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Background: This study aims to tackle the lack of freshwater ecotoxicological effect factors (EFs) crucial for determining freshwater ecotoxicity characterization factors (CFs) using the widely accepted scientific consensus USEtox model for ecotoxicity impact characterization. The objectives are: (1) to offer a collection of experimental EFs to support USEtox ecotoxicity characterization factor computations and (2) to contrast ecotoxicity data produced by various quantitative structure–activity relationship (QSAR) models against experimental data. Results: Experimental ecotoxicity data were gathered from the REACH database and CompTox Version 2.1.1, which includes toxicity information from ToxValDB v9.4. QSAR-driven ecotoxicity data were extracted from ECOSAR v1.11 and T.E.S.T. v5.1.2. The experimental and estimated data underwent a harmonization process to ensure consistency. Subsequently, aquatic ecotoxicological EFs were determined. The merged REACH and CompTox databases list EFs for 11,295 substances, each identified by a unique CAS number. Among these, the USEtox database already catalogs 2426 substances with freshwater ecotoxicological EFs. This study expanded on that by calculating EFs for an additional 8869 substances. Using estimated data, EFs were determined for 6029 chemicals based on ECOSAR data and 6762 chemicals using TEST data. Conclusions: This study calculated EFs for an additional 8869 substances, thereby broadening their inclusion in LCA evaluations. When integrated with the USEtox EFs database, this research encompasses 11,368 chemicals. The high correlation observed between experimental EFs and those in the USEtox database lends significant confidence to the calculations for chemicals not listed in USEtox. Conversely, the low correlation between estimated EFs and those in USEtox suggests limited confidence in calculations based on estimated data. Furthermore, the disparity in correlations between EFs calculated using ECOSAR and TEST indicates that different QSARs can yield varied results. This discrepancy underscores the need for caution when relying on estimated data. Given that EFs are contingent on data availability, it is imperative to periodically update EFs as new data emerges. [ABSTRACT FROM AUTHOR]

Purpose: This paper addresses the lack of ecotoxicity characterization factors (CFs) for persistent and mobile (PM) chemicals in life cycle assessment. The specific aims are (1) to provide CFs for 64 selected chemicals and benchmark them against the USEtox database, (2) to propose an ecotoxicity data harmonization strategy, and (3) to analyze the influence of ecotoxicity data sources and data harmonization strategies. Methods: Sixty-four per- and polyfluoroalkyl substances (PFAS), triazines, and triazoles were selected. An ecotoxicity data harmonization strategy was developed to ensure data consistency. A screening strategy for including transformation products was also developed. Existing CFs in the USEtox organic substances database (version 2.01) were identified, and new CFs were calculated based on available data sources. The USEtox model (version 2.13) was used for calculations, and the collected ecotoxicity data from different sources were varied to test their influence. Results and discussion: The ecotoxicity data harmonization strategy excluded a considerable amount of incompatible data. To the list of 64 chemicals, 3 transformation products were added. Out of the 67 chemicals, experimental ecotoxicity data were available for 47, leading to the use of in silico tools and average values to fill data gaps for 20 chemicals. CFs for 67 chemicals could thus be provided. Comparing CFs calculated based on experimental and estimated ecotoxicity data reveals that the estimated data leads to considerably different CF values. Conclusions: The paper provides strategies for ecotoxicity data harmonization and the inclusion of transformation products. The limited availability of experimental ecotoxicity data and differing results of the applied estimation methods highlight the need for further development of estimation methods. In addition, further development in including transformation products is recommended, which is particularly relevant for PM chemicals. [ABSTRACT FROM AUTHOR]

