Background:The increasing incidence of cancers and infectious diseases worldwide presents a significant public health challenge that requires immediate intervention.Our strategy to tackle this issue involves the devel...Background:The increasing incidence of cancers and infectious diseases worldwide presents a significant public health challenge that requires immediate intervention.Our strategy to tackle this issue involves the development of pharmaceutical formulations that combine phytopolyphenols(P),targeted drugs(T),and metal ions(M),collectively referred to as PTM regimens.The diverse pharmacological properties of PTM regimens are hypothesized to effectively reduce the risk factors associated with both cancers and infectious diseases.Methods:The effects of the pharmaceutical agents on the proliferation of cultured cancer cells and pathogens were assessed after 72 h and 48 h,respectively,using the MTT(3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide)assay and optical density at 600 nm(OD600).The synergistic effects of drug combinations were evaluated by combination index(CI),where CI<1 indicates synergism,CI=1 indicates addition,and CI>1 indicates antagonism.Efficacy index(EI)was also calculated.Assays of efflux pump ATPase activities were conducted using a colorimetric method.Results:This study evaluated the anticancer and antibacterial efficacy of PTM regimens that included phytopolyphenols(specifically curcumin(C)and green tea polyphenols(G)),repurposed drugs(memantine(Mem),thioridazine(TRZ),cisplatin(Cis),and 5-fluorouracil(5FU)),and ZnSO_(4)(Zn)across three cultured cancer cell lines and four cultured pathogens.The most effective regimens,GC·Mem·Zn and GC·TRZ·Zn,significantly enhanced the anticancer efficacy(EI)of cisplatin across the three cancer lines(OECM-1,A549 and DLD-1)by 7,11 and 21;7,9,and 17 fold,respectively,while the enhancements for 5-fluorouracil were 5,6 and 12;5,5 and 9 fold,respectively.Furthermore,these PTM regimens demonstrated substantial synergistic inhibition of Na^(+)-K^(+)-Mg^(2+)-ATPase and Mg^(2+)-ATPase in the cultured cancer cells,as well as a reduction in biofilm formation by the four cultured pathogens,suggesting their potential to address the challenges of multidrug resistance in cancers and infectious diseases.Conclusion:Given that all drugs incorporated in the PTM regimens have been clinically validated for safety and efficacy,particularly regarding their synergistic selective anticancer efficacy,inhibition of efflux pump ATPase,and antibiofilm formation of pathogens,these regimens may offer a promising therapeutic strategy to alleviate the severe side effects and drug resistance typically associated with chemotherapeutic agents.Further preclinical and clinical investigations are warranted.展开更多
A clinical trial of nab-paclitaxel plus capecitabine as a first-line treatment for advanced biliary tract cancers was conducted.We analyzed the development of systemic therapy recommended by the National Comprehensive...A clinical trial of nab-paclitaxel plus capecitabine as a first-line treatment for advanced biliary tract cancers was conducted.We analyzed the development of systemic therapy recommended by the National Comprehensive Cancer Network guidelines and the development of nab-paclitaxel combination chemotherapy for advanced biliary tract cancers(BTCs)and concluded that nab-paclitaxel plus capecitabine is a promising first-line regimen for advanced BTCs.展开更多
BACKGROUND Hepatic artery infusion chemotherapy(HAIC)is a widely used local therapeutic approach for intermediate to advanced-stage hepatocellular carcinoma(HCC),exhibiting considerable efficacy.However,the prevalence...BACKGROUND Hepatic artery infusion chemotherapy(HAIC)is a widely used local therapeutic approach for intermediate to advanced-stage hepatocellular carcinoma(HCC),exhibiting considerable efficacy.However,the prevalence of postoperative pain highlights the importance of pain management.Owing to the limitations inherent in existing pain management strategies,this study investigates and assesses the analgesic effectiveness of a multimodal treatment protocol in mitigating pain after HAIC procedures.AIM To provide patients with a more comprehensive and effective pain management strategy.METHODS A total of 100 patients with primary HCC who underwent HAIC were randomly assigned to a control group(n=50)and a multimodal group(n=50).Baseline characteristics and perioperative data were collected.Upon