Discovery of orally bioavailable inhibitors of MALT1 with in vivo activity for psoriasis.

We report the design, synthesis, and biological activity of a series of compounds that exhibit potent mucosa-associated lymphoid tissue lymphoma translocation 1 (MALT1) inhibition. Structural transformation of the substructures of a starting compound gave amidomethyl derivatives and sulfonylguanidine derivatives that exhibited potent inhibition of MALT1. Compound 37 had good oral bioavailability and showed anti-psoriatic activity in an imiquimod-induced psoriasis mouse model after oral administration.

Challenges to Accurate Estimation of Methane Emission from Septic Tanks with Long Emptying Intervals.

Septic tanks in low- and middle-income countries are often not emptied for a long time, potentially resulting in poor pollutant removal efficiency and increased greenhouse gas emissions, including methane (CH4). We examined the impact of long emptying intervals (4.0-23 years) on the biochemical oxygen demand (BOD) removal efficiency of 15 blackwater septic tanks and the CH4 emission rates of 23 blackwater septic tanks in Hanoi. The average BOD removal efficiency was 37% (-2-65%), and the average CH4 emission rate was 10.9 (2.2-26.8) g/(cap·d). The emptying intervals were strongly negatively correlated with BOD removal efficiency (R = -0.676, p = 0.006) and positively correlated with CH4 emission rates (R = 0.614, p = 0.001). CH4 emission rates were positively correlated with sludge depth (R = 0.596, p = 0.002), but against expectation, negatively correlated with BOD removal efficiency (R = -0.219, p = 0.451). These results suggest that shortening the emptying interval improves the BOD removal efficiency and reduces the CH4 emission rate. Moreover, the CH4 emission estimation of the Intergovernmental Panel on Climate Change, which is a positive conversion of BOD removal, might be inaccurate for septic tanks with long emptying intervals. Our findings suggest that emptying intervals, sludge depth, and per-capita emission factors reflecting long emptying intervals are potential parameters for accurately estimating CH4 emissions from septic tanks.

Seasonal effects, spatial distribution, and possible sources of microplastics in the Chao Phraya River estuary, Thailand.

Microplastics (MPs) in estuaries are sources of plastic debris that enter the marine environment. However, there is limited information on the seasonal effect on the accumulation of MPs in the estuaries of Thailand. The abundance and spatial distribution of MPs in the dry and wet seasons were investigated in the Chao Phraya River estuary, and possible emission sources were traced. Dominant factors affecting the distribution patterns of MPs have also been reported. All collected water samples contained MPs, with a mean abundance of 4.0 ± 2.8 × 105 particles/km2 in the wet season and 5.2 ± 3.3 × 105 particles/km2 in the dry season. Fragments were mostly observed, with polypropylene and polyethylene being the dominant polymers. The findings also showed that accumulation of MPs was directly influenced by the river discharge rate into the estuary. Further, the spatial distribution of MPs was closely related to seasonal variations in sea surface currents. Microplastic pollution status with seasonal variations and possible emission sources could provide important information to the government and local environmental organizations for MP pollution prevention and future MP studies in estuarine environments.

A simplified material flow analysis employing local expert judgment and its impact on uncertainty.

Material flow analysis (MFA) is an effective tool for waste management, but low- and middle-income countries lack essential data for MFA. This study proposed a simplified MFA (sMFA) utilizing local expert judgment (LEJ) and examining the impact of simplification on its uncertainty. A stochastic sMFA model was developed for nitrogen and phosphorus in urban Mandalay, Myanmar. This model was compared with the intensive MFA (iMFA) model employing intensive surveys for primary data collection. For the total loadings to the environment, the medians of the sMFA were higher by 3% and 11%, respectively, for nitrogen and phosphorus than those of the iMFA. The widths of the 80% confidence intervals of these loadings in the sMFA, normalized by those in the iMFA, were - 0.05 and - 0.11, respectively. The three largest flows to the environment were the same for the two models: on-site sanitation effluent/leakage, greywater, and industrial wastewater. Large median gaps between the models were observed for industrial wastewater, fecal sludge, and human excreta, associated with informal waste management, whereby LEJ did not work well. Overall, the sMFA demonstrated a good estimation of nitrogen and phosphorus flows with limited increase of uncertainty, still requiring focused attention on informal waste streams. Supplementary Information: The online version contains supplementary material available at 10.1007/s10163-023-01660-5.