Background: CC-115, a dual mTORC1/2 and DNA-PK inhibitor, has promising antitumour activity when combined with androgen receptor (AR) inhibition in pre-clinical models. Methods: Phase 1b multicentre trial evaluating enzalutamide with escalating doses of CC-115 in AR inhibitor-naive mCRPC patients (n = 41). Primary endpoints were safety and RP2D. Secondary endpoints included PSA response, time-to-PSA progression, and radiographic progression. Results: Common adverse effects included rash (31.7% Grades 1–2 (Gr); 31.7% Gr 3), pruritis (43.9% Gr 1–2), diarrhoea (37% Gr 1–2), and hypertension (17% Gr 1–2; 9.8% Gr 3). CC-115 RP2D was 5 mg twice a day. In 40 evaluable patients, 80% achieved ≥50% reduction in PSA (PSA50), and 58% achieved ≥90% reduction in PSA (PSA90) by 12 weeks. Median time-to-PSA progression was 14.7 months and median rPFS was 22.1 months. Stratification by PI3K alterations demonstrated a non-statistically significant trend towards improved PSA50 response (PSA50 of 94% vs. 67%, p = 0.08). Exploratory pre-clinical analysis suggested CC-115 inhibited mTOR pathway strongly, but may be insufficient to inhibit DNA-PK at RP2D. Conclusions: The combination of enzalutamide and CC-115 was well tolerated. A non-statistically significant trend towards improved PSA response was observed in patients harbouring PI3K pathway alterations, suggesting potential predictive biomarkers of response to a PI3K/AKT/mTOR pathway inhibitor. Clinical trial registration: ClinicalTrials.gov identifier: NCT02833883. [ABSTRACT FROM AUTHOR]

Background: To date, single-agent immune checkpoint inhibitor (CPI) therapy has proven to be ineffective against biomarker-unselected extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PDNECs). The efficacy of CPI in combination with chemotherapy remains under investigation. Methods: Patients with advanced, progressive EP-PDNECs were enrolled in a two-part study of pembrolizumab-based therapy. In Part A, patients received pembrolizumab alone. In Part B, patients received pembrolizumab plus chemotherapy. Primary endpoint: objective response rate (ORR). Secondary endpoints: safety, progression-free survival (PFS) and overall survival (OS). Tumours were profiled for programmed death-ligand 1 expression, microsatellite-high/mismatch repair deficient status, mutational burden (TMB), genomic correlates. Tumour growth rate was evaluated. Results: Part A (N = 14): ORR (pembrolizumab alone) 7% (95% CI, 0.2–33.9%), median PFS 1.8 months (95% CI, 1.7–21.4), median OS 7.8 months (95% CI, 3.1–not reached); 14% of patients (N = 2) had grade 3/4 treatment-related adverse events (TRAEs). Part B (N = 22): ORR (pembrolizumab plus chemotherapy) 5% (95% CI, 0–22.8%), median PFS 2.0 months (95% CI, 1.9–3.4), median OS 4.8 months (95% CI, 4.1–8.2); 45% of patients (N = 10) had grade 3/4 TRAEs. The two patients with objective response had high-TMB tumours. Discussion: Treatment with pembrolizumab alone and pembrolizumab plus chemotherapy was ineffective in advanced, progressive EP-PDNECs. Clinical trial registration: ClinicalTrials.gov NCT03136055. [ABSTRACT FROM AUTHOR]

Geogenic fluoride contaminates the water of tens of millions of people. However, many are unaware of the fluoride content due in part to shortcomings of detection methods. Biosensor tests are a relatively new approach to water quality testing that address many of these shortcomings but have never been tested by non-experts in a "real-world" setting. We therefore sought to assess the accuracy and usability of a point-of-use fluoride biosensor using surveys and field tests in Nakuru County, Kenya. Biosensor tests accurately classified elevated fluoride (≥1.5 ppm) in 89.5% of the 57 samples tested. Usability was also high; all participants were able to use the test and correctly interpreted all but one sample. These data suggest that biosensor tests can provide accurate, meaningful water quality data that help non-experts make decisions about the water they consume. Further scaling of these technologies could provide new approaches to track global progress towards Sustainable Development Goal 6. [ABSTRACT FROM AUTHOR]