enrollment,patients in the multimodal group received parecoxib(40 mg)30 minutes before HAIC,followed by 48 hours of patient-controlled analgesia with sufentanil.In contrast,the control group underwent standard preoperative preparation(psychological support)and received dezocine(5 mg)intraoperatively,with intravenous flurbiprofen(100 mg)administered every 12 hours for 48 hours postoperatively.RESULTS Compared to the control group,the multimodal analgesia group exhibited significantly lower resting and movement visual analog scale pain scores at postoperative 0,2,4,6,and 12 hours(P<0.05).Furthermore,the multimodal group experienced a reduced incidence of postoperative nausea and vomiting,as well as a lower overall frequency of adverse events,compared to the control group(P<0.05).Patient satisfaction was also significantly higher in the multimodal group than in the control group(P<0.05).CONCLUSION Our study demonstrates that multimodal analgesia is effective in reducing postoperative pain,minimizing adverse reactions,and improving patient satisfaction in HCC patients undergoing HAIC.This approach provides valuable clinical strategies for optimizing pain management in this patient population.展开更多
Diffuse large B-cell lymphoma(DLBCL),the most common subtype of non-Hodgkin’s lymphoma(NHL)worldwide,accounts for 39% and 44% of nodal and extranodal NHL cases in China,respectively1.Standard first-line treatment for...Diffuse large B-cell lymphoma(DLBCL),the most common subtype of non-Hodgkin’s lymphoma(NHL)worldwide,accounts for 39% and 44% of nodal and extranodal NHL cases in China,respectively1.Standard first-line treatment for DLBCL is chemo-immunotherapy with rituximab,cyclophos-phamide,doxorubicin,vincristine,and prednisone,which cures 50%-60% of patients2.展开更多
BACKGROUND Gastric cancer is one of the most common malignant tumors worldwide,with its incidence and mortality rates ranking among the highest in gastrointestinal cancers.The overexpression or gene amplification of h...BACKGROUND Gastric cancer is one of the most common malignant tumors worldwide,with its incidence and mortality rates ranking among the highest in gastrointestinal cancers.The overexpression or gene amplification of human epidermal growth factor receptor 2(HER-2)occurs in approximately 15%-20%of gastric cancers and serves as a critical molecular target influencing prognosis and treatment out-comes.For patients with HER-2-positive gastric cancer,trastuzumab combined with platinum-based chemotherapy has been established as the standard first-line treatment.However,despite the demonstrated clinical benefits in prolonging survival,the overall efficacy remains limited.In recent years,with the successful application of immune checkpoint inhibitors(ICIs)in various malignant tumors,combining ICIs with existing standard treatment regimens has emerged as a promising approach to enhance the therapeutic efficacy of HER-2-positive gastric cancer.Nevertheless,the efficacy and prognostic factors of ICIs combined with trastuzumab and chemotherapy in HER-2-positive gastric cancer remain unclear.AIM To analyze the efficacy of ICIs combined with standard treatment regimens and the prognostic factors in patients with advanced HER-2-positive gastric cancer.METHODS Clinical data from 104 patients with advanced HER-2-positive gastric cancer who were treated at our hospital between March 2021 and May 2023 were retrospectively analyzed.Patients were divided into a control group(n=54,treated with trastuzumab combined with platinum-based chemotherapy as the standard regimen)and an observation group(n=50,treated with ICIs in addition to the standard regimen).The therapeutic efficacy,survival outcomes,and adverse reactions were compared between the two groups.Univariate and Cox multivariate analyses were performed to identify factors influencing patient prognosis.RESULTS With a median follow-up time of 14.6 months,there were no significant differences between the two groups in terms of objective response rate or disease control rate(P>0.05).The median progression-free survival(mPFS)and mPFS for patients with immunohistochemistry 3+in the observation group were significantly higher than those in the control group(P<0.05).Among patients in the observation group,those with positive programmed death-ligand 1(PD-L1)expression had a significantly higher mPFS than those with negative PD-L1 expression(P<0.05).Regarding adverse events,significant differences were observed between the