Assessing relative risks of municipal wastewater disposal options for Southeast Florida.

A comparative assessment of the risks of the three current wastewater effluent disposal options and three other potential options was conducted for Southeast Florida communities. The question was how the risk to humans from the use of potable reuse compares to the other five available wastewater disposal alternatives. The need for this type of risk assessment is due to the potential to use potable reuse as a water supply and the potential resistance from the public as a result of such a proposal. Water quality data relevant to disposal of wastewater treatment plant effluent from South Florida utilities along with water quality data on the receiving waters and drinking water standards were obtained for the project. The comparison of the public health risks associated with these disposal alternatives indicated that health risks associated with deep wells and direct potable reuse were generally lower than those of the other alternatives.

Detection of enteric viruses and SARS-CoV-2 in beach sand.

Beach sand harbors a diverse group of microbial organisms that may be of public health concern. Nonetheless, little is known about the presence and distribution of viruses in beach sand. In this study, the first objective was to evaluate the presence of seven viruses (Aichi virus, enterovirus, hepatitis A virus, human adenovirus, norovirus, rotavirus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)) in sands collected at public beaches. The second objective was to assess the spatial distribution of enteric viruses in beach sand. To that end, 27 beach sand samples from different beaches in Portugal were collected between November 2018 and August 2020 and analyzed for the presence of viruses. At seven beaches, samples were collected in the supratidal and intertidal zones. Results show that viruses were detected in 89 % (24/27) of the sand samples. Aichi virus was the most prevalent (74 %). Noroviruses were present in 19 % of the samples (norovirus GI - 15 %, norovirus GII - 4 %). Human adenovirus and enterovirus were detected in 48 % and 22 % of the samples, respectively. Hepatitis A virus and rotavirus were not detected. Similarly, SARS-CoV-2 in beach sand collected during the initial stages of the pandemic was also not detected. The detection of three or more viruses occurred in 15 % of the samples. Concentrations of viruses were as high as 7.2 log copies (cp)/g of sand. Enteric viruses were found in higher prevalence in sand collected from the supratidal zone compared to the intertidal zone. Human adenovirus was detected in 43 % of the supratidal and 14 % in the intertidal samples and Aichi virus in 57 % and 86 % of the intertidal and supratidal areas, respectively. Our findings suggest that beach sand can be a reservoir of enteric viruses, suggesting that it might be a vehicle for disease transmission, particularly for children, the elderly, and immunocompromised users.

Search for the Pair Production of Dark Particles X with K_{L}

We present the first search for the pair production of dark particles X via K_{L}^{0}→XX with X decaying into two photons using the data collected by the KOTO experiment. No signal was observed in the mass range of 40-110 MeV/c^{2} and 210-240 MeV/c^{2}. This sets upper limits on the branching fractions as B(K_{L}^{0}→XX)<(1-4)×10^{-7} and B(K_{L}^{0}→XX)<(1-2)×10^{-6} at the 90% confidence level for the two mass regions, respectively.

Chlorine dioxide is a more potent antiviral agent against SARS-CoV-2 than sodium hypochlorite.

BACKGROUND: A new coronavirus (SARS-CoV-2) abruptly emerged in Wuhan, China, in 2019 and rapidly spread globally to cause the COVID-19 pandemic. AIM: To examine the anti-SARS-CoV-2 activity of the potent disinfectant Cleverin, the major disinfecting component of which is chlorine dioxide (ClO2); and to compare the results with that of sodium hypochlorite in the presence or absence of 0.5% or 1.0% foetal bovine serum (FBS). METHODS: Concentrated SARS-CoV-2 viruses were treated with various concentrations of ClO2 and sodium hypochlorite and 50% tissue culture infective dose was calcurated to evaluate the antiviral activity of each chemical. FINDINGS: When SARS-CoV-2 viruses were treated with 0.8 ppm ClO2 or sodium hypochlorite, viral titre was decreased only by 1 log10 TCID50/mL in 3 min. However, the viral titre was decreased by more than 4 log10 TCID50/mL when treated with 80 ppm of each chemical for 10 s regardless of presence or absence of FBS. It should be emphasized that treatment with 24 ppm of ClO2 inactivated more than 99.99% SARS-CoV-2 within 10 s or 99.99% SARS-CoV-2 in 1 min in the presence of 0.5% or 1.0% FBS, respectively. By contrast, 24 ppm of sodium hypochlorite inactivated only 99% or 90% SARS-CoV-2 in 3 min under similar conditions. Notably, except for ClO2, the other components of Cleverin such as sodium chlorite, decaglycerol monolaurate, and silicone showed no significant antiviral activity. CONCLUSION: Altogether, the results strongly suggest that although ClO2 and sodium hypochlorite are strong antiviral agents in absence of organic matter but in presence of organic matter, ClO2 is a more potent antiviral agent against SARS-CoV-2 than sodium hypochlorite.