The androgen receptor (AR) signaling inhibitor enzalutamide (enza) is one of the principal treatments for metastatic castration-resistant prostate cancer (CRPC). Several emergent enza clinical resistance mechanisms have been described, including lineage plasticity in which the tumors manifest reduced dependency on the AR. To improve our understanding of enza resistance, herein we analyze the transcriptomes of matched biopsies from men with metastatic CRPC obtained prior to treatment and at progression (n = 21). RNA-sequencing analysis demonstrates that enza does not induce marked, sustained changes in the tumor transcriptome in most patients. However, three patients' progression biopsies show evidence of lineage plasticity. The transcription factor E2F1 and pathways linked to tumor stemness are highly activated in baseline biopsies from patients whose tumors undergo lineage plasticity. We find a gene signature enriched in these baseline biopsies that is strongly associated with poor survival in independent patient cohorts and with risk of castration-induced lineage plasticity in patient-derived xenograft models, suggesting that tumors harboring this gene expression program may be at particular risk for resistance mediated by lineage plasticity and poor outcomes. Lineage plasticity is increasingly recognized as an emergent resistance mechanism after treatment with androgen receptor signalling inhibitors. To understand determinants of resistance, the authors analyzed the transcriptomes of patient tumor biopsies before enzalutamide treatment and at progression and identified a gene expression program associated with lineage plasticity risk and poor outcomes. [ABSTRACT FROM AUTHOR]

Circulating tumour DNA (ctDNA) in blood plasma is an emerging tool for clinical cancer genotyping and longitudinal disease monitoring1. However, owing to past emphasis on targeted and low-resolution profiling approaches, our understanding of the distinct populations that comprise bulk ctDNA is incomplete2–12. Here we perform deep whole-genome sequencing of serial plasma and synchronous metastases in patients with aggressive prostate cancer. We comprehensively assess all classes of genomic alterations and show that ctDNA contains multiple dominant populations, the evolutionary histories of which frequently indicate whole-genome doubling and shifts in mutational processes. Although tissue and ctDNA showed concordant clonally expanded cancer driver alterations, most individual metastases contributed only a minor share of total ctDNA. By comparing serial ctDNA before and after clinical progression on potent inhibitors of the androgen receptor (AR) pathway, we reveal population restructuring converging solely on AR augmentation as the dominant genomic driver of acquired treatment resistance. Finally, we leverage nucleosome footprints in ctDNA to infer mRNA expression in synchronously biopsied metastases, including treatment-induced changes in AR transcription factor signalling activity. Our results provide insights into cancer biology and show that liquid biopsy can be used as a tool for comprehensive multi-omic discovery.Deep whole-genome sequencing of serial blood samples and matched metastatic tissue reveals that circulating tumour DNA profiling enables detailed study of treatment-driven subclone dynamics, epigenomics and genome-wide somatic evolution in metastatic human cancers. [ABSTRACT FROM AUTHOR]

Purpose of Review: Prostate cancer (PCa) is the most frequently diagnosed malignancy in men in developed countries and a leading cause of cancer death worldwide. Effective methods for diagnosing and staging PCa are necessary to guide treatment options in a personalized manner. The purpose of this paper is to review recent advances in molecular imaging and therapeutics and their expanding role in imaging and treating PCa. Recent Findings: Compared with conventional imaging, PSMA PET has proven more accurate at detecting PCa in patients with newly diagnosed PCa or biochemically recurrent PCa. PSMA PET can also induce management changes in patients due to its superior accuracy in detecting metastatic disease. Further research is necessary to understand the appropriate role of PSMA PET in patients with known metastatic PCa and the impact on clinical outcomes in patients who undergo treatment planning using findings from PSMA PET. Summary: We review the role of molecular imaging in primary and biochemically recurrent PCa. We find that molecular imaging is effective in detecting PCa and may lead to management changes. [ABSTRACT FROM AUTHOR]