two groups in hypothyroidism and neutropenia(P<0.05).Cox multivariate analysis showed that Eastern Cooperative Oncology Group(ECOG)performance status,peritoneal metastasis,positive programmed death-1 expression,and treatment regimen were independent factors influencing PFS(hazard ratio>1,P<0.05).CONCLUSION ICIs combined with standard treatment regimens for patients with advanced HER-2-positive gastric cancer demonstrate favorable clinical efficacy,significantly prolonging PFS with manageable safety.ECOG performance status,peritoneal metastasis,positive PD-L1 expression,and treatment regimen are independent factors influ-encing PFS,warranting increased clinical attention to patients exhibiting these factors.展开更多
Oral anticoagulation therapy with warfarin is used to prevent and treat venous and arterial thrombosis and embolism. Its narrow therapeutic index should be monitored carefully in order to reach the desired outcomes. T...Oral anticoagulation therapy with warfarin is used to prevent and treat venous and arterial thrombosis and embolism. Its narrow therapeutic index should be monitored carefully in order to reach the desired outcomes. The complexity of the pharmacokinetic and pharmacodynamics profile of warfarin makes it a challenge to use during treatment. Its manufacturing characteristics play a key role in its dosage. The aim of this study is to examine and evaluate the effect of two different warfarin regimens in Chinese patients. A cross-sectional study design was adopted. Medical records of all patients （n = 368） who received warfarin therapy in cardio-thoracic surgery wards between Sep. 2008 and Dec. 2009 were reviewed. Details of antithrombotic results of international normalized ratio （INR） monitoring were obtained. Statistical analysis was performed to assess factors predictive of INR therapeutic range at patients＇ discharge time according to different warfarin regimens （2.5 mg in China and 3.0 mg in USA）. The patients＇ mean age was （48.23~12.96） years. The percentage of patients within the INR therapeutic range in the group treated with 2.5 mg warfarin （35.17%） was much lower than that in group treated with 3.0 mg warfarin （47.72%）. Therefore, a significance difference was observed （P = 0.032〈0.05）. In this study, statistical values have shown that most of the patients were related to medical case requesting INR target range of 1.8-2.2 and 2.0-2.5, respectively. There was a statistically significant difference between the two groups. The study showed that the 2.5 mg-warfarin regimen was less suitable than the 3.0 mg-warfarin regimen. Medication regimen should be simplified as much as possible, especially during different treatment period.展开更多
Biowaste valorization through anaerobic digestion is an attractive option to achieve both climate protection goals and renewable energy production.In this paper,a complete set of batch trials was carried out on kitche...Biowaste valorization through anaerobic digestion is an attractive option to achieve both climate protection goals and renewable energy production.In this paper,a complete set of batch trials was carried out on kitchen waste to investigate the effects of mild thermal pretreatment,temperature regimen and substrate/inoculum ratio.Thermal pretreatment was effective in the solubilisation of macromolecular fractions,particularly carbohydrates.The ability of the theoretical methodologies in estimating hydrogen and methane yields of complex substrates was evaluated by comparing the experimental results with the theoretical values.Despite the single batch configuration,a significant initial hydrogen production was observed,prior to methane yield.Main pretreatment effect was the gain in hydrogen production;the extent was highly variable according to the other parameters values.High hydrogen yields,up to 113 mL H2/g VSfed,were related to the prompt transformation of soluble sugars.Thermophilic regimen resulted,as expected,in faster digestions(up to 78 mL CH4/gVS/day) and sorted out pH inhibition.The relatively low methane yields(342-398 mL CH4/g VSfed) were the result of the consistent lignocellulosic content and low lipid content.Thermal pretreatment proved to be a promising option for the enhancement of hydrogen production in food waste dark fermentation.展开更多
