Coagulation pretreatment coupled with indigenous microalgal-bacterial consortium system for on-site treatment of rural black wastewater.

Improper treatment of rural black wastewater (RBW) presents substantial challenges, including the wastage of resource, environmental contamination, and economic consequences. This study proposed an integrated process for RBW treatment, consisting of coagulation/flocculation (C/F) pretreatment and subsequent inoculation of indigenous microalgal-bacterial consortium (IMBC) for nitrogen recovery, namely C/F-IMBC process. Specifically, the optimal C/F conditions (polyaluminium chloride of 4 g/l, polyacrylamide of 50 mg/l, and pH of 6) were determined through a series of single-factor experiments, considering CN, turbidity, and dissolved organic matter (DOM) removal, economic cost, and potential influence on the water environment. Compared to the sole IMBC system for RBW treatment, the proposed C/F-IMBC process exhibited a remarkable 1.23-fold increase in microalgal growth and a substantial 17.6-22.6 % boost in nitrogen recovery. The altered RBW characteristic induced by C/F pretreatment was supposed to be responsible for the improved system performance. In particular, the abundance of DOM was decreased and its composition was simplified after C/F pretreatment, based on the analysis for excitation-emission matrices with parallel factor and gas chromatography-mass spectrometry, thus eliminating the potential impacts of toxic DOM components (e.g., Bis(2-ethylhexyl) phthalate) on IMBC activity. It should also be noted that C/F pretreatment modified microbial community structure as well, thereby regulating the expression of nitrogen-related genes and enhancing the system nitrogen recovery capacity. For instance, the functional Cyanobacteria responsible for nutrient recovery was enriched by 1.95-fold and genes involved in the assimilatory nitrate reduction to ammonia pathway were increased by 1.52-fold. These fundamental findings are expected to offer insights into the improvement of DOM removal and nitrogen recovery for IMBC-based wastewater treatment system, and provide valuable guidance for the development of sustainable on-site RBW treatment technologies.

Adverse drug reactions of non-statin antihyperlipidaemic drugs in China from 1989 to 2019: a national database analysis.

OBJECTIVE: This study aims to understand the adverse drug reactions (ADRs) for non-statin antihyperlipidaemic drugs included in the China Anti-hyperlipidemic Drug Database. DESIGN: An approach of Chinese national database analysis was employed to screen clinical trials involving non-statin antihyperlipidaemic drugs from 1989 to 2019. SETTING: The database was provided by the China National Medical Products Administration Information Centre. PARTICIPANTS: In total, 117 clinical studies with 8800 patients were selected from 2650 clinical trials of the Anti-hyperlipidemic Drug Database. INTERVENTIONS: The non-statin antihyperlipidaemic drugs were divided into three groups: (1) fibrates (fenofibrate, gemfibrozil, bezafibrate, etofylline clofibrate); (2) nicotinic acid and derivatives (niacin, acipimox) and (3) others (probucol, cholestyramine). RESULTS: The results of this study show that first, gastrointestinal symptoms were the most common reactions (6.975%), which account for approximately 50% of the reported cases with ADRs. Second, cholestyramine (16.418%) and gemfibrozil (13.158%) were the most common gastrointestinal side effect-causing non-statin antihyperlipidaemic drugs, which account for one-third of the population. Third, niacin (7.879%) and gemfibrozil (5.000%) were the most likely cause of liver disease symptoms. Finally, niacin (10.909%) and acipimox (18.847%) were the major non-statin antihyperlipidaemic drugs with skin symptoms. CONCLUSION: This study revealed that gastrointestinal symptoms were the most common ADRs of fibrates, probucol and cholestyramine in the Chinese population. For nicotinic acid and derivatives, the ADRs of skin symptoms were the most common in China.

Adverse drug reactions of statin therapy in China from 1989 to 2019: a national database analysis.