Delta-like protein 3 (DLL3) is highly expressed in solid tumors, including neuroendocrine carcinomas/neuroendocrine tumors (NEC/NET). Rovalpituzumab tesirine (Rova-T) is a DLL3-targeting antibody-drug conjugate. Patients with NECs and other advanced DLL3-expressing tumors were enrolled in this phase I/II study (NCT02709889). The primary endpoint was safety. Two hundred patients were enrolled: 101 with NEC/NET (large-cell NEC, gastroenteropancreatic NEC, neuroendocrine prostate cancer, and other NEC/NET) and 99 with other solid tumors (melanoma, medullary thyroid cancer [MTC], glioblastoma, and other). The recommended phase II dose (RP2D) was 0.3 mg/kg every 6 weeks (q6w) for two cycles. At the RP2D, grade 3/4 adverse events included anemia (17%), thrombocytopenia (15%), and elevated aspartate aminotransferase (8%). Responses were confirmed in 15/145 patients (10%) treated at 0.3 mg/kg, including 9/69 patients (13%) with NEC/NET. Rova-T at 0.3 mg/kg q6w had manageable toxicity, with antitumor activity observed in patients with NEC/NET, melanoma, MTC, and glioblastoma. [ABSTRACT FROM AUTHOR]

Pulmonary embolism (PE) is a major cause of cardiovascular morbidity and mortality. Recent hospitalization or surgery is a leading risk factor for PE, yet there are minimal data examining its effect on treatment and outcomes. We conducted a retrospective review of institutional billing codes for hospitalized patients with acute PE from August 2012 to August 2018. Patients were stratified based on whether they had a recent major medical encounter (MME), defined as surgery or hospitalization within 90 days. Primary outcomes included in-hospital mortality and 30- and 90-day readmission rates. Secondary outcomes included length of stay (LOS), use of advanced therapies, major bleeding, discharge anticoagulation and recurrent venous thromboembolism (VTE) at 90 days. Outcomes were adjusted for confounders using multivariable regression modeling. 2063 patients were hospitalized for an acute PE; 633 (30.7%) had a recent MME. Patients with a recent MME had a higher average Charlson Comorbidity Index (4.6 vs. 4.0, p < 0.01). Both 30- and 90-day readmission rates were higher in patients with a recent MME (21.7% vs. 14.4%; adjusted OR 1.06 [1.00, 1.12], p = 0.037; 30.8% vs 18.7%; adjusted OR 1.11 [1.11, 1.62], p = 0.003, respectively). After adjustment, there were no between-group differences in in-hospital mortality, LOS, use of advanced therapies, major bleeding, or recurrent VTE at 90 days. In-hospital mortality was higher for patients with a recent medical hospitalization compared to those with a recent surgery (10.2% vs. 5.6%, adjusted OR 1.08 [1.01, 1.15] p = 0.032). Despite recent hospitalization and/or surgery and greater number of comorbidities, patients admitted with a PE and recent MME had similar in-hospital outcomes, but experienced higher readmission rates. In-hospital mortality was higher in those with a recent medical compared to surgical encounter. Clinicians should optimize post-discharge transitional care in this subset of patients. [ABSTRACT FROM AUTHOR]

Prostate cancer is the most commonly diagnosed neoplasm in American men. Although existing biomarkers may detect localized prostate cancer, additional strategies are necessary for improving detection and identifying aggressive disease that may require further intervention. One promising, minimally invasive biomarker is cell-free DNA (cfDNA), which consist of short DNA fragments released into circulation by dying or lysed cells that may reflect underlying cancer. Here we investigated whether differences in cfDNA concentration and cfDNA fragment size could improve the sensitivity for detecting more advanced and aggressive prostate cancer. This study included 268 individuals: 34 healthy controls, 112 men with localized prostate cancer who underwent radical prostatectomy (RP), and 122 men with metastatic castration-resistant prostate cancer (mCRPC). Plasma cfDNA concentration and fragment size were quantified with the Qubit 3.0 and the 2100 Bioanalyzer. The potential relationship between cfDNA concentration or fragment size and localized or mCRPC prostate cancer was evaluated with descriptive statistics, logistic regression, and area under the curve analysis with cross-validation. Plasma cfDNA concentrations were elevated in mCRPC patients in comparison to localized disease (OR5ng/mL = 1.34, P = 0.027) or to being a control (OR5ng/mL = 1.69, P = 0.034). Decreased average fragment size was associated with an increased risk of localized disease compared to controls (OR5bp = 0.77, P = 0.0008). This study suggests that while cfDNA concentration can identify mCRPC patients, it is unable to distinguish between healthy individuals and patients with localized prostate cancer. In addition to PSA, average cfDNA fragment size may be an alternative that can differentiate between healthy individuals and those with localized disease, but the low sensitivity and specificity results in an imperfect diagnostic marker. While quantification of cfDNA may provide a quick, cost-effective approach to help guide treatment decisions in advanced disease, its use is limited in the setting of localized prostate cancer. [ABSTRACT FROM AUTHOR]