Staphylococcus pettenkoferi bacteremia in a tertiary care hospital in Japan: Report of three cases.

Staphylococcus pettenkoferi is a coagulase-negative staphylococci (CoNS) species first isolated in 2002. Human infections caused by S. pettenkoferi are rare. We herein report three cases of S. pettenkoferi bacteremia in a tertiary care hospital in Japan. Staphylococcus pettenkoferi can be a causative pathogen of catheter related blood stream infection including complicated infection, and unknown source of bacteremia. All of the patients presented with fever and shaking chills, and good clinical outcome. Further research is needed to determine the role of this organism as a pathogen and frequency.

Human source identification by using a human-associated Escherichia coli genetic marker in the Mae Klong River, Thailand.

Contamination caused by microbial fecal pollution in water bodies is a serious problem in many countries, especially in low- and middle-income countries. Therefore, fecal source tracking is an important method used to understand the source of fecal contamination and to decrease the hazard of waterborne diseases that occurs in the environment. In this study, a human-associated genetic marker for Escherichia coli (H8) was used to investigate the source of fecal contamination in the Mae Klong River, Thailand. Real-time PCR was performed with this marker for 500 E. coli isolates collected from 10 sampling sites along the river, including MK10 (upstream) to MK1 (downstream). The results showed that the proportions of H8-positive isolates were 46, 14, 10, 18, 14, 38, 12, 26, 32, and 14% at MK10-MK1, respectively. All positive proportions were significantly different between the locations (p < 0.001). The higher occurrence of E. coli with H8 marker detection indicated that domestic wastewater was largely discharged without proper treatment, which is attributable to the high population and the absence of proper sewage treatment in those areas.

Assessment of microplastic contamination in the urban lower Chao Phraya River of Bangkok city, Thailand.

Rivers are one of the major pathways for the transportation of microplastics (MPs) from land-based sources to the ocean. However, there are only a few studies on MPs in freshwater environments, particularly in Asian countries. In this study, MP contamination in the Chao Phraya River in selected locations distributed throughout Bangkok, Thailand was investigated. MPs were collected using a Manta net with a mesh size of 335 µm. After digestion and distinction based on density, MPs were observed using a stereomicroscope, and polymer types were identified using Fourier Transform Infrared Spectroscopy. MP concentrations detected in the five sampling locations of the river water from upstream to downstream were 11, 35, 40, 15, and 4 particles/m3, with an average concentration of 21±16 particles/m3. Most MPs were identified as either fragments or sheets/films. Polypropylene was the dominant polymer type. The number of MPs increases as their size decreases. Potential sources of MPs may include the degradation of single-use plastic products, especially containers and plastic packaging. MP concentrations and characteristics varied for different locations, indicating different sources and pathways of MPs in urban contexts. Further investigation on the different pathways of the transportation of MPs to river water from land-based sources is required.

Greenhouse Gas Emissions from Blackwater Septic Systems.

Septic systems are potentially a significant source of greenhouse gases (GHGs). The present study investigated GHGs from the blackwater septic systems that are widely used especially in low- and middle-income countries. Ten blackwater septic tanks in Hanoi, Vietnam, were investigated using the floating chamber method. The average methane and carbon dioxide emission rates measured at the first compartment (65% of total capacity) of the septic tanks were 11.92 and 20.24 g/cap/day, respectively, whereas nitrous oxide emission was negligible. Methane emission rate was significantly correlated with septage oxidation-reduction potential (ORP) (R = -0.67, p = 0.034), chemical oxygen demand mass (R = 0.78, p = 0.007), and biochemical oxygen demand mass (R = 0.78, p = 0.008), whereas it was not significantly correlated with water temperature (R = 0.26, p = 0.47) and dissolved oxygen (R = -0.59, p = 0.075) within the limited range: 30.6-31.7 °C and 0.03-0.34 mg-O2/L. The methane emission rates from septic tanks accumulating septage for >5 years were significantly higher than those at 0-5 years (p = 0.016). These results suggest that lower ORP and higher biodegradable carbon mass, in association with longer septage storage periods are key conditions for methane emissions. To the best of our knowledge, this is the first study to characterize GHG emissions from septic systems.