BACKGROUND: The baseline incidence of the adverse events of statin therapy varies between countries. Notably, Chinese patients seem more susceptible to myopathy induced by simvastatin. OBJECTIVES: This research studies the adverse drug reactions (ADRs) of statin therapy in China by analysing trial-based data from the Anti-hyperlipidaemic Drug Database built by the China National Medical Products Administration Information Centre. METHODS: All clinical trials involving statin therapy (including simvastatin, atorvastatin, fluvastatin, lovastatin, pravastatin and rosuvastatin) in China from 1989 to 2019 were screened. In total, 569 clinical studies with 37 828 patients were selected from 2650 clinical trials in the database. RESULTS: Among the reported cases with ADRs (2822/37 828; 7.460%), gastrointestinal symptoms were the most common (1491/37 828; 3.942%), followed by liver disease (486/37 828; 1.285%), muscle symptoms (444/37 828; 1.174%) and neurological symptoms (247/37 828; 0.653%). Pravastatin (231/1988; 11.620%) caused the most common gastrointestinal side effects, followed by fluvastatin (333/3094; 10.763%). The least likely to cause gastrointestinal irritation was rosuvastatin (82/1846; 4.442%). CONCLUSION: In Chinese clinical trials, gastrointestinal symptoms were the most common ADR of statin use for hyperlipidaemia and other cardiovascular diseases.

Effect of free ammonia shock on Chlorella sp. in wastewater: Concentration-dependent activity response and enhanced settleability.

The unstable microbial activity and unsatisfactory settling performance impede the development and implementation of microalgal wastewater treatment, especially in high-ammonium wastewater in the presence of free ammonia (FA). The shock of FA due to the nutrient fluctuation in wastewater was demonstrated as the primary stress factor suppressing microalgal activities. Recent study has clearly revealed the inhibition mechanism of FA at a specific high level (110.97 mg/L) by inhibiting the genetic information processing, photosynthesis, and nutrient metabolism. However, the effects of various FA shock concentrations on microalgal activities and settling performance remain unknown, limiting the wastewater bioremediation efficiencies improvement and the process development. Herein, a concentration-dependent shock FA (that was employed on microalgae during their exponential growth stages) effect on microalgal growth and photosynthesis was observed. Results showed that the studied five FA shock concentrations ranging from 25 to 125 mg/L significantly inhibited biomass production by 14.7-57.0%, but sharp reductions in photosynthesis with the 36.0-49.0% decreased Fv/Fm values were only observed when FA concentration was above 75.0 mg/L. On the other hand, FA shock enhanced microalgal settling efficiency by 12.8-fold, which was believed to be due to the stimulated intra- and extracellular protein contents and thereby the enhanced extracellular polymer substances (EPS) secretion. Specifically, FA shock induced 40.2 ± 2.3% higher cellular protein content at the cost of the decreased carbohydrates (22.6 ± 1.3%) and fatty acid (39.0 ± 0.8%) contents, further improving the protein secretion by 1.21-fold and the EPS production by 40.2 ± 2.3%. These FA shock-induced variations in intra- and extracellular biomolecules were supported by the up-regulated protein processing and export at the assistance of excessive energy generated from fatty acid degradation and carbohydrates consumption. In addition, FA shock significantly decreased the biomass nutritional value as indicated by the 1.86-fold lower essential amino acid score and nearly 50% reduced essential to non-essential amino acids ratio, while slightly decreased the biodiesel quality. This study is expected to enrich the knowledge of microalgal activities and settling performance in response to fluctuant ammonium concentrations in wastewater and to promote the development of microalgal wastewater treatment.

Molecular Surveillance and in vitro Drug Sensitivity Study of Plasmodium falciparum Isolates from the China-Myanmar Border.

The emergence and spread of resistance in Plasmodium falciparum to the frontline treatment artemisinin-based combination therapies in Southeast Asia require close monitoring of the situation. Here, we collected 36 clinical samples of P. falciparum from the China-Myanmar border in 2014-2016, adapted these parasites to continuous culture, and performed in vitro drug assays on seven antimalarial drugs. Data for 23 parasites collected in 2010 and 2012 from the same area reported in an early study were used to assess longitudinal changes in drug sensitivity. Parasites remained highly resistant to chloroquine (CQ) and pyrimethamine, whereas they were generally sensitive to mefloquine (MFQ), lumefantrine (LMF), naphthoquine (NQ), and pyronaridine (PND). Parasites showed a similar temporal trend in sensitivity to CQ, NQ, and PND, with gradual reduction in the half-maximal inhibitory concentrations (IC50s) after 2012. The IC50s to the aminoalcohol drugs MFQ, LMF, and quinine (QN) all significantly declined in 2014, followed by various degrees of increase in 2016. Pyrimethamine displayed a continuous increase in IC50 over the years. The Dd2-like P. falciparum chloroquine-resistant transporter mutations were fixed or nearly fixed in the parasite population. The P. falciparum multidrug resistance 1 F1226Y mutation was detected in 80% parasites in 2016 and associated with reduced sensitivity to LMF and QN (P < 0.05). The N51I in P. falciparum dihydrofolate reductase and K540E/N and A581G in P. falciparum dihydropteroate synthase that are associated with antifolate resistance were either fixed or were approaching fixation in recent years. This study provides an updated picture and temporal trend of antimalarial drug resistance in the China-Myanmar border region, which will serve as a reference for antimalarial treatment.