Measurement of a time dependent spatial beam profile of an RF-driven H- ion source.

The AC component of a beam current extracted from a negative hydrogen (H-) ion source was detected through a 0.1 mm wide, 66.5 mm long entrance slit to observe the spatial distribution. An internal antenna type multicusp source driven by a 2 MHz radio frequency (RF) power delivered beams to an electrostatic accelerator coupled to a pair of magnetic lenses. The local beam intensity measured by a Faraday cup after the entrance slit exhibited an oscillation showing two main frequency components: the RF power supply frequency and the frequency two times the driving RF. The frequency spectrum of the detected signal showed sharp peaks at 2 MHz, 4 MHz, and 6 MHz as well as at 3 MHz and 5 MHz. A 1 mm displacement of the Faraday cup slit position from the center of the beam axis increased the oscillation amplitude, corresponding to a larger amplitude of the AC component at the beam edge.

Intratumoural immune cell landscape in germinoma reveals multipotent lineages and exhibits prognostic significance.

AIMS: Alterations in microenvironments are a hallmark of cancer, and these alterations in germinomas are of particular significance. Germinoma, the most common subtype of central nervous system germ cell tumours, often exhibits massive immune cell infiltration intermingled with tumour cells. The role of these immune cells in germinoma, however, remains unknown. METHODS: We investigated the cellular constituents of immune microenvironments and their clinical impacts on prognosis in 100 germinoma cases. RESULTS: Patients with germinomas lower in tumour cell content (i.e. higher immune cell infiltration) had a significantly longer progression-free survival time than those with higher tumour cell contents (P = 0.03). Transcriptome analyses and RNA in-situ hybridization indicated that infiltrating immune cells comprised a wide variety of cell types, including lymphocytes and myelocyte-lineage cells. High expression of CD4 was significantly associated with good prognosis, whereas elevated nitric oxide synthase 2 was associated with poor prognosis. PD1 (PDCD1) was expressed by immune cells present in most germinomas (93.8%), and PD-L1 (CD274) expression was found in tumour cells in the majority of germinomas examined (73.5%). CONCLUSIONS: The collective data strongly suggest that infiltrating immune cells play an important role in predicting treatment response. Further investigation should lead to additional categorization of germinoma to safely reduce treatment intensity depending on tumour/immune cell balance and to develop possible future immunotherapies.

Intraoperative evaluation of blood flow for soft tissues in orthopaedic surgery using indocyanine green fluorescence angiography: A pilot study.

OBJECTIVES: Indocyanine green (ICG) fluorescence angiography is an emerging technique that can provide detailed anatomical information during surgery. The purpose of this study is to determine whether ICG fluorescence angiography can be used to evaluate the blood flow of the rotator cuff tendon in the clinical setting. METHODS: Twenty-six patients were evaluated from October 2016 to December 2017. The participants were categorized into three groups based on their diagnoses: the rotator cuff tear group; normal rotator cuff group; and adhesive capsulitis group. After establishing a posterior standard viewing portal, intravenous administration of ICG at 0.2 mg/kg body weight was performed, and fluorescence images were recorded. The time from injection of the drug to the beginning of enhancement of the observed area was measured. The hypovascular area in the rotator cuff was evaluated, and the ratio of the hypovascular area to the anterolateral area of the rotator cuff tendon was calculated (hypovascular area ratio). RESULTS: ICG fluorescence angiography allowed for visualization of blood flow in the rotator cuff in all groups. The adhesive capsulitis group showed significantly earlier enhancement than the other groups. Furthermore, the adhesive capsulitis group had a significantly smaller hypovascular area ratio than the other groups. CONCLUSION: ICG fluorescence angiography allowed for evaluation of real-time blood flow of the rotator cuff in arthroscopic shoulder surgery. The techniques of ICG fluorescence angiography are simple and easy to observe, observer reliability is high, and it has utility for evaluating blood flow during surgery.Cite this article: N. Doi, T. Izaki, S. Miyake, T. Shibata, T. Ishimatsu, Y. Shibata, T. Yamamoto. Intraoperative evaluation of blood flow for soft tissues in orthopaedic surgery using indocyanine green fluorescence angiography: A pilot study. Bone Joint Res 2019;8:118-125. DOI: 10.1302/2046-3758.83.BJR-2018-0151.R1.