Purpose: There are several important positron emission tomography (PET) imaging scenarios that require imaging with very low photon statistics, for which both quantitative accuracy and visual quality should not be neglected. For example, PET imaging with the low photon statistics is closely related to active efforts to significantly reduce radiation exposure from radiopharmaceuticals. We investigated two examples of low-count PET imaging: (a) imaging [90Y]microsphere radioembolization that suffers the very small positron emission fraction of Y-90's decay processes, and (b) cancer imaging with [68Ga]citrate with uptake time of 3-4 half-lives, necessary for visualizing tumors. In particular, we investigated a type of penalized likelihood reconstruction algorithm, block sequential regularized expectation maximization (BSREM), for improving both image quality and quantitative accuracy of these low-count PET imaging cases.Procedures: The NEMA/IEC Body phantom filled with aqueous solution of Y-90 or Ga-68 was scanned to mimic the low-count scenarios of corresponding patient data acquisitions on a time-of-flight (TOF) PET/magnetic resonance imaging system. Contrast recovery, background variation, and signal-to-noise ratio were evaluated in different sets of count densities using both conventional TOF ordered subset expectation (TOF-OSEM) and TOF-BSREM algorithms. The regularization parameter, beta, in BSREM that controls the tradeoff between image noise and resolution was evaluated to find a value for improved confidence in image interpretation. Visual quality assessment of the images obtained from patients administered with [68Ga]citrate (n = 6) was performed. We also made preliminary visual image quality assessment for one patient with [90Y]microspheres. In Y-90 imaging, the effect of 511-keV energy window selection for minimizing the number of random events was also evaluated.Results: Quantitatively, phantom images reconstructed with TOF-BSREM showed improved contrast recovery, background variation, and signal-to-noise ratio values over images reconstructed with TOF-OSEM. Both phantom and patient studies of delayed imaging of [68Ga]citrate show that TOF-BSREM with beta = 500 gives the best tradeoff between image noise and image resolution based on visual assessment by the readers. The NEMA-IQ phantom study with [90Y]microspheres shows that the narrow energy window (460-562 keV) recovers activity concentrations in small spheres better than the regular energy window (425-650 keV) with the beta value of 2000 using the TOF-BSREM algorithm. For the images obtained from patients with [68Ga]citrate using TOF-BSREM with beta = 500, the visual analogue scale (VAS) was improved by 17 % and the Likert score was increased by 1 point on average, both in comparison to corresponding scores for images reconstructed using TOF-OSEM.Conclusion: Our investigation shows that the TOF-BSREM algorithm improves the image quality and quantitative accuracy in low-count PET imaging scenarios. However, the beta value in this algorithm needed to be adjusted for each radiopharmaceutical and counting statistics at the time of scans. [ABSTRACT FROM AUTHOR]

Background: RRx-001, a minimally toxic next-generation checkpoint inhibitor that targets myeloid suppressor cells in the tumor microenvironment, has also been shown to protect normal tissues from the cytotoxic effects of chemotherapy and radiation. The following experiments were carried out to determine whether the cytoprotective functions of RRx-001 in normal cells were operative in tumor cells. Design: The effects of RRx-001 on normal cells, and ovarian cancer A2780 and UWB1 cells were evaluated with a colony-forming assay. Western blot densitometry was used to measure Nrf2 nuclear translocation in Caco2 cells after exposure to RRx-001. Following incubation with RRx-001, levels of the antioxidant, NQO1, were determined in Caco2 cells by measuring absorbance over 300 min at 440 nm. RRx-001-mediated cytotoxicity in HCT-116 colorectal cancer cells was evaluated with an MTT assay. In addition, the effect of RRx-001 incubation on the protein expression of Nrf2, PARP, cleaved PARP, procaspases 3, 8, and 9, Bcl-2, and Bax in HCT-116 colorectal cells was determined by western blot analysis. Results: RRx-001 is demonstrated to induce Nrf2 in normal tissues, mediating protection, and to downregulate the Nrf2-controlled antiapoptotic target gene, B-cell lymphoma 2 (Bcl-2) in tumors, mediating cytotoxicity. Conclusion: Through Nrf2 induction in normal cells and inhibition of Bcl-2 in tumor cells, RRx-001 selectively protects normal cells against lethality in normal cells, but induces apoptosis in tumor cells. [ABSTRACT FROM AUTHOR]