Efficacy of directly-observed chloroquine-primaquine treatment for uncomplicated acute Plasmodium vivax malaria in northeast Myanmar: A prospective open-label efficacy trial.

BACKGROUND: Chloroquine (CQ) and primaquine (PQ) remain the frontline drugs for radical cure of uncomplicated P. vivax malaria in the Greater Mekong Sub-region (GMS). Recent reports of decreased susceptibility of P. vivax to CQ in many parts of the GMS raise concerns. METHODS: From April 2014 to September 2016, 281 patients with uncomplicated P. vivax infection attending clinics in border settlements for internally displaced people in northeast Myanmar were recruited into this study. Patients were treated with standard regimen of 3-day CQ and concurrent 14-day PQ (3.5 mg/kg total dose) as directly observed therapy, and followed for recurrent parasitemia within 28 days post-patency. RESULTS: Within the 28-day follow-up period, seven patients developed recurrent parasitemia, resulting in a cumulative rate of parasite recurrence of 2.6%. Five of the seven parasitemias recurred within two weeks, and two of those failed to clear within seven days, indicating high-grade resistance. CONCLUSION: Although failure of CQ/PQ treatment of P. vivax was relatively infrequent in northeast Myanmar, this study nonetheless confirms that CQ/PQ-resistant strains do circulate in this area, some of them of a highly resistant phenotype. It is thus recommended that patients who acquire vivax malaria in Myanmar be treated an artemisinin-combination therapy along with hypnozoitocidal primaquine therapy to achieve radical cure.

Increasing trends of malaria in a border area of the Greater Mekong Subregion.

BACKGROUND: Intensive malaria transmission along international borders is a significant impediment to malaria elimination in the Greater Mekong Subregion (GMS) of Southeast Asia. Passive case detection (PCD) was used to study the dynamics and trends of malaria transmission at the China-Myanmar border to provide epidemiologic information for improved malaria control. METHODS: PCD was conducted in one hospital and 12 clinics near the Laiza town in northeast Myanmar from 2011 to 2016. Clinical malaria was diagnosed by microscopy and demographic information was captured using a structured questionnaire at the time of the patient's presentation for care. RESULTS: Over the study period, 6175 (19.7%) malaria cases were confirmed by microscopy from 31,326 suspected cases. The four human malaria parasite species were all identified, with Plasmodium vivax and Plasmodium falciparum accounting for 5607 (90.8%) and 481 (7.8%) of the confirmed cases, respectively. In contrast to the steady decline of malaria in the general GMS, the study site had an upward trend of malaria incidence with vivax malaria outbreaks in 2013 and 2016. Adult males, children under the age of 15, and those with occupations such as farming, being a soldier or student, had significantly higher risks of clinical malaria compared to having fevers from other aetiologies. A self-reported history of clinical malaria was also associated with a higher risk of confirmed malaria. CONCLUSIONS: The China-Myanmar border area has experienced an overall upward trend of malaria incidence in recent years with P. vivax becoming the predominant species. Evidence-based control strategies need to focus on high-risk populations.

In vitro susceptibility of Plasmodium falciparum isolates from the China-Myanmar border area to artemisinins and correlation with K13 mutations.