Evaluation of the effect of lanthanum carbonate hydrate on the pharmacokinetics of roxadustat in non-elderly healthy adult male subjects.

WHAT IS KNOWN AND OBJECTIVE: Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor currently being investigated for the treatment of anemia in chronic kidney disease. Lanthanum carbonate is a phosphate binder that is commonly used to treat hyperphosphatemia in patients with chronic kidney disease. This study investigated the effect of lanthanum carbonate on the pharmacokinetics, safety and tolerability of a single oral dose of roxadustat in healthy non-elderly adult male subjects. METHODS: This was an open-label, randomized, two-period, two-sequence crossover study in non-elderly healthy adult males. Subjects randomized to Group 1 received roxadustat alone during Period 1 and roxadustat concomitantly with lanthanum carbonate during Period 2; subjects randomized to Group 2 received roxadustat concomitantly with lanthanum carbonate during Period 1 and roxadustat alone during Period 2. All subjects received a single oral dose of 100 mg roxadustat on Day 1 in both periods. Subjects receiving concomitant lanthanum carbonate received 750 mg lanthanum carbonate three times daily on Days 1 and 2. Pharmacokinetic assessments were conducted on Days 1-4 in both periods. The primary study outcomes were the area under the concentration-time curve from the time of dosing extrapolated to infinity (AUCinf ), and maximum concentration (Cmax ); the geometric least squares mean ratio (GMR; roxadustat + lanthanum carbonate/roxadustat alone) and corresponding 90% confidence interval (CI) was calculated for AUCinf and Cmax . Safety was assessed by the occurrence of treatment-emergent adverse events (TEAEs), laboratory test results, vital signs and standard 12-lead electrocardiogram. RESULTS AND DISCUSSION: A total of 18 subjects were enrolled (Group 1, n = 9; Group 2, n = 9); no subjects discontinued from the study. Roxadustat was rapidly absorbed, reaching maximum plasma concentration between 1 and 4 hours. The GMRs for AUCinf and Cmax were 88.00% (90% CI: 84.01, 92.17) and 98.58% (90% CI: 92.92, 104.58), respectively. The 90% CIs for both parameters were within the no-effect boundaries of 80% and 125%, indicating a lack of effect of lanthanum carbonate on roxadustat absorption. No deaths or serious TEAEs occurred. WHAT IS NEW AND CONCLUSIONS: Concomitant administration of a single oral dose of 100 mg roxadustat and 750 mg lanthanum carbonate three times daily did not impact the AUCinf or Cmax of roxadustat and was considered safe and well tolerated in non-elderly healthy adult male Japanese subjects.

Results of a multi-institutional, randomized, non-inferiority, phase III trial of accelerated fractionation versus standard fractionation in radiation therapy for T1-2N0M0 glottic cancer: Japan Clinical Oncology Group Study (JCOG0701).