Background: ACCORD and SPRINT are the best randomized controlled trial data evaluating the effects of blood pressure targets below 140 mmHg. These trials had contradictory results regarding the benefits of intensive antihypertensive therapy. We investigate if this discordance was driven by SPRINT’s inclusion of Heart Failure in its primary outcome, as this is a parameter not included in ACCORD’s original primary outcome. This analysis helps to resolve a significant area of contention.Methods: Individual patient data from 4733 participants in ACCORD were analyzed from time of randomization. All participants were diabetic and at increased cardiovascular risk. Participants were assigned to their original intervention, a standard blood pressure target of less than 140 mmHg or an intensive target of less than 120 mmHg. Primary composite outcome was defined as in SPRINT: a composite of first occurrence of myocardial infarction, stroke, heart failure, death from cardiovascular causes, and other acute coronary syndromes.Results: Primary outcome was not significantly different between standard and intensive groups [HR: 0.89; 95% CI: (0.76-1.03); p = 0.108]. The primary composite outcome occurred in 370 participants in the standard group (15.6%) and 324 participants in the intensive group (13.7%), with an event rate of 3.38% per year for the standard group and 3.01% per year for the intensive group.Conclusions: Differing results between ACCORD and SPRINT are not attributable to ACCORD’s exclusion of Heart Failure from its original primary outcome measurement. No significant differences in primary outcome were observed between intensive and standard blood pressure groups in the ACCORD patients under the SPRINT primary outcome definition. Caution should be taken in extrapolating the intensive blood pressure control benefits of SPRINT to the diabetic population. [ABSTRACT FROM AUTHOR]

Supplier selection is one of the key activities of purchase management in supply chain. Supplier selection is a multifaceted problem relating qualitative and quantitative multi-criteria. This paper deals with a supplier selection problem in an Indian automobile company. The work presents selection of headlamp supplier using integrated fuzzy multi-criteria decision-making approaches: analytical hierarchy process (AHP) and technique for order of preference by similarity to ideal solution (TOPSIS). The selection process starts with identifying the criteria based on literature review and interviewing industry experts. Weights to criteria are assigned using AHP, and suppliers are ranked using AHP and TOPSIS. Consistency tests are carried out to check the quality of expert’s inputs. Also, sensitivity analysis is done to check the robustness of the approach. The results address that fuzzy approaches could be effective and more accurate than the existing approaches for supplier selection problems. [ABSTRACT FROM AUTHOR]

