A 2-year prospective evaluation of the Prostate Health Index in guiding biopsy decisions in a large cohort.

OBJECTIVES: To prospectively evaluate how the Prostate Health Index (PHI) impacts on clinical decision in a real-life setting for men with a prostate-specific antigen (PSA) level between 4 and 10 ng/mL and normal digital rectal examination. PATIENTS AND METHODS: Since 2016, the PHI has been available at no cost to eligible men in all Hong Kong public hospitals. All eligible patients who received PHI testing in all public Urology units (n = 16) in Hong Kong between May 2016 and August 2017 were prospectively included and followed up. All included men had a PHI test, with its result and implications explained; the subsequent follow-up plan was then decided via shared decision-making with urologists. Patients were followed up for 2 years, with outcomes including prostate biopsy rates and biopsy findings analysed in relation to the initial PHI measurements. RESULTS: A total of 2828 patients were followed up for 2 years. The majority (82%) had PHI results in the lower risk range (score <35). Knowing the PHI findings, 83% of the patients with elevated PSA decided not to undergo biopsy. In all, 11% and 45% opted for biopsy in the PHI score <35 and ≥35 groups, respectively. The initial detection rate of International Society of Urological Pathology (ISUP) Grade Group (GG) ≥2 cancer was higher in the PHI score ≥35 group (23%) than in the PHI score <35 group (7.9%). Amongst patients with no initial positive biopsy findings, the subsequent positive biopsy rate for ISUP GG ≥2 cancer was higher in the PHI score ≥35 group (34%) than the PHI score <35 group (13%) with a median follow-up of 2.4 years. CONCLUSION: In a real-life setting, with the PHI incorporated into the routine clinical pathway, 83% of the patients with elevated PSA level decided not to undergo prostate biopsy. The PHI pathway also improved the high-grade prostate cancer detection rate when compared to PSA-driven strategies. Higher baseline PHI predicted subsequent biopsy outcome at 2 years. The PHI can serve as a tool to individualise biopsy decisions and frequency of follow-up visits.

Metformin reduces the clonal fitness of Dnmt3aR878H hematopoietic stem and progenitor cells by reversing their aberrant metabolic and epigenetic state.

Clonal hematopoiesis (CH) arises when a hematopoietic stem cell (HSC) acquires a mutation that confers a competitive advantage over wild-type (WT) HSCs, resulting in its clonal expansion. Individuals with CH are at an increased risk of developing hematologic neoplasms and a range of age-related inflammatory illnesses1-3. Therapeutic interventions that suppress the expansion of mutant HSCs have the potential to prevent these CH-related illnesses; however, such interventions have not yet been identified. The most common CH driver mutations are in the DNA methyltransferase 3 alpha (DNMT3A) gene with arginine 882 (R882) being a mutation hotspot. Here we show that murine hematopoietic stem and progenitor cells (HSPCs) carrying the Dnmt3aR878H/+ mutation, which is equivalent to human DNMT3AR882H/+, have increased mitochondrial respiration compared with WT cells and are dependent on this metabolic reprogramming for their competitive advantage. Importantly, treatment with metformin, an oral anti-diabetic drug with inhibitory activity against complex I in the electron transport chain (ETC), reduced the fitness of Dnmt3aR878H/+ HSCs. Through a multi-omics approach, we discovered that metformin acts by enhancing the methylation potential in Dnmt3aR878H/+ HSPCs and reversing their aberrant DNA CpG methylation and histone H3K27 trimethylation (H3K27me3) profiles. Metformin also reduced the fitness of human DNMT3AR882H HSPCs generated by prime editing. Our findings provide preclinical rationale for investigating metformin as a preventive intervention against illnesses associated with DNMT3AR882 mutation-driven CH in humans.

Microfluidic Device-Based Virus Detection and Quantification in Future Diagnostic Research: Lessons from the COVID-19 Pandemic.