Due to the wide use of silver nanoparticles(AgNPs) in various fields, it is crucial to explore the potential negative impacts on the aquatic environment of AgNPs entering into the environment in different ways. In thi...Due to the wide use of silver nanoparticles(AgNPs) in various fields, it is crucial to explore the potential negative impacts on the aquatic environment of AgNPs entering into the environment in different ways. In this study, comparative experiments were conducted to investigate the toxicological impacts of polyvinylpyrrolidone-coated silver nanoparticles(PVP-AgNPs) with two kinds of dosing regimens, continuous and one-time pulsed dosing, in different exposure media(deionized water and XiangJiang River water). There were a number of quite different experimental results(including 100% mortality of zebrafish,decline in the activity of enzymes, and lowest number and length of adventitious roots) in the one-time pulsed dosing regimen at high PVP-AgNP concentration exposure(HOE)compared to the three other treatments. Meanwhile, we determined that the concentration of leached silver ions from PVP-AgNPs was too low to play a role in zebrafish death. Those results showed that HOE led to a range of dramatic ecosystem impacts which were more destructive than those of other treatments. Moreover, compared with the continuous dosing regimen, despite the fact that higher toxicity was observed for HOE, there was little difference in the removal of total silver from the aquatic environment for the different dosing regimens. No obvious differences in ecological impacts were observed between different water columns under low concentration exposure. Overall, this work highlighted the fact that the toxicity of Ag NPs was impacted by different dosing regimens in different exposure media, which may be helpful for assessments of ecological impacts on aquatic environments.展开更多
Little is known about the prevalence of drug-resistant mutations in HIV-1-positive individuals in Suzhou, China. To elucidate the transmitted drug resistance(TDR) and acquired drug resistance mutation(ADR) profiles, w...Little is known about the prevalence of drug-resistant mutations in HIV-1-positive individuals in Suzhou, China. To elucidate the transmitted drug resistance(TDR) and acquired drug resistance mutation(ADR) profiles, we collected blood specimens from 127 drug-naive and 117 first-line drugtreated HIV-1-infected individuals sampled from 2014 to 2016 in Suzhou. We successfully amplified po/fragments from 100 drug-naive and 20 drug-treated samples. We then determined the drugresistant mutations to protease(PR) and reverse-transcriptase(RT) inhibitors according to the Stanford drug resistance database. Overall, 11 and 13 individuals had transmitted(drug-naive group) and acquired(treated group) resistance mutations, respectively. Six transmitted drugresistant mutations were found, including two mutations(L33F and L76V) in the protease region and four(K70N/E and V179D/E) in the RT region. Only L76 V was a major mutation, and K70N/E and V179D/E are known to cause low-level resistance to RT inhibitors. All 13 treated participants who had major drug resistance mutations demonstrated intermediate to high resistance to efavirenz and nevirapine, and six had a treatment duration of less than three months. No major mutations to RT inhibitors were found, implying that the epidemic of transmitted resistance mutations was not significant in this area. Our results suggest that more frequent virus load and drug resistance mutation tests should be conducted for individuals receiving antiretroviral treatment, especially for newly treated patients. Our research provides insights into the occurrence of HIV-1 drug resistance in Suzhou and will help to optimize the treatment strategy for this population.展开更多
Post-exposure prophylaxis（PEP） has proved to be the most important measure for rabies prevention and control. There is little information regarding adverse reactions to the Essen and 2-1-1 regimens in preschool chil...Post-exposure prophylaxis（PEP） has proved to be the most important measure for rabies prevention and control. There is little information regarding adverse reactions to the Essen and 2-1-1 regimens in preschool children（aged 0-6）. We reexamined the outcomes of 1,109 preschool children who were vaccinated using SPEEDA under the Essen regimen between January 2011 and December 2012 and 1,267 preschool children under the 2-1-1 regimen between January 2013 and December 2014. We find that, in preschool children, the febrile reaction after the first 2-dose injection in the 2-1-1 regimen was significantly higher than that induced by the first 1-dose in the Essen procedure. Thus, we recommend that the Essen regimen should still be used for rabies PEP in preschool children.展开更多