Background: We assessed the non-inferiority of accelerated fractionation (AF) (2.4 Gy/fraction) compared with standard fractionation (SF) (2 Gy/fraction) regarding progression-free survival (PFS) in patients with T1-2N0M0 glottic cancer (GC). Patients and methods: In this multi-institutional, randomized, phase III trial, patients were enrolled from 32 Japanese institutions. Key inclusion criteria were GC T1-2N0M0, age 20-80, Eastern Cooperative Oncology Group performance status of 0-1, and adequate organ function. Patients were randomly assigned to receive either SF of 66-70 Gy (33-35 fractions), or AF of 60-64.8 Gy (25-27 fractions). The primary end point was the proportion of 3-year PFS. The planned sample size was 360 with a non-inferiority margin of 5%. Results: Between 2007 and 2013, 370 patients were randomized (184/186 to SF/AF). Three-year PFS was 79.9% (95% confidence interval [CI] 73.4-85.4) for SF and 81.7% (95% CI 75.4-87.0) for AF (difference 1.8%, 91% CI-5.1% to 8.8%; one-sided P = 0.047 > 0.045). The cumulative incidences of local failure at 3 years for SF/AF were 15.9%/10.3%. No significant difference was observed in 3-year overall survival (OS) between SF and AF. Grade 3 or 4 acute and late toxicities developed in 22 (12.4%)/21 (11.5%) and 2 (1.1%)/1 (0.5%) in the SF/AF arms. Conclusion: Although the non-inferiority of AF was not confirmed statistically, the similar efficacy and toxicity of AF compared with SF, as well as the practical convenience of its fewer treatment sessions, suggest the potential of AF as a treatment option for early GC. Clinical trials registration: UMIN Clinical Trial Registry, number UMIN000000819.

Rituximab for the treatment of type B insulin resistance syndrome: a case report and review of the literature.

BACKGROUND: Type B insulin resistance syndrome is a rare disease characterized by refractory transient hyperglycaemia and severe insulin resistance associated with circulating anti-insulin receptor antibodies. A standardized treatment regimen for type B insulin resistance syndrome has yet to be established. CASE REPORT: We report the case of a 64-year-old man undergoing haemodialysis for antineutrophil cytoplasmic antibody-associated vasculitis and diabetic nephropathy, who developed rapid onset of hyperglycaemia (glycated albumin 52.1%). Type B insulin resistance syndrome was diagnosed, on the basis of positivity for anti-insulin receptor antibodies and the man's autoimmune history of antineutrophil cytoplasmic antibody-associated vasculitis and idiopathic thrombocytopenic purpura. Although severe hyperglycaemia persisted in spite of corticosteroids and high-dose insulin therapy, rituximab treatment resulted in remarkable improvement of the man's severe insulin resistance and disappearance of anti-insulin receptor antibodies without any adverse effects. CONCLUSIONS: According to a literature review of 11 cases in addition to the present case, rituximab appears to be a safe and effective strategy for the treatment of corticosteroid-resistant type B insulin resistance syndrome.

Surrogacy of progression-free survival (PFS) for overall survival (OS) in esophageal cancer trials with preoperative therapy: Literature-based meta-analysis.

BACKGROUND: There have been no reports evaluating progression-free survival (PFS) as a surrogate endpoint in resectable esophageal cancer. This study was conducted to evaluate the trial level correlations between PFS and overall survival (OS) in resectable esophageal cancer with preoperative therapy and to explore the potential benefit of PFS as a surrogate endpoint for OS. METHODS: A systematic literature search of randomized trials with preoperative chemotherapy or preoperative chemoradiotherapy for esophageal cancer reported from January 1990 to September 2014 was conducted using PubMed and the Cochrane Library. Weighted linear regression using sample size of each trial as a weight was used to estimate coefficient of determination (R2) within PFS and OS. The primary analysis included trials in which the HR for both PFS and OS was reported. The sensitivity analysis included trials in which either HR or median survival time of PFS and OS was reported. In the sensitivity analysis, HR was estimated from the median survival time of PFS and OS, assuming exponential distribution. RESULTS: Of 614 articles, 10 trials were selected for the primary analysis and 15 for the sensitivity analysis. The primary analysis did not show a correlation between treatment effects on PFS and OS (R2 0.283, 95% CI [0.00-0.90]). The sensitivity analysis did not show an association between PFS and OS (R2 0.084, 95% CI [0.00-0.70]). CONCLUSION: Although the number of randomized controlled trials evaluating preoperative therapy for esophageal cancer is limited at the moment, PFS is not suitable for primary endpoint as a surrogate endpoint for OS.