The global economic and healthcare crises experienced over the past three years, as a result of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has significantly impacted the commonplace habits of humans around the world. SARS-CoV-2, the virus responsible for the coronavirus 2019 (COVID-19) phenomenon, has contributed to the deaths of millions of people around the world. The potential diagnostic applications of microfluidic devices have previously been demonstrated to effectively detect and quasi-quantify several different well-known viruses such as human immunodeficiency virus (HIV), influenza, and SARS-CoV-2. As a result, microfluidics has been further explored as a potential alternative to our currently available rapid tests for highly virulent diseases to better combat and manage future potential outbreaks. The outbreak management during COVID-19 was initially hindered, in part, by the lack of available quantitative rapid tests capable of confirming a person's active infectiousness status. Therefore, this review will explore the use of microfluidic technology, and more specifically RNA-based virus detection methods, as an integral part of improved diagnostic capabilities and will present methods for carrying the lessons learned from COVID-19 forward, toward improved diagnostic outcomes for future pandemic-level threats. This review will first explore the context of the COVID-19 pandemic and how diagnostic technology was shown to have required even greater advancements to keep pace with the transmission of such a highly infectious virus. Secondly, the historical significance of integrating microfluidic technology in diagnostics and how the different types of genetic-based detection methods may vary in their potential practical applications. Lastly, the review will summarize the past, present, and future potential of RNA-based virus detection/diagnosis and how it might be used to better prepare for a future pandemic.

S-methyl cysteine sulfoxide and its potential role in human health: a scoping review.

Higher intakes of cruciferous and allium vegetables are associated with a lower risk of cardiometabolic-related outcomes in observational studies. Whilst acknowledging the many healthy compounds within these vegetables, animal studies indicate that some of these beneficial effects may be partially mediated by S-methyl cysteine sulfoxide (SMCSO), a sulfur-rich, non-protein, amino acid found almost exclusively within cruciferous and alliums. This scoping review explores evidence for SMCSO, its potential roles in human health and possible mechanistic action. After systematically searching several databases (EMBASE, MEDLINE, SCOPUS, CINAHL Plus Full Text, Agricultural Science), we identified 21 original research articles meeting our inclusion criteria. These were limited primarily to animal and in vitro models, with 14/21 (67%) indicating favorable anti-hyperglycemic, anti-hypercholesterolemic, and antioxidant properties. Potential mechanisms included increased bile acid and sterol excretion, altered glucose- and cholesterol-related enzymes, and improved hepatic and pancreatic ß-cell function. Raising antioxidant defenses may help mitigate the oxidative damage observed in these pathologies. Anticancer and antibacterial effects were also explored, along with one steroidogenic study. SMCSO is frequently overlooked as a potential mediator to the benefits of sulfur-rich vegetables. More research into the health benefits of SMCSO, especially for cardiometabolic and inflammatory-based pathology, is warranted. Human studies are especially needed.

SARS-CoV-2 infection correlates with male benign prostatic hyperplasia deterioration.

INTRODUCTION: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) affects extra-respiratory systems, with small-scale studies showing worsened male lower urinary tract symptoms (LUTS) after coronavirus disease 2019 (COVID-19). This study explores the correlation between SARS-CoV-2 infection and male benign prostatic hyperplasia (BPH) complications using large-scale real world data. MATERIALS AND METHODS: All male patients attending the public healthcare system in Hong Kong receiving alpha-blocker monotherapy for LUTS from 2021 to 2022 were included in this study. Patients with and without positive polymerase chain reaction (PCR) test for SARS-CoV-2 are selected as the exposure group and control group, respectively. Baseline characteristics are retrieved, with propensity score matching performed to ensure balance of covariates between the two groups. BPH complications were then compared and subgroup analyses were performed. RESULTS: After propensity score matching, 17,986 patients were included for analysis, among which half had PCR-confirmed SARS-CoV-2 infection (n = 8993). When compared to controls, the SARS-CoV-2 group demonstrated statistically significant higher incidence of retention of urine (4.55% vs. 0.86%, p < 0.001), haematuria (1.36% vs. 0.41%, p < 0.001), clinical urinary tract infection (UTI) (4.31% vs. 1.49%, p < 0.001), culture-proven bacteriuria (9.02% vs. 1.97%, p < 0.001) and addition of 5ARI (0.50% vs. 0.02%, p < 0.001). Subgroup analysis demonstrated similar differences across different age groups. There are no statistically significance differences in incidence of retention, haematuria, or addition of 5ARI across different COVID-19 severities. CONCLUSIONS: SARS-CoV-2 infection is associated with increased incidence of urinary retention, haematuria, UTI and the addition of combination therapy in the short term, regardless of COVID-19 severity. This is the largest study demonstrating the detrimental urological effects of SARS-CoV-2 infection.