AIM: To compare two different anti-vascular endothelial growth factor(anti-VEGF) treatment regimens'-a priori pro re nata(PRN) and PRN regimen following^(th)e loading phaseanatomical and functional results in neov...AIM: To compare two different anti-vascular endothelial growth factor(anti-VEGF) treatment regimens'-a priori pro re nata(PRN) and PRN regimen following^(th)e loading phaseanatomical and functional results in neovascular agerelated macular degeneration(n AMD) patients. METHODS: Totally 544 n AMD patients followed and treated with aflibercept(n=135) and ranibizumab(n=409)at 9 different centers between 2013 and 2015 were enrolled into^(th)is retrospective multicenter study. Patients with initial best corrected visual acuity(BCVA) interval of 1.3-0.3(log MAR) and a minimum follow-up of 12 mo were included. Patients under two different regimens-a priori pro re nata(1+PRN) or 3 consecutive intravitreal injections followed by a PRN regimen(3+PRN)-were compared in BCVA at 3^(th), 6^(th) and 12^(th) months, and in central macular^(th)ickness(CMT) at 6^(th) and 12^(th) months. The total study group, intravitreal ranibizumab(IVR) and intravitreal aflibercept(IVA) groups were evaluated separately. RESULTS: The mean CMT decreased in^(th)e 1+PRN(n=101) regimen from 407 to 358 and 340 μm and in^(th)e 3+PRN(n=443) group from 398 to 318 and finally to 310 μm at months 6 and 12, respectively. Anatomically,^(th)e CMT reduction at 6^(th) month(48.5 vs 76.4;P<0.05) was statistically significant in favor of 3+PRN group. BCVA changed in 1+PRN group from 0.77 to 0.78, 0.75 and 0.75;in 3+PRN group from 0.81 to 0.69, 0.72, and 0.76 at months 3, 6, and 12, respectively. Visual gain was statistically better in 3+PRN group at 3^(th) month(-0.01 vs 0.12;P<0.001). In IVR group, CMT reduction was in greater in 3+PRN at 6^(th)(44 vs 72) and 12^(th) month(61 vs 84), but statistically insignificant. The 3+PRN group revealed statistically better visual results at 3^(th) month(-0.02 vs 0.11, P<0.05). In IVA group, although statistically insignificant, CMT reduction(61 vs 89, 6^(th) month;85 vs 97, 12^(th) month) and visual gain(0.02 vs 0.16;0.02 vs 0.14;0.05 vs 0.11) was found in favor of 3+PRN group at all visits.CONCLUSION: The loading dose of anti-VEGF treatments in n AMD leads to significantly better anatomical and functional results, regardless of the agent, specially in early follow-up interval.展开更多
For drugs obeying parallel first-order and Michaelis-Menten elimination kinetics,mathematical analysis concerning the optimum dosage regimen of intravenous infusion is conducted and following equations are derived:whe...For drugs obeying parallel first-order and Michaelis-Menten elimination kinetics,mathematical analysis concerning the optimum dosage regimen of intravenous infusion is conducted and following equations are derived:where Xo is the intravenous loading dose,Cb the plasma concentration level desired in clinical therapy,V the apparent distribution volume,k0 the rate constant of intravenouns infusion,K the first－order elimination rate constant,Vm the theoretical maximum rate of the Michaelis－Menten elimination process,Km the Michaelis constant.From this dosage regimen,plasma level maintains a constant Cb during the administration period.When K=0 the dosage regimen above is also suitable for drugs obeying Michaelis-Menten elimination kinetics.展开更多
Background Body phosphorus metabolism exhibits a circadian rhythm over the 24-h daily cycle.The egg laying behavior makes laying hens a very special model for investigating phosphorus circadian rhythms.There is lack o...Background Body phosphorus metabolism exhibits a circadian rhythm over the 24-h daily cycle.The egg laying behavior makes laying hens a very special model for investigating phosphorus circadian rhythms.There is lack of information about the impact of adjusting phosphate feeding regimen according to daily rhythm on the phosphorus homeostasis and bone remodeling of laying hens.Methods and results Two experiments were conducted.In Exp.1,Hy-Line Brown laying hens(n=45)were sampled according the oviposition cycle(at 0,6,12,and 18 h post-oviposition,and at the next oviposition,respectively;n=9 at each time point).Diurnal rhythms of body calcium/phosphorus ingestions and excretions,serum calcium/phosphorus levels,oviduct uterus calcium