Seasonal and gender impacts on fecal exposure trends in an urban slum.

Seasonal and gender impacts have not been well considered in fecal exposure assessment, especially in low- and middle-income countries. This study examined the seasonal and gender impacts on fecal exposure trends in children through daily living activities in an urban slum in Bangladesh. We determined Escherichia coli concentrations in seven types of environmental samples (n = 232) and the activity data of children via diary recording, questionnaires, and interview surveys. Daily and monthly exposures were stochastically estimated for drinking, eating, pond bathing, well bathing, and hand-to-mouth contact. Of the five pathways, pond bathing and drinking contributed a large part of the daily and monthly exposure. Significant seasonal differences were observed in daily exposures for bathing, which were higher in the rainy season (2.59 × 102 CFU/day for boys and 6.19 × 10-1 CFU/day for girls) than in the dry season (1.69 × 102; 4.30 × 10-2), because of longer pond bathing time and more contaminated bathing water in the rainy season. In contrast, eating had significantly higher exposure in the dry season (3.71 × 10; 3.22 × 10) than the rainy season (1.50 × 10; 1.24 × 10) due to the higher dish contamination. Significantly higher daily exposure was observed in the bathing for boys than girls, as boys spent longer time for bathing at a heavily contaminated pond.

Informal Emptying Business in Mandalay: Its Reasons and Financial Impacts.

Globally, 2.8 billion people use on-site sanitation facilities, which need regular emptying of accumulated fecal sludge. Illegal dumping from informal emptying businesses, one of the major challenges in environmental management, is widely observed. Considering Mandalay, Myanmar, this study aimed to determine why informal emptying businesses are selected and estimate the lost revenue for a formal emptying service provider (FP) due to the informal businesses. We interviewed 400 households on their recognition and experiences regarding emptying services and willingness-to-pay for improved service. Revenue loss was estimated by comparing the present and theoretical maximum revenues. Results showed that 91.0% of households recognized FP only. Among 134 emptying-experienced households, 32.8%, 59.7%, and 4.5% chose FP with legal contact, FP with illegal contact, and informal service providers, respectively. The service fees from FP with illegal contact did not become revenue for FP; this was a major informal emptying business in the city. Differently from previous studies, the major illegal dumping was done by FP in this area. A great financial loss was estimated that FP lost 76.5% of the theoretical maximum revenue due to informal business. Logistic regression analysis indicated people's intention to shorten the waiting time through illegal contact, even by paying a higher fee. As emptying services are typically required immediately after fecal sludge is over-accumulated, shorter waiting times and faster contact methods were the reasons why the informal business was selected. Less bureaucratic and more customer friendly system could reduce revenue loss, charge more, and increase profits.

Evaluation of a human-associated genetic marker for Escherichia coli (H8) for fecal source tracking in Thailand.

High levels of microbial fecal pollution are a major concern in many countries. A human-associated genetic marker for Escherichia coli (H8) has recently been developed for fecal source tracking. The assessment of the H8 marker performance is crucial before it can be applied as a suitable method for fecal source tracking in each country. The performance (specificity and sensitivity) of the H8 marker was evaluated by using non-target host groups (cattle, buffalo, chicken, duck, and pig feces) and target host groups (influent and effluent from a wastewater treatment plant and septages). SYBR based real-time PCR (polymerase chain reaction) was done on 400 E. coli isolates from non-target and target host groups after E. coli isolation. It was found that the specificity from animal feces samples collected in Thailand was 96%. Moreover, influent, effluent, and septage samples showed the values of the sensitivity at 18, 12, and 36%, respectively. All of the non-target host groups were found to be significantly different with positive proportions from the target host group (septage samples) (p ≤ 0.01). Based on the results, this marker is recommended for use as a human-associated E. coli marker for identifying sources of fecal pollution in Thailand.

Levels of perfluorinated compounds (PFCs) in groundwater around improper municipal and industrial waste disposal sites in Thailand and health risk assessment.