Toward a quantitative interfacial description of solvation for Li metal battery operation under extreme conditions.

The future application of Li metal batteries (LMBs) at scale demands electrolytes that endow improved performance under fast-charging and low-temperature operating conditions. Recent works indicate that desolvation kinetics of Li+ plays a crucial role in enabling such behavior. However, the modulation of this process has typically been achieved through inducing qualitative degrees of ion pairing into the system. In this work, we find that a more quantitative control of the ion pairing is crucial to minimizing the desolvation penalty at the electrified interface and thus the reversibility of the Li metal anode under kinetic strain. This effect is demonstrated in localized electrolytes based on strongly and weakly bound ether solvents that allow for the deconvolution of solvation chemistry and structure. Unexpectedly, we find that maximum degrees of ion pairing are suboptimal for ultralow temperature and high-rate operation and that reversibility is substantially improved via slight local dilution away from the saturation point. Further, we find that at the optimum degree of ion pairing for each system, weakly bound solvents still produce superior behavior. The impact of these structure and chemistry effects on charge transfer are then explicitly resolved via experimental and computational analyses. Lastly, we demonstrate that the locally optimized diethyl ether-based localized-high-concentration electrolytes supports kinetic strained operating conditions, including cycling down to -60 °C and 20-min fast charging in LMB full cells. This work demonstrates that explicit, quantitative optimization of the Li+ solvation state is necessary for developing LMB electrolytes capable of low-temperature and high-rate operation.

Efficacy and feasibility of 3D printed redesigned Venezia™ applicator for treating advanced cervix and recurrent endometrial cancer.

PURPOSE: Venezia™ is an interstitial brachytherapy applicator for treating advanced cervical and vaginal vault recurrent cancer. However, there are limitations that lead to suboptimal target coverage. 3D printing introduction allows the redesign of Venezia™ for bulky and irregular-shaped tumors. METHODS: This study first describes three new designs included: 1) add-on needles template allowed for an extra layer of straight and oblique needles, 2) redesigned vaginal cap so straight and oblique needles can be used together and 3) redesigned central tube allowed vaginal vault interstitial needle insertion. Drawbacks to original Venezia™ and rationale for using these new designs were discussed. Dosimetric analysis by comparing the original Venezia™ with new design for 10 cases in Oncentra treatment planning system v4.5 (Elekta, Stockholm, Sweden) to observe the dose differences in gross tumor volume (GTV), high risk clinical target volume (HRCTV), intermediate clinical target volume (IRCTV) and organs at risk. RESULTS: For the dosimetric comparison, there were statistically significantly increased median minimal dose to 98% (D98%) of GTV, 90% (D90%) of HRCTV, and IRCTV for the new design with p-value of 0.008, 0.005 and 0.0018, respectively. Comparing the physical dose of D98% of GTV, D90% of HRCTV, and IRCTV when using the new design, it averagely increased by 11.7%, 8.0%, 19.4%, respectively per fraction. CONCLUSIONS: Dosimetric comparison revealed the new designs increased the dose to GTV, HRCTV and IRCTV and fulfilled the dose constraints of bladder, rectum and sigmoid. The 3D printed new design is biocompatible, inexpensive and can be patient specific.