Purpose: The management of advanced or recurrent prostate cancer is limited in part by the lack of effective imaging agents. Metabolic changes in prostate cancer have previously been exploited for imaging, culminating in the recent US FDA approval of [C]choline for the detection of subclinical recurrent disease after definitive local therapy. Despite this milestone, production of [C]choline requires an on-site cyclotron, limiting the scope of medical centers at which this scan can be offered. In this pilot study, we tested whether prostate cancer could be imaged with positron emission tomography (PET) using [Ga]citrate, a radiotracer that targets iron metabolism but is produced without a cyclotron. Procedures: Eight patients with castrate-resistant prostate cancer were enrolled in this single-center feasibility study. All patients had evidence of metastatic disease by standard of care imaging [X-ray computed tomography (CT), bone scan, or magnetic resonance imaging (MRI)] prior to PET with [Ga]citrate. Patients were intravenously injected with increasing doses of [Ga]citrate (136.9 to a maximum of 259 MBq). Uptake time was steadily increased from 1 h to approximately 3.5 h for the final 4 patients, and all patients were imaged with a PET/MRI. Qualitative and semi-quantitative (maximum standardized uptake value (SUV)) assessment of the metastatic lesions was performed and compared to the standard of care imaging. Results: At 1- and 2-h imaging times post injection, there were no detectable lesions with [Ga]citrate PET. At 3- to 4-h uptake time, there were a total of 71 [Ga]citrate-positive lesions (67 osseous, 1 liver, and 3 lymph node). Of these, 65 lesions were visible on the standard of care imaging (CT and/or bone scan). One PET-avid osseous vertebral body metastasis was not apparent on either CT or bone scan. Twenty-five lesions were not PET-avid but seen on CT and bone scan (17 bone, 6 lymph node, 1 pleural, and 1 liver). The average of the maximum SUVs for bone or soft tissue metastases for patients treated at higher doses and uptake time was statistically higher than the corresponding parameter in normal liver, muscle, and bone. Visually obvious blood pool activity was observed even 3-4 h post injection, suggesting that further optimization of the [Ga]citrate imaging protocol is required to maximize signal-to-background ratios. Conclusions: Our preliminary results support that PET with [Ga]citrate may be a novel tool for imaging prostate cancer. Future studies are needed to determine the optimal imaging protocol, the clinical significance of [Ga]citrate uptake, and its role in therapeutic decisions. [ABSTRACT FROM AUTHOR]

Purpose: The management of advanced or recurrent prostate cancer is limited in part by the lack of effective imaging agents. Metabolic changes in prostate cancer have previously been exploited for imaging, culminating in the recent US FDA approval of [11C]choline for the detection of subclinical recurrent disease after definitive local therapy. Despite this milestone, production of [11C]choline requires an on-site cyclotron, limiting the scope of medical centers at which this scan can be offered. In this pilot study, we tested whether prostate cancer could be imaged with positron emission tomography (PET) using [68Ga]citrate, a radiotracer that targets iron metabolism but is produced without a cyclotron.Procedures: Eight patients with castrate-resistant prostate cancer were enrolled in this single-center feasibility study. All patients had evidence of metastatic disease by standard of care imaging [X-ray computed tomography (CT), bone scan, or magnetic resonance imaging (MRI)] prior to PET with [68Ga]citrate. Patients were intravenously injected with increasing doses of [68Ga]citrate (136.9 to a maximum of 259 MBq). Uptake time was steadily increased from 1 h to approximately 3.5 h for the final 4 patients, and all patients were imaged with a PET/MRI. Qualitative and semi-quantitative (maximum standardized uptake value (SUVmax)) assessment of the metastatic lesions was performed and compared to the standard of care imaging.Results: At 1- and 2-h imaging times post injection, there were no detectable lesions with [68Ga]citrate PET. At 3- to 4-h uptake time, there were a total of 71 [68Ga]citrate-positive lesions (67 osseous, 1 liver, and 3 lymph node). Of these, 65 lesions were visible on the standard of care imaging (CT and/or bone scan). One PET-avid osseous vertebral body metastasis was not apparent on either CT or bone scan. Twenty-five lesions were not PET-avid but seen on CT and bone scan (17 bone, 6 lymph node, 1 pleural, and 1 liver). The average of the maximum SUVs for bone or soft tissue metastases for patients treated at higher doses and uptake time was statistically higher than the corresponding parameter in normal liver, muscle, and bone. Visually obvious blood pool activity was observed even 3-4 h post injection, suggesting that further optimization of the [68Ga]citrate imaging protocol is required to maximize signal-to-background ratios.Conclusions: Our preliminary results support that PET with [68Ga]citrate may be a novel tool for imaging prostate cancer. Future studies are needed to determine the optimal imaging protocol, the clinical significance of [68Ga]citrate uptake, and its role in therapeutic decisions. [ABSTRACT FROM AUTHOR]