Mutations in the Kelch domain of the K13 gene (PF3D7_1343700) were previously associated with artemisinin resistance in Plasmodium falciparum. This study followed the dynamics of the K13 polymorphisms in P. falciparum parasites from the China-Myanmar border area obtained in 2007-2016, and their in vitro sensitivities to artesunate (AS) and dihydroartemisinin (DHA). The 50% effective concentration (EC5072h) values of 133 culture-adapted field isolates to AS and DHA, measured by the conventional 72 h SYBR Green I-based assay, varied significantly among the parasites from different years; all were significantly higher than that of the reference strain 3D7. Compared with parasites from 2007 to 2008, ring survival rates almost doubled in parasites obtained in later years. Sequencing the full-length K13 genes identified 11 point mutations present in 85 (63.9%) parasite isolates. F446I was the predominant (55/133) variant, and its frequency was increased from 17.6% (3/17) in 2007 to 55.9% (19/34) in 2014-2016. No wild-type (WT) Kelch domain sequences were found in the 34 samples obtained from 2014 to 2016. In the 2014-2016 samples, a new mutation (G533S) appeared and reached 44.1% (15/34). Collectively, parasites with the Kelch domain mutations (after amino acid 440) had significantly higher ring survival rates than the WT parasites. Individually, F446I, G533S and A676D showed significantly higher ring survival rates than the WT. Although the drug sensitivity phenotypes measured by the RSA6h and EC5072h assays may be intrinsically linked to the in vivo clinical efficacy data, the values determined by these two assays were not significantly correlated. This study identified the trend of K13 mutations in parasite populations from the China-Myanmar border area, confirmed an overall correlation of Kelch domain mutations with elevated ring-stage survival rates, and emphasized the importance of monitoring the evolution and spread of parasites with reduced artemisinin sensitivity along the malaria elimination course.

Longitudinal surveillance of drug resistance in Plasmodium falciparum isolates from the China-Myanmar border reveals persistent circulation of multidrug resistant parasites.

Multidrug-resistant Plasmodium falciparum in the Greater Mekong Subregion of Southeast Asia is a major threat to malaria elimination and requires close surveillance. In this study, we collected 107 longitudinal clinical samples of P. falciparum in 2007-2012 from the malaria hypoendemic region of the China-Myanmar border and measured their in vitro susceptibilities to 10 antimalarial drugs. Overall, parasites had significantly different IC50 values to all the drugs tested as compared to the reference 3D7 strain. Parasites were also genotyped in seven genes that were associated with drug resistance including pfcrt, pfmdr1, pfmrp1, pfdhfr, pfdhps, pfnhe1, and PfK13 genes. Despite withdrawal of chloroquine and antifolates from treating P. falciparum, parasites remained highly resistant to these drugs and mutations in pfcrt, pfdhfr, and pfdhps genes were highly prevalent and almost reached fixation in the study parasite population. Except for pyronaridine, quinine and lumefantrine, all other tested drugs exhibited significant temporal variations at least between some years, but only chloroquine and piperaquine had a clear temporal trend of continuous increase of IC50s. For the pfmrp1 gene, several mutations were associated with altered sensitivity to a number of drugs tested including chloroquine, piperaquine, lumefantrine and dihydroartemisinin. The association of PfK13 mutations with resistance to multiple drugs suggests potential evolution of PfK13 mutations amid multidrug resistance genetic background. Furthermore, network analysis of drug resistance genes indicated that certain haplotypes associated multidrug resistance persisted in these years, albeit there were year-to-year fluctuations of the predominant haplotypes.

Vascular and perivascular niches, but not the osteoblastic niche, are numerically restored following allogeneic hematopoietic stem cell transplantation in patients with aplastic anemia.

Bone marrow (BM) niches, including the osteoblastic, vascular, and perivascular niches, are numerically impaired in patients with aplastic anemia (AA). It remains unclear whether these niches are numerically restored in AA patients after allogenic hematopoietic stem cell transplantation (allo-HSCT). To investigate changes in BM niches, we monitored 52 patients with AA who had undergone allo-HSCT and performed immunohistochemical studies of BM niches using antibodies against CD34, CD146, and osteopontin. After allo-HSCT, patients with AA exhibited a remarkable increase in the number of cellular elements in the BM niches, including the vascular and perivascular cells. However, no significant differences in endosteal cells were detected. We explored the cause of this restoration by analyzing the origin of BM mesenchymal stem cells (BM-MSCs) and the expression of cytokines in BM plasma. STR-PCR revealed that the BM-MSCs were derived from the host, not the donor. In addition, significantly elevated levels of vascular endothelial growth factor (VEGF) were found after allo-HSCT. Our data indicates that vascular and perivascular niches are numerically restored, but the endosteal niche remains numerically impaired in patients with AA after allo-HSCT, and that levels of VEGF, but not donor-derived BM-MSCs, may correlate with the restoration of BM niches.