Chemoimmunotherapy in patients with extensive-stage small cell lung cancer and a poor performance status.

BACKGROUND: Immune checkpoint inhibitor combined with platinum-etoposide is the standard first-line therapy for patients with extensive-stage small cell lung cancer (ES-SCLC). The phase 3 clinical trials that led to the approval of chemoimmunotherapy in ES-SCLC excluded patients who had an Eastern Cooperative Group (ECOG) performance status (PS) of 2-3. Therefore, data on the efficacy of chemoimmunotherapy in patients with an ECOG PS of 2-3 are limited. METHODS: A retrospective analysis was performed on patients diagnosed with ES-SCLC who received chemoimmunotherapy (atezolizumab or durvalumab) within the Mayo Clinic Health System between January 2016 and January 2021. The objective of this study was to compare the overall survival (OS), progression-free survival (PFS), and best clinical response to therapy in patients with an ECOG PS of 0-1 vs. patients with an ECOG PS of 2-3 who received chemoimmunotherapy for newly diagnosed ES-SCLC. RESULTS: In total, 82 patients were included in the study. The mean ± standard deviation age was 68.1 ± 8.3 years. Of these, 56 patients were identified with an ECOG PS of 0-1, and 26 patients were identified with an ECOG PS of 2-3. The median PFS was similar regardless of ECOG PS (5.8 months [95% CI, 4.3-6.0 months] in the ECOG PS 0-1 group vs. 4.1 months [95% CI, 3.8-6.9 months] in the ECOG PS 2-3; p = .2994). The median OS was also similar regardless of ECOG PS (10.6 months [95% CI, 8.4-13.4 months] in the ECOG PS 0-1 group vs. 9.3 months [95% CI, 4.9-12.8 months]; p = .2718) in the ECOG PS 2-3 group. CONCLUSIONS: The study results demonstrated no significant difference in PFS or OS among the ECOG PS 2-3 and ECOG PS 0-1 groups. Therefore, chemoimmunotherapy should be considered for patients who have ES-SCLC with an ECOG PS of 2-3.

Well-being factors associated with confidence in providing calm, compassionate care in pediatric residents.

OBJECTIVE: Engagement in calm, compassionate care (CCC) is important in fostering patient-centered care. We aimed to study factors which predict confidence in providing CCC in pediatric residents. METHODS: We performed a retrospective, multi-center, cohort study utilizing data from the Pediatric Resident Burnout and Resilience Study (PRB-RSC) from 2016 to 2018. The Calm Compassionate Care Scale (CCCS) was used to assess confidence in delivering CCC. We examined cross-sectional associations between CCC, demographic measures, programmatic features, and psychological scales. RESULTS: The following showed significant positive associations with confidence in providing CCC: Cognitive and Affective Mindfulness Scale, Neff's Self Compassion, Patient Reported Outcomes Measures-mental health, and Interpersonal Reactivity Index-empathetic concern. For the Maslach Burnout Index subscales, decreased personal accomplishment, increased emotional exhaustion, and increased depersonalization showed significant negative associations. CONCLUSIONS: We found that several well-being measures and an increased sense of personal accomplishment are associated with increased confidence in providing CCC. These findings underscore the interrelatedness of these measures and highlight the importance of personal accomplishment as a positive factor in trainee development. PRACTICE IMPLICATIONS: Program level interventions that decrease trainee burnout and enhance resiliency as well as support trainees' development of empathy and compassion may help trainees develop skills that promote patient-centered, compassionate care.

Progression of fibrosis in liver transplant recipients with hepatitis C before and after sustained virologic response.