Dissecting the structural basis for the intracellular delivery of OSW-1 by fluorescent probes.

The structural basis for the intracellular delivery of OSW-1 is investigated using fluorescent derivatives of OSW-1 and its closely related congeners. Despite the large differences in activity, all the fluorescent probes are found to translocate across the plasma membrane to the ER and Golgi apparatus. This observation suggests that the glycosylated cholestane moiety plays an important role in the cell internalization and intracellular localization property of OSW-1.

Susceptibility of isogeneic ginbuna Carassius auratus langsdorfii Temminck et Schlegel to cyprinid herpesvirus-2 (CyHV-2) as a model species.

Herpesviral haematopoietic necrosis (HVHN), caused by cyprinid herpesvirus-2 (CyHV-2), has affected the commercial production of the goldfish Carassius auratus and gibelio carp Carassius auratus gibelio. High water temperature treatments are reported to reduce the mortality rate of infected goldfish and elicit immunity in the survivors. To define the mechanism by which this intervention induces resistance, clonal ginbuna Carassius auratus langsdorfii, which is closely related to both species and has been used in fish immunology, may represent a promising model species. In this study, we investigated the susceptibility of clonal ginbuna strains to CyHV-2 and the effect of high water temperature treatment on infected ginbuna and goldfish. Experimental intraperitoneal infection with CyHV-2 at 25 °C caused 100% mortality in ginbuna strains, which was accompanied by histopathological changes typical of HVHN. Both infected ginbuna S3n strain and goldfish, exposed to high temperature for 6 days [shifting from 25 °C (permissive) to 34 °C (non-permissive)], showed reduced mortalities after the 1st inoculation, and subsequent 2nd virus challenge to 0%, indicating induction of immunity. It was concluded that ginbuna showed a similar susceptibility and disease development in CyHV-2 infection compared to goldfish, suggesting that ginbuna can be a useful fish model for the study of CyHV-2 infection and immunity.

Synthesis of a fluorescent photoaffinity probe of OSW-1 by site-selective acylation of an inactive congener and biological evaluation.

A novel fluorescent photoaffinity probe of OSW-1 was prepared in two steps from a naturally occurring inactive congener by a sequential site-selective acylation strategy using Me2SnCl2. It displayed highly potent anticancer activity and a similar intracellular localization property to that of a fluorescently-tagged OSW-1, thereby demonstrating its potential utility in live cell studies.

Myeloperoxidase in blood neutrophils during normal and abnormal menstrual cycles in women of reproductive age.

INTRODUCTION: We previously reported that granulocyte colony-stimulating factor (G-CSF) plays a critical role in ovulation, suggesting that neutrophils may maintain ovulation. We assessed myeloperoxidase (MPO), a major and specific enzyme of neutrophils, in women with abnormal and normal menstrual cycles to clarify the relationship between MPO and ovulation. METHODS: We analyzed MPO activity in blood neutrophils of women with abnormal menstrual cycles (indicative of anovulation, n = 12) and age- and body mass index-matched normal menstrual cycles (indicative of ovulation, n = 24) using two parameters as a marker of MPO, Neut X and mean peroxidase index (MPXI). RESULTS: MPO of women with abnormal menstrual cycles was significantly lower than that of women with normal menstrual cycles [Neut X: 62.6 ± 1.1 (mean ± standard error of the mean) vs. 66.2 ± 0.3, P = 0.009; MPXI: -0.54 ± 1.66 vs. 4.91 ± 0.53, P = 0.008]. Among women with normal menstrual cycles, MPO was highest in the follicular phase (Neut X: 67.0 ± 0.3; P = 0.033). CONCLUSION: The difference in MPO between women with abnormal and normal menstrual cycles and the upregulation of MPO before ovulation suggest that neutrophils and MPO are closely related to ovulation.

Correction: Synthesis of a fluorescent photoaffinity probe of OSW-1 by site-selective acylation of an inactive congener and biological evaluation.

Correction for 'Synthesis of a fluorescent photoaffinity probe of OSW-1 by site-selective acylation of an inactive congener and biological evaluation' by K. Sakurai et al., Chem. Commun., 2017, DOI: .