The aims of this study were to examine the levels of perfluorinated compounds (PFCs) in groundwater around improperly developed municipal and industrial waste disposal sites, including estimating non-cancer risk and cancer risk from ingestion of the groundwater. A total of 27 groundwater samples were collected from two cities in Thailand, Ayutthaya and Chonburi. Seven target compounds were extracted by solid phase extraction (SPE) and analyzed by high-performance liquid chromatography-tandem mass spectrometer (HPLC-MS/MS). The results showed that the total PFCs in groundwater around municipal waste disposal sites (MWDSs) varied from 1.68 to 7.75 ng/L. In groundwater around the industrial waste disposal site (IWDS), total PFCs varied from 2.64 to 42.01 ng/L, which were significantly different from those found in groundwater around the MWDSs at p < 0.01. PFOS and PFOA were ubiquitous in both areas, while perfluorohexane sulfonate (PFHxS) was frequently found in the samples around IWDS. The findings possibly suggest that PFHxS has been introduced for use as an alternative substance for most current C8 and higher due to it having shorter chain length and shorter half-lives. The results for both non-cancer risk and cancer risk in all samples were acceptable.

Microplastics in wastewater and sludge from centralized and decentralized wastewater treatment plants: Effects of treatment systems and microplastic characteristics.

Domestic wastewater treatment plants (WWTPs) play a vital role in limiting the release of microplastics (MP) into the environment. This study examined MP removal efficiency from five centralized and four decentralized domestic WWTPs in Bangkok, Thailand. MP concentrations in wastewater and sludge were comparable between centralized and decentralized WWTPs, despite these decentralized WWTPs serving smaller populations and having limited treatment capacity. The elimination of MPs ranged from 50 to 96.8% in centralized WWTPs and 14.2-53.6% in decentralized WWTPs. It is noted that the retained MPs concentrations in sludge ranged from 20,000 to 228,100 MP/kg dry weight. The prevalence of synthetic fibers and fragments could be attributed to their pathways from laundry or car tires, and the accidental release of a variety of plastic wastes ended up in investigated domestic WWTPs. Removal of MPs between the centralized and decentralized WWTPs was influenced by several impact factors including initial MP concentrations, longer retention times, MP fragmentation, and variations of MP concentrations in sludge leading to different activated sludge process configurations. Sewage sludge has become a primary location for the accumulation of incoming microplastics in WWTPs. The MPs entering and leaving each unit process were varied due to the unique characteristics of MPs, and their different treatment efficiencies. While the extended hydraulic retention period in decentralized WWTPs decreased the MP removal efficacy, the centralized WWTP with the two-stage activated sludge process achieved the highest MP removal efficiency.

The importance of infectious disease specialists consulting on a weekly basis in a Japanese tertiary care hospital: A retrospective observational study.

Limited data are available regarding part-time infectious disease consultations (IDCs) and their importance in tertiary care teaching hospitals in Japan. This is a retrospective review of IDCs from June 2016 to March 2021 and describes IDC services provided by part-time infectious disease specialists once a week for 4 hours, and their impact on the quality of medical care, including antimicrobial stewardship. Data, such as the requesting department, requesting reasons, and final diagnoses, were analyzed. In April 2018, part-time infectious disease specialists launched consultation services and attended an antimicrobial stewardship team conference. Meropenem, tazobactam/piperacillin, and cefepime monthly days of therapy (DOT) were calculated to assess the effect of each intervention; a pre-post analysis was conducted using the Kruskal-Wallis test. Additional quality improvement (QI) projects related to infectious diseases were implemented. There were 237 IDCs during the study period. Consultations were mostly requested by the General Internal Medicine, Emergency Medicine, and Cardiology departments. The most common diagnoses were bone/joint, respiratory, and genitourinary infections. Infectious disease services, even on a part-time basis, achieve good outcomes in patient management, antimicrobial stewardship, and QI projects. DOT/1000 patient-days were reduced for meropenem and cefepime, while it increased for tazobactam/piperacillin. The DOT/1000 patient-days for the 3-antipseudomonal agents significantly decreased during this period. After implementing the QI tetanus vaccination project in the Emergency Room, the number of tetanus toxoid vaccinations per month increased.

The Changes in Broad-spectrum Antimicrobial Consumption during the COVID-19 Pandemic in a Japanese Acute Tertiary-care Hospital: An Interrupted Time-series Analysis.