BACKGROUND: Liver transplant (LT) recipients with untreated hepatitis C (HCV) are at risk for cirrhosis graft failure. The advent of direct acting antiviral agents (DAA) has improved outcomes in HCV. AIMS: We aim to examine liver transplant outcomes and allograft fibrosis development/progression after sustained virologic response (SVR). METHODS: We performed a retrospective cohort study of 226 consecutive liver transplant recipients with HCV from 2007 to 2018. The cohort was split into transplants pre (Group A) and post (Group B) 2014 to reflect the introduction of DAAs. Fibrosis was monitored with liver biopsy and non-invasive imaging. RESULTS: Group B had significantly improved HCV treatment rates and earlier SVR compared to Group A, with a cumulative incidence rate of SVR at 2 years of 86.7% versus 15.4% (HR = .11, p < .001). Prior to achieving SVR, Group A demonstrated worsening of fibrosis stage per year (+.21, p < .001) whereas Group B showed minimal change on protocol annual biopsy (-.02, p = .80). After SVR, most patients were followed non-invasively and demonstrated stable or improved fibrosis stage over time. Patients undergoing transient elastography showed regression in fibrosis stage per year (-.19, p < .001). CONCLUSION: HCV patients undergoing LT after 2014 had higher rates of SVR and improved clinically relevant transplant outcomes, namely less graft loss and death relating to HCV. Fibrosis progression halted or improved after SVR in both cohorts, suggesting that LT recipients with SVR do not require fibrosis monitoring even with established fibrosis prior to SVR.

Chemoimmunotherapy as the First-Line Treatment for Patients With Extensive-Stage Small-Cell Lung Cancer and an ECOG Performance Status 2 or 3.

BACKGROUND: Studies demonstrated that chemoimmunotherapy prolongs progression-free survival (PFS) and overall survival (OS) in patients with extensive-stage small-cell lung cancer (ES-SCLC) and an Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1. However, there is little data regarding chemoimmunotherapy in patients with ES-SCLC and an ECOG PS 2 or 3. This study aims to evaluate the benefits of chemoimmunotherapy compared to chemotherapy in the first-line treatment of patients with ES-SCLC and ECOG PS 2 or 3. MATERIALS AND METHODS: This retrospective study analyzed 46 adults treated at Mayo Clinic between 2017 and 2020 with de novo ES-SCLC and an ECOG PS 2 or 3. Twenty patients received platinum-etoposide and 26 patients received platinum-etoposide and atezolizumab. Progression-free survival (PFS) and Overall survival (OS) were calculated using Kaplan-Meier methods. RESULTS: PFS was longer in the chemoimmunotherapy group compared to the chemotherapy group, 4.1 months (95% confidence interval [CI]: 3.8-6.9) vs. 3.2 months (95% CI: 0.6-4.8), respectively; P = 0.0491. However, there was no statistically significant difference in the OS between the chemoimmunotherapy and chemotherapy group, 9.3 months (95% CI: : 4.9-12.8) vs. 7.6 months (95% CI: 0.6-11.9), respectively; P = .21. CONCLUSION: Chemoimmunotherapy prolongs PFS compared to chemotherapy in patients with newly diagnosed ES-SCLC and an ECOG PS 2 or 3.  No OS difference was observed among the chemoimmunotherapy and chemotherapy groups; nevertheless, this may be attributed due to the small sample size of the study.

A prospective evaluation of the effect of finasteride on prostate health index (phi).

PURPOSE: 5-alpha reductase inhibitor (5ARI) reduces prostate-specific antigen (PSA) by half but its effect on prostate health index (phi) is unknown. This study aims to investigate this effect and to enable accurate interpretation of phi in men with elevated PSA and on 5ARI. METHODS: This is a prospective study evaluating the effect of finasteride on PSA, free PSA (fPSA), [ - 2]proPSA (p2PSA) and phi at 6 and 12 moths in men with PSA 4-20 ng/mL, no prior 5ARI use, and one negative prostate biopsy within 6 months before recruitment. The 5ARI Finasteride (5 mg/day) for 1 year was offered if International Prostatic Symptom Score (IPSS) was ≥ 8 at baseline. 5ARI group included patients taking finasteride, while control group included patients not on finasteride. The blood results were compared with t-test between baseline and different time points in each group and between groups at 1 year. RESULTS: 164 men fit the inclusion criteria and 150 were analyzed. In 5ARI group (n = 100) at 1 year, mean PSA reduced by 51.4% from 8.9(± SD 3.7) to 4.4(± SD 2.8)ng/mL (paired t-test, p < 0.001), fPSA reduced by 52.4% from 1.6(± 0.6) to 0.8(± 0.4)ng/mL (p < 0.001), p2PSA reduced by 55.3% from 18.4(± 8.8) to 8.3(± 5.6)pg/mL (p < 0.001), and phi reduced by 34.2% from 33.7(± 11.9) to 22.4(± 12.5) (p < 0.001). PSA and phi values in the control group remained static over 1 year and significantly higher than those in 5ARI group. CONCLUSION: This study demonstrated p2PSA and phi are reduced by about 55% and 34% in men on 5ARI. A conversion factor of division by 0.66 is needed for phi in men on finasteride to allow the interpretation and use of phi in men on 5ARI.

