell lymphoma (AITL) and B-cell lymphoma. The patient recovered well after R0 resection and received chemotherapy with four cycles of CHOP combined with chidamide 2 weeks after surgery. The patient has had a complete response for over 60 months. Conclusion: In conclusion, we reported a composite lymphoma of AITL combined with B-cell lymphomas. Our experience provides the first successful attempt to treat this rare disease with combined surgery and chemotherapy.

Smoking and lower urinary tract symptoms in Reduction by Dutasteride of Prostate Cancer Events Trial.

BACKGROUND: Benign prostatic hyperplasia is common in older men, with many developing lower urinary tract symptoms (LUTS) that impair quality of life. Smoking has many well-established adverse effects, but its effects on benign prostatic hypertrophy (BPH) and associated LUTS are unclear. We sought to determine if smoking is a risk factor for the incidence of LUTS in asymptomatic men and for the progression of LUTS in symptomatic men. METHODS: We performed a post-hoc analysis of Reduction by Dutasteride of Prostate Cancer Events in 3060 "asymptomatic" men with baseline International Prostate Symptom Score (IPSS) < 8 and in 2198 symptomatic men with baseline IPSS ≥ 8 not taking 5α-reductase inhibitors or α-blockers. We used multivariable Cox regression models to assess associations between smoking status at baseline and LUTS incidence and progression. Among asymptomatic men, incident LUTS was defined as the first report of medical or surgical treatment for BPH, or sustained clinically significant LUTS (two reports of IPSS > 14). Among symptomatic men, LUTS progression was defined as IPSS increase of ≥4 points from baseline, surgical intervention for BPH, or starting a new BPH drug. RESULTS: Of 3060 asymptomatic men, 15% (n = 467) were current, 40% (n = 1231) former, and 45% (n = 1362) never-smokers. Of 2198 symptomatic men, 14% (n = 320) were current, 39% (n = 850) former, and 47% (n = 1028) never-smokers. In asymptomatic men, compared with never-smokers, current and former smoking at baseline were not associated with LUTS incidence (adjusted hazard ratio [adj-HR] = 1.08; 95% confidence interval [95% CI]: 0.78-1.48 and adj-HR = 1.01; 95% CI: 0.80-1.30). In symptomatic men, compared with never-smokers, current and former smoking at baseline were not associated with the progression of LUTS (adj-HR = 1.11; 95% CI: 0.92-1.33 and adj-HR = 1.03; 95% CI: 0.90-1.18). CONCLUSIONS: In REDUCE, smoking status was not associated with either incident LUTS in asymptomatic men or progression of LUTS in symptomatic men.

Magrolimab in Combination With Azacitidine in Patients With Higher-Risk Myelodysplastic Syndromes: Final Results of a Phase Ib Study.

PURPOSE: Magrolimab is a monoclonal antibody that blocks cluster of differentiation 47, a don't-eat-me signal overexpressed on cancer cells. Cluster of differentiation 47 blockade by magrolimab promotes macrophage-mediated phagocytosis of tumor cells and is synergistic with azacitidine, which increases expression of eat-me signals. We report final phase Ib data in patients with untreated higher-risk myelodysplastic syndromes (MDS) treated with magrolimab and azacitidine (ClinicalTrials.gov identifier: NCT03248479). PATIENTS AND METHODS: Patients with previously untreated Revised International Prognostic Scoring System intermediate-/high-/very high-risk MDS received magrolimab intravenously as a priming dose (1 mg/kg) followed by ramp-up to a 30 mg/kg once-weekly or once-every-2-week maintenance dose. Azacitidine 75 mg/m2 was administered intravenously/subcutaneously once daily on days 1-7 of each 28-day cycle. Primary end points were safety/tolerability and complete remission (CR) rate. RESULTS: Ninety-five patients were treated. Revised International Prognostic Scoring System risk was intermediate/high/very high in 27%, 52%, and 21%, respectively. Fifty-nine (62%) had poor-risk cytogenetics and 25 (26%) had TP53 mutation. The most common treatment-emergent adverse effects included constipation (68%), thrombocytopenia (55%), and anemia (52%). Median hemoglobin change from baseline to first postdose assessment was -0.7 g/dL (range, -3.1 to +2.4). CR rate and overall response rate were 33% and 75%, respectively. Median time to response, duration of CR, duration of overall response, and progression-free survival were 1.9, 11.1, 9.8, and 11.6 months, respectively. Median overall survival (OS) was not reached with 17.1-month follow-up. In TP53-mutant patients, 40% achieved CR with median OS of 16.3 months. Thirty-four patients (36%) had allogeneic stem-cell transplant with 77% 2-year OS. CONCLUSION: Magrolimab + azacitidine was well tolerated with promising efficacy in patients with untreated higher-risk MDS, including those with TP53 mutations. A phase III trial of magrolimab/placebo + azacitidine is ongoing (ClinicalTrials.gov identifier: NCT04313881 [ENHANCE]).