Nanocomposites of CdS nanocrystals (NCs) embedded in a polyvinyl pyrrolidone are grown using one-step chemical bath deposition technique. While this method eliminates an additional step for the growth of NCs, it also leads to the formation of nearly monodispersive CdS NCs as indicated by absorption, reflection, and photoluminescence spectroscopy. Further, scanning electron microscopy, energy-dispersive spectroscopy, and transmission electron microscopic investigations reveal the formation of nearly monodispersive CdS NCs (~6 to 10 nm) embedded in PVP spheres of sizes ~100 to 600 nm. Systematic study of variation in Cadmium acetate (Cd ion source), Thiourea (S ion source), PVP concentration, deposition time, and heating/cooling cycles elucidates the co-operative growth mechanism for CdS-PVP nanocomposite. The experimental observations of this study are corroborated with existing theoretical simulations for nanocomposite growth, which explicates that collapse of PVP into a sphere is crucial to inclusion of only nearly monodispersive CdS NCs. Important insights obtained from this work give control on the growth of nearly monodispersive CdS NCs embedded in PVP, using a simple and inexpensive growth technique. [ABSTRACT FROM AUTHOR]

Purpose: Inhibition of the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is associated with metabolic and immunologic perturbations that impact drug tolerability. Here, we studied whether PI3 kinase/mTOR pathway inhibitors are associated with greater metabolic impact and decreased tolerability in Asian patients. Methods: A retrospective analysis was conducted of consecutive patients with advanced malignancies treated on phase 1 trials of PI3K/mTOR inhibitors. Adverse events related to PI3K/mTOR inhibition, fasting plasma glucose (FPG), insulin, and c-peptide levels, hemoglobin A1c (HgbA1c), and T cell subsets were prospectively collected. Mann-Whitney and Chi-square tests were used to compare continuous and categorical variables, respectively, between Asian and Caucasian patients. Results: A total of 103 patients (31 Asian; 72 Caucasian) were treated consecutively across five clinical trials. Baseline age, gender distribution, and metabolic parameters were comparable with the exception of lower median body mass index (BMI) in Asian patients (23.0 vs. 24.8 kg/m, p = 0.024). There were no differences in drug tolerability, adherence, or duration of therapy. Asian patients experienced a higher incidence of grade ≥2 hyperglycemia (37.5 vs. 18.1 %, p = 0.03), and greater increases in FPG, HgbA1c, and insulin resistance. No differences in incidence or severity of mucositis, rash, or pneumonitis were observed. Drug effects on neutrophils, lymphocytes, and T cell subsets were similar. Conclusions: PI3K/mTOR inhibitors have greater glycemic impact in Asian patients, despite similar baseline metabolic parameters, comparable dose intensity, and a lower median BMI. Further studies are warranted to explore the mechanisms underlying these differences and optimize dosing in Asian patients. [ABSTRACT FROM AUTHOR]

Trauma is the leading cause of death in the pediatric age group. About 25,000 children die each year and one million children are injured each year in the USA. Aggressive resuscitation determines the outcome of these injured children. The initial hour following the traumatic injury is referred to as the "golden hour" during which we have an opportunity to intervene and improve the outcome. It is not only the first hour which is important but every minute in trauma resuscitation is important. The outcome of traumatic children has a direct correlation to resuscitation. In order to manage traumatic shock there are four basic principles: (a) control of active hemorrhage, (b) assessment of circulatory status, (c) rapid intravascular access, and (d) aggressive fluid resuscitation. Following the four principles of management of traumatic shock and aggressive resuscitation improves the outcome. [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract disease in infants and young children. Most infections due to RSV are mild and do not require hospitalization. RSV causes both upper respiratory tract infections as well as lower respiratory tract infections. Infants with underlying disease states like bronchopulmonary dyslasia, congenital heart disease and prematurity appear more prone to develop severe infection and have a higher incidence of hospitalization. The exact pathogenesis of RSV is not well understood. The mortality associated with primary RSV infection in healthy children is estimated to be between .005% to .02%. In hospitalized children the mortality rate is estimated to be from 1% to 3%. Several treatment modalities in the form of bronchodilators, corticosteroids, ribavirin, intravenous immune gammaglobulin and antibiotics are available. Studies have failed to show the true beneficial effect of any of the above treatment modalities. Supportive care is only needed. The best treatment is the supportive care in the form of oxygen and fluids and close monitoring of the vital signs including oxygen saturation. [ABSTRACT FROM AUTHOR]