A Three-Dimensional ResNet and Transformer-Based Approach to Anomaly Detection in Multivariate Temporal-Spatial Data.

Anomaly detection in multivariate time series is an important problem with applications in several domains. However, the key limitation of the approaches that have been proposed so far lies in the lack of a highly parallel model that can fuse temporal and spatial features. In this paper, we propose TDRT, a three-dimensional ResNet and transformer-based anomaly detection method. TDRT can automatically learn the multi-dimensional features of temporal-spatial data to improve the accuracy of anomaly detection. Using the TDRT method, we were able to obtain temporal-spatial correlations from multi-dimensional industrial control temporal-spatial data and quickly mine long-term dependencies. We compared the performance of five state-of-the-art algorithms on three datasets (SWaT, WADI, and BATADAL). TDRT achieves an average anomaly detection F1 score higher than 0.98 and a recall of 0.98, significantly outperforming five state-of-the-art anomaly detection methods.

Prognostic factors in resected pulmonary carcinoid tumors: A retrospective study with 10 years of follow­up.

The objective of the present study was to characterize the difference in 10-year carcinoid-specific survival (CSS) and disease-free survival (DFS) among patients with resected pulmonary typical carcinoid (TC) and atypical carcinoid (AC). Patients diagnosed with pulmonary carcinoid tumors (PCT) between January 1, 1997, and December 31, 2016, were identified. All patients underwent video-assisted thoracoscopic surgery or thoracotomy with thoracic lymphadenectomy. Cumulative CSS was estimated using the Kaplan-Meier model. The analysis of hazard ratios (HRs) and 95% confidence intervals (CIs) was performed using univariate and multivariate Cox proportional hazards models. A total of 404 patients with PCT were included in the present study. The 10-year CSS and DFS rates of patients with AC were significantly worse than those of patients with TC (49.1 vs. 86.8% and 52.2 vs. 92.6%, respectively; P<0.001). In the CSS multivariate analysis, older age and lymph node involvement (HR, 2.45; P=0.022) were associated with worse survival in AC, while age, male sex, M1 stage, cigarette smoking and inadequate N2 lymphadenectomy were associate with worse survival in TC. In the recurrence multivariate analysis, N1-3 stage (HR, 2.62; 95% CI, 1.16-5.95; P=0.018) and inadequate N2 lymphadenectomy (HR, 2.13; 95% CI, 1.04-4.39; P=0.041) were associated with an increase in recurrence in AC, while male sex (HR, 3.72; 95% CI, 1.33-10.42; P=0.010) and M1 stage (HR, 14.93; 95% CI, 4.77-46.77; P<0.001) were associated with an increase in recurrence in TC. In conclusion, patients with AC tumors had significantly worse CSS and DFS rates compared with patients with TC. The degree of nodal involvement in AC was a prognostic marker, in contrast to that in TC. Inadequate lymphadenectomy increased the risk of recurrence in AC and mortality in TC, although surgical approaches did not have a significant impact. The present study therefore emphasizes the importance of mediastinal nodal dissection in patients with PCTs.