Surface Lattice Modulation through Chemical Delithiation toward a Stable Nickel-Rich Layered Oxide Cathode.

Nickel-rich layered oxides (NLOs) are considered as one of the most promising cathode materials for next-generation high-energy lithium-ion batteries (LIBs), yet their practical applications are currently challenged by the unsatisfactory cyclability and reliability owing to their inherent interfacial and structural instability. Herein, we demonstrate an approach to reverse the unstable nature of NLOs through surface solid reaction, by which the reconstructed surface lattice turns stable and robust against both side reactions and chemophysical breakdown, resulting in improved cycling performance. Specifically, conformal La(OH)3 nanoshells are built with their thicknesses controlled at nanometer accuracy, which act as a Li+ capturer and induce controlled reaction with the NLO surface lattices, thereby transforming the particle crust into an epitaxial layer with localized Ni/Li disordering, where lithium deficiency and nickel stabilization are both achieved by transforming oxidative Ni3+ into stable Ni2+. An optimized balance between surface stabilization and charge transfer is demonstrated by a representative NLO material, namely, LiNi0.83Co0.07Mn0.1O2, whose surface engineering leads to a highly improved capacity retention and excellent rate capability with a strong capability to inhibit the crack of NLO particles. Our study highlights the importance of surface chemistry in determining chemical and structural behaviors and paves a research avenue in controlling the surface lattice for the stabilization of NLOs toward reliable high-energy LIBs.

COLEC10 Induces Endoplasmic Reticulum Stress by Occupying GRP78 and Inhibits Hepatocellular Carcinoma.

Collectin subfamily member 10 (COLEC10), a C-type lectin mainly expressed in the liver, is involved in the development of hepatocellular carcinoma (HCC). However, its underlying molecular mechanism in HCC progression remains unknown. In this study, reduced COLEC10 expression in tumor tissues was validated using various HCC cohorts and was associated with poor patient prognosis. COLEC10 overexpression attenuated HCC cell growth and migration abilities in vitro and in vivo. We identified that COLEC10 was a novel interactor of 78-kDa glucose-regulated protein (GRP78), a master modulator of the unfolded protein response in the endoplasmic reticulum (ER). COLEC10 overexpression potentiated ER stress in HCC cells, as demonstrated by elevated expression levels of phosphorylated protein kinase RNA-like ER kinase, phosphorylated inositol-requiring protein 1α, activating transcription factor 4, DNA damage-inducible transcript 3, and X-box-binding protein 1s. The ER in COLEC10-overexpressing cells also showed a dilated and fragmented pattern. Mechanistically, COLEC10 overexpression increases GRP78 occupancy through direct binding by the C-terminal carbohydrate recognition domain in the ER, which released and activated the ER stress transducers protein kinase RNA-like ER kinase and phosphorylated inositol-requiring protein 1α, triggering the unfolded protein response activity. COLEC10-overexpressing HCC cells generated a relatively high reactive oxygen species level and switched to apoptotic cell death under sorafenib-treated conditions. Our study provides the first novel view that COLEC10 inhibits HCC progression by regulating GRP78-mediated ER stress signaling and may serve as a promising therapeutic and prognostic biomarker.