Neutron emission and dose distribution from natural carbon irradiated with a 12 MeV amu-1 12C5+ ion beam.

Measured neutron energy distribution emitted from a thick stopping target of natural carbon at 0°, 30°, 60° and 90° from nuclear reactions caused by 12 MeV amu-1 incident 12C5+ ions were converted to energy differential and total neutron absorbed dose as well as ambient dose equivalent H *(10) using the fluence-to-dose conversion coefficients provided by the ICRP. Theoretical estimates were obtained using the Monte Carlo nuclear reaction model code PACE and a few existing empirical formulations for comparison. Results from the PACE code showed an underestimation of the high-energy part of energy differential dose distributions at forward angles whereas the empirical formulation by Clapier and Zaidins (1983 Nucl. Instrum. Methods 217 489-94) approximated the energy integrated angular distribution of H *(10) satisfactorily. Using the measured data, the neutron doses received by some vital human organs were estimated for anterior-posterior exposure. The estimated energy-averaged quality factors were found to vary for different organs from about 7 to about 13. Emitted neutrons having energies above 20 MeV were found to contribute about 20% of the total dose at 0° while at 90° the contribution was reduced to about 2%.

Efficacy and possible mechanisms of topical tranexamic acid in melasma.

BACKGROUND: Tranexamic acid (TA) has been suggested as an effective treatment for melasma. AIM: To investigate the effects and mechanism of action of topical TA in the treatment of melasma. METHODS: In this study, 23 participants with melasma applied a 2% TA formulation to the whole face for 12 weeks. Clinical effects were evaluated using the modified Melasma Area and Severity Index (mMASI) and a chromameter. Skin biopsies were obtained from 10 participants to evaluate pigmentation, vascularity and the expression levels of possible paracrine factors contributing to the effect of TA. RESULTS: Most of the participants had mild melasma, with mMASI of < 5. The mMASI scores significantly improved in 22 of 23 participants after application. The L* values were increased and the a* values were decreased in both lesional and perilesional normal skin. Fontana-Masson staining showed a significant decrease in melanin content in the epidermis. The number of CD31-positive vessels and the expression of the vascular endothelial growth factor both tended to decrease. Endothelin (ET)-1 was found to be downregulated with TA. CONCLUSIONS: Topical TA is effective for melasma. This immunohistochemical study found that suppression of ET-1 could be one of the mechanisms of action of TA on melasma.

A phase I study of binimetinib (MEK162) in Japanese patients with advanced solid tumors.

PURPOSE: Binimetinib is a potent, selective MEK1/2 inhibitor with demonstrated efficacy against BRAF- and RAS-mutant tumors. Retinal adverse events associated with MEK inhibitors have been reported in some cases. The aim of this study was to assess single-agent binimetinib, with detailed ophthalmologic monitoring, in Japanese patients with advanced solid tumors. METHODS: This was an open-label phase I dose-escalation and dose-expansion study (NCT01469130). Adult patients with histologically confirmed, evaluable, advanced solid tumors were enrolled and treated with binimetinib 30 or 45 mg twice daily (BID). The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of single-agent binimetinib in Japanese patients. RESULTS: Twenty-one patients were enrolled; 3 and 8 patients had documented BRAF and KRAS mutations, respectively. Two of 6 patients (33 %) receiving binimetinib 45 mg BID in dose-escalation experienced recurrent grade 2 retinal adverse events (AEs) which were reversible, and this dose was declared the MTD and RP2D. All patients experienced ≥1 AE suspected to be treatment related; the most common (>50 %) were blood creatine phosphokinase increase (76 %), retinal detachment and aspartate aminotransferase increase (62 % each), and diarrhea (52 %). There were no complete or partial responses; 14 patients (67 %) had stable disease, which lasted >180 days in 5 patients. Expression of phospho-ERK decreased in the skin following binimetinib treatment at both dose levels, indicating target inhibition. CONCLUSIONS: Binimetinib demonstrated efficacy and acceptable safety in Japanese patients with solid tumors, supporting the 45 mg BID dose of binimetinib as the RP2D.