Multilevel Graph Matching Networks for Deep Graph Similarity Learning.

While the celebrated graph neural networks (GNNs) yield effective representations for individual nodes of a graph, there has been relatively less success in extending to the task of graph similarity learning. Recent work on graph similarity learning has considered either global-level graph-graph interactions or low-level node-node interactions, however, ignoring the rich cross-level interactions (e.g., between each node of one graph and the other whole graph). In this article, we propose a multilevel graph matching network (MGMN) framework for computing the graph similarity between any pair of graph-structured objects in an end-to-end fashion. In particular, the proposed MGMN consists of a node-graph matching network (NGMN) for effectively learning cross-level interactions between each node of one graph and the other whole graph, and a siamese GNN to learn global-level interactions between two input graphs. Furthermore, to compensate for the lack of standard benchmark datasets, we have created and collected a set of datasets for both the graph-graph classification and graph-graph regression tasks with different sizes in order to evaluate the effectiveness and robustness of our models. Comprehensive experiments demonstrate that MGMN consistently outperforms state-of-the-art baseline models on both the graph-graph classification and graph-graph regression tasks. Compared with previous work, multilevel graph matching network (MGMN) also exhibits stronger robustness as the sizes of the two input graphs increase.

Ultralow-Temperature Li/CFx Batteries Enabled by Fast-Transport and Anion-Pairing Liquefied Gas Electrolytes.

Lithium fluorinated-carbon (Li/CFx ) is one of the most promising chemistries for high-energy-density primary energy-storage systems in applications where rechargeability is not required. Though Li/CFx demonstrates high energy density (>2100 Wh kg-1 ) under ambient conditions, achieving such a high energy density when exposed to subzero temperatures remains a challenge, particularly under high current density. Here, a liquefied gas electrolyte with an anion-pair solvation structure based on dimethyl ether with a low melting point (-141 °C) and low viscosity (0.12 mPa s, 20 °C), leading to high ionic conductivity (>3.5 mS cm-1 ) between -70 and 60 °C is reported. Besides that, through systematic X-ray photoelectron spectroscopy integrated with transmission electron microscopy characterizations, the interface of CFx is evaluated for low-temperature performance. The fast transport and anion-pairing solvation structure of the electrolyte are concluded to bring about reduced charge-transfer resistance at low temperatures, which results in significantly enhanced performance of Li/CFx cells (1690 Wh kg-1 , -60 °C based on active materials). Utilizing 50 mg cm-2 loading electrodes, the Li/CFx still displays 1530 Wh kg-1 at -60 °C. This work provides insights into the electrolyte design that may overcome the operational limits of batteries in extreme environments.

Dosimetric benefits of 3D-printed modulated electron bolus following lumpectomy and whole-breast radiotherapy for left breast cancer.

Radiotherapy with electrons is commonly applied to the tumor bed after whole-breast radiotherapy following breast conservation surgery for breast cancer patients. However, the radiation dose to adjacent organs-at-risk (OARs) and conformity of planning target volume (PTV) cannot be optimized. In this study, we examine the feasibility of using modulated electron bolus (MEB) to improve PTV conformity and reduce the dose to these OARs. Twenty-seven patients with left breast cancer were retrospectively selected in this study. For each patient, a tangential photon plan in RayStation treatment planning system with prescription of 26 Gy in 5 fractions was created as base plan. Two electron plans, one without bolus and one with MEB using Adaptiiv software based on the PTV were created. Various dosimetric parameters of OARs including left lung, heart, left anterior descending artery (LAD) and ribs and the conformity indices of PTV of these 2 electron plans together with the base plans were compared. Statistically significant decreases in the dosimetric parameters (V5Gy, V10Gy, V20Gy, and mean dose) of the ipsilateral left lung and the heart were observed with MEB. The median maximum dose to the LAD and the ribs decreased by 6.2% and 4.5% respectively. The median conformity index was improved by 14.3% with median increases of monitor units by 1.7%. Our results show that MEB is feasible resulting in reduction of doses to the predefined OARs and an improved conformity of PTV. By using 3D printing, MEB might be considered as an alternative to conventional electron boost.