Objective The novel coronavirus disease 2019 (COVID-19) pandemic has spread worldwide, and hospitals in Japan have been forced to respond to the situation. This study evaluated the broad-spectrum antimicrobial use before and during the COVID-19 pandemic in an acute tertiary-care hospital. Methods This single-center, retrospective study was conducted between January 2019 and June 2021. Patients We reviewed patients treated with three broad-spectrum antipseudomonal agents: carbapenems, tazobactam/piperacillin, and cefepime. Monthly aggregated hospital antimicrobial consumption was measured as days of therapy (DOTs) per 1,000 patient-days, and the monthly incidences of Clostridioides difficile infection (CDI), multidrug-resistant Pseudomonas aeruginosa (MRPA), and carbapenemase-producing Enterobacteriaceae (CPE) were recorded. Results The median monthly carbapenem-DOTs during the pre-pandemic and pandemic era were 8.4 and 8.2 per 1,000 patient-days, respectively. A time-series analysis showed non-significant changes in the level between periods (coefficients: 2.08; 95% confidence interval [CI]: -2.9 to 7.0; p=0.44). No change in the trend of monthly carbapenem-DOTs was observed after intervention. No post-intervention changes in the incidence of MRPA or CPE were observed; however, the trend in the incidence of CDI per 1,000 patient-days significantly differed between the two periods (coefficient: -0.04; 95% CI: -0.07, 0.00; p=0.01), and a downward trend was observed in the monthly CDI incidence during the COVID-19 period. Conclusion The consumption of broad intravenous antimicrobial agents has not changed significantly during the pandemic. We need to maintain the quality of medical care, including antimicrobial stewardship, even in specialized resource-limited facilities during a pandemic.

Repetitive administration of cultured human CD34+ cells improve adenine-induced kidney injury in mice.

BACKGROUND: There is no established treatment to impede the progression or restore kidney function in human chronic kidney disease (CKD). AIM: To examine the efficacy of cultured human CD34+ cells with enhanced proliferating potential in kidney injury in mice. METHODS: Human umbilical cord blood (UCB)-derived CD34+ cells were incubated for one week in vasculogenic conditioning medium. Vasculogenic culture significantly increased the number of CD34+ cells and their ability to form endothelial progenitor cell colony-forming units. Adenine-induced tubulointerstitial injury of the kidney was induced in immunodeficient non-obese diabetic/severe combined immunodeficiency mice, and cultured human UCB-CD34+ cells were administered at a dose of 1 × 106/mouse on days 7, 14, and 21 after the start of adenine diet. RESULTS: Repetitive administration of cultured UCB-CD34+ cells significantly improved the time-course of kidney dysfunction in the cell therapy group compared with that in the control group. Both interstitial fibrosis and tubular damage were significantly reduced in the cell therapy group compared with those in the control group (P < 0.01). Microvasculature integrity was significantly preserved (P < 0.01) and macrophage infiltration into kidney tissue was dramatically decreased in the cell therapy group compared with those in the control group (P < 0.001). CONCLUSION: Early intervention using human cultured CD34+ cells significantly improved the progression of tubulointerstitial kidney injury. Repetitive administration of cultured human UCB-CD34+ cells significantly improved tubulointerstitial damage in adenine-induced kidney injury in mice via vasculoprotective and anti-inflammatory effects.

Discovery and structure-activity relationship of 2,6-disubstituted pyrazines, potent and selective inhibitors of protein kinase CK2.

We report the discovery and structure-activity relationship of 2,6-disubstituted pyrazines, which are potent and selective CK2 inhibitors. Lead compound 1 was identified, and derivatives were prepared to develop potent inhibitory activity. As a result, we obtained compound 7, which was the smallest unit that retained potency. Then, introducing an aminoalkyl group at the 6-position of the indazole ring resulted in improved efficacy in both enzymatic and cell-based CK2 inhibition assays. Moreover, compound 13 showed selectivity against other kinases and in vivo efficacy in a rat nephritis model. These results show that 2,6-disubstituted pyrazines have potential as therapeutic agents for nephritis.

Worldwide surveys of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) in water environment in recent years.