Increased nitrate intake from beetroot juice does not alter soluble cellular adhesion molecules and circulating inflammatory cytokines in individuals with treated hypertension: a randomised, controlled trial.

Dietary nitrate, found predominantly in green leafy vegetables and other vegetables such as radish, celery, and beetroot, has been shown to beneficially modulate inflammatory processes and immune cell function in animals and healthy individuals. The impact of increased nitrate intake on soluble inflammatory mediators in individuals with hypertension is unclear. We assessed whether the daily consumption of dietary nitrate via beetroot juice for 1-week lowered levels of circulating inflammatory markers in men and women with treated hypertension. Twenty-seven male and female participants were recruited to a randomized, placebo-controlled, double-blind crossover trial. The effects of 1-week intake of nitrate-rich beetroot juice versus 1-week intake of nitrate-depleted beetroot juice (placebo) were investigated. Plasma concentrations of circulating soluble adhesion molecules (ICAM-1, VCAM-1, CD62E, CD62P), inflammatory cytokines (IL-1ß, IL-6, IL-10, IL-12p70, TNF-α) and chemokines (IL-8, MCP-1) were measured by multiplex flow cytometric bead array in samples collected on day 7 of each intervention period. Other outcomes included alterations in nitrate metabolism assessed by measuring nitrate and nitrite concentrations in plasma, saliva, and urine. One week of beetroot juice did not alter levels of the soluble adhesion markers or cytokines assessed. A 7-fold increase in salivary nitrite, an 8-fold increase in salivary nitrate, a 3-fold increase in plasma nitrate and nitrite, and a 4-fold increase in urinary nitrate and nitrite compared to the placebo was observed (p < 0.001 for all comparisons). Increasing dietary nitrate consumption over 7 days is not effective in reducing soluble inflammatory mediators in individuals with treated hypertension. This trial was registered at anzctr.org.au as ACTRN 12613000116729.

Targeting STAT5 Signaling Overcomes Resistance to IDH Inhibitors in Acute Myeloid Leukemia through Suppression of Stemness.

Mutant isocitrate dehydrogenase 1 (IDH1) and IDH2 block the differentiation of acute myeloid leukemia (AML) cells through production of R-2-hydroxyglutarate (R-2-HG). IDH inhibitors can induce differentiation of AML cells by lowering R-2-HG but have limited clinical efficacy as single agents. Here, we performed a genome-wide CRISPR knockout screen in an Idh1-mutated hematopoietic progenitor cell line to identify genes that increased the differentiation response to ivosidenib, an IDH1 inhibitor. The screen identified C-type lectin member 5a (Clec5a), which encodes a spleen tyrosine kinase (SYK)-coupled surface receptor, as one of the top hits. Knockout of Clec5a and Syk rendered cells more sensitive to ivosidenib-induced differentiation through a reduction in STAT5-dependent expression of stemness-related genes, including genes in the homeobox (HOX) family. Importantly, direct inhibition of STAT5 activity was sufficient to increase the differentiation response to IDH inhibitors in primary human IDH1- and IDH2-mutated AML cells, including those harboring mutations in receptor tyrosine kinase (RTK) and MAPK genes that have been linked to drug resistance. In patient-derived xenograft models of IDH1-mutated AML, combination treatment with ivosidenib and the STAT5 inhibitor pimozide was superior to each agent alone in inducing differentiation in leukemic cells without compromising normal hematopoiesis. These findings demonstrate that STAT5 is a critical mediator of resistance to IDH inhibitors and provide the rationale for combining STAT5 and IDH inhibitors in the treatment of IDH-mutated AML. SIGNIFICANCE: A CRISPR knockout screen identifies a mechanism of resistance to IDH inhibitors in AML involving activated STAT5 signaling, suggesting a potential strategy to improve the clinical efficacy of IDH inhibitors.