Recently, perfluorinated compounds (PFCs) have been noted as causes of some of the important environmental problems in recent years due to their occurrences and properties. The most commonly used PFCs are perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), which have been used in many kinds of products. They have been found in surface water and tap water in both developed and developing countries around the world including in North America, Europe and Asia. In most countries, rivers are the source of tap water, which is one of the important pathways in which PFCs reach humans. It is essential to evaluate PFOS and PFOA contamination in the river basin. The purpose of this field study was to determine the presence of PFOS and PFOA in rivers around the world. The surveys were conducted in 15 countries during 2004 to 2010. In total, 539 samples were collected from the rivers in 41 cities. A solid phase extraction (SPE) coupled with HPLC-ESI-MS/MS were used for the analysis of these chemicals. PFOS and PFOA were detected in all 41 cities not only in industrialized areas but also in non-industrialized areas, representing that these compounds undergo long-range transportation in the environment. The average concentration of PFOS in each city ranged from not detected to 70.1 ng/L. The average concentration of PFOA in each city was in the range 0.2-1,630.2 ng/L. The industrialized areas show higher contamination in both PFOS and PFOA concentrations than non-industrialized areas. Industrial activities are some of the major sources of PFCs contamination in rivers.

Rapid and efficient removal of organic matter from sewage sludge for extraction of microplastics.

Microplastic pollution is recognized as an emerging global issue; however, no standardized method for the extraction of these pollutants from the environment currently exists and existing methods are ineffective for specific environmental matrices. An appropriate organic matter removal method is essential for the extraction of microplastics from organic-rich sludge to minimize interference during their identification and enhance compatibility of the identification steps. The present study aimed to establish an effective technique for the digestion of organic matter-rich sludge using hydrogen peroxide and Fenton's reagent at varying temperatures, times, and concentrations of an iron catalyst. The organic matter removal efficiency of the five protocols utilized varied from 81.5 % to 87.1 %. Polymers such as polyvinyl chloride (PVC), high density polyethylene (HDPE), low density polyethylene (LDPE), polypropylene (PP), and polystyrene (PS) retained most of their physical and chemical properties after the treatments, with minor changes in the surface area, weight, and FTIR spectra properties. Polyethylene terephthalate (PET), PET fiber, polyamide (PA) fiber, and polymethyl methacrylate (PMMA) fiber were significantly degraded via treating with H2O2 at 50 °C for 24 h. Protocol 4, treating with Fenton's reagent (H2O2 (30 %) + (0.05 M) FeSO4.7H2O) at 50 °C for 1 h is proposed as a rapid and effective method for the removal of organic matter from sludge. In addition to its rapidity, this method minimally impacts most polymers, and its high organic matter removal efficiency is associated with a significant reduction of suspended solids in sludge. The present study provides a validated approach that facilitates as an effective organic removal step during the extraction of MPs in sludge.

Impact of the antimicrobial stewardship program on hospital-acquired candidemia.

Antibiotic stewardship programs reduce antibiotic use without negative clinical outcomes. However, epidemiological data describing the relationship between implementing antimicrobial stewardship and candidemia incidence are scarce. This study aimed to evaluate the effect of antibiotic stewardship on the incidence of hospital acquired candidemia. We conducted a retrospective study from April 2017 to September 2020. We reviewed patients that were treated with three broad-spectrum antipseudomonal agents: carbapenem, tazobactam/piperacillin, and cefepime. Monthly aggregated hospital antimicrobial consumption was measured as days of therapy (DOTs) per 1000 patient-days, and the monthly incidence of hospital acquired candidemia was recorded. The median monthly carbapenem-DOTs during pre-intervention and intervention were 28.4 and 10.0, respectively. Time-series analysis showed significant level changes after intervention: - 10.0 DOTs (p = 0.02). There was a downward trend in the monthly carbapenem-DOTs after intervention. The median hospital-acquired candidemia incidence was 0.17 and 0.08 per 1000 patient-days during pre-intervention and intervention periods, respectively. Time-series analysis showed a significant level change after intervention (- 0.16 per 1000 patient-days; p = 0.048). The trend in the incidence of hospital-acquired candidemia did not significantly change between pre-intervention and intervention. Decreased broad-spectrum antibiotic use (particularly carbapenem) by our antimicrobial stewardship term may reduce hospital-acquired candidemia incidences.