transporter expressions,and medullary bone(MB)remodeling were illustrated.In Exp.2,two diets with different phosphorus levels(0.32%and 0.14%non-phytate phosphorus(NPP),respectively)were alternately presented to the laying hens.Briefly,four phosphorus feeding regimens in total(each included 6 replicates of 5 hens):(1)fed 0.32%NPP at both 09:00 and 17:00;(2)fed 0.32%NPP at 09:00 and 0.14%NPP at 17:00;(3)fed 0.14%NPP at 09:00 and 0.32%NPP at 17:00;(4)fed 0.14%NPP at both 09:00 and 17:00.As a result,the regimen fed 0.14%NPP at 09:00 and 0.32%NPP at 17:00,which was designed to strengthen intrinsic phosphate circadian rhythms according to the findings in Exp.1,enhanced(P<0.05)MB remodeling(indicated by histological images,serum markers and bone mineralization gene expressions),elevated(P<0.05)oviduct uterus calcium transportation(indicated by transient receptor potential vanilloid 6 protein expression),and subsequently increased(P<0.05)eggshell thickness,eggshell strength,egg specific gravity and eggshell index in laying hens.Conclusions These results underscore the importance of manipulating the sequence of daily phosphorus ingestion,instead of simply controlling dietary phosphate concentrations,in modifying the bone remodeling process.Body phosphorus rhythms will need to be maintained during the daily eggshell calcification cycle.展开更多
Objective This study aimed to compare the current Essen rabies post-exposure immunization schedule(0-3-7-14-28)in China and the simple 4-dose schedule(0-3-7-14)newly recommended by the World Health Organization in ter...Objective This study aimed to compare the current Essen rabies post-exposure immunization schedule(0-3-7-14-28)in China and the simple 4-dose schedule(0-3-7-14)newly recommended by the World Health Organization in terms of their safety,efficacy,and protection.Methods Mice were vaccinated according to different immunization schedules,and blood was collected for detection of rabies virus neutralizing antibodies(RVNAs)on days 14,21,28,35,and 120after the first immunization.Additionally,different groups of mice were injected with lethal doses of the CVS-11 virus on day 0,subjected to different rabies immunization schedules,and assessed for morbidity and death status.In a clinical trial,185 rabies-exposed individuals were selected for post-exposure vaccination according to the Essen schedule,and blood was collected for RVNAs detection on days 28and 42 after the first immunization.Results A statistically significant difference in RVNAs between mice in the Essen and 0-3-7-14 schedule groups was observed on the 35th day(P<0.05).The groups 0-3-7-14,0-3-7-21,and 0-3-7-28 showed no statistically significant difference(P>0.05)in RVNAs levels at any time point.The post-exposure immune protective test showed that the survival rate of mice in the control group was 20%,whereas that in the immunization groups was 40%.In the clinical trial,the RVNAs positive conversion rates on days 28(14 days after 4 doses)and 42(14 days after 5 doses)were both 100%,and no significant difference in RVNAs levels was observed(P>0.05).Conclusion The simple 4-dose schedule can produce sufficient RVNAs levels,with no significant effect of a delayed fourth vaccine dose(14–28 d)on the immunization potential.展开更多
To evaluate the effectiveness and tolerability of a split-dose 2 L polyethylene glycol (PEG)/ascorbic acid (AA) regimen for healthy examinees who visited for comprehensive medical check-up in the early morning.METHODS...To evaluate the effectiveness and tolerability of a split-dose 2 L polyethylene glycol (PEG)/ascorbic acid (AA) regimen for healthy examinees who visited for comprehensive medical check-up in the early morning.METHODSFrom February 2015 to March 2015, examinees of average risk who were scheduled for a colonoscopy in the morning were retrospectively enrolled.RESULTSThe 189 examinees were divided into split-dose and non-split-dose groups. The adequacy of bowel preparation for the split-dose group vs the non-split-dose group was 96.8% vs 85.2%, respectively, P < 0.001, and the compliance of the last meal restriction was 74.6% vs 58.2%, respectively, P < 0.001. The sleep disturbance (P < 0.001) was more prevalent in the split-dose group, however the willingness to repeat the same preparation method (P = 0.243) was not different in both groups. The split-dose regimen was the most important factor influencing adequate bowel preparation in multivariate analysis (HR = 10.89, 95%CI: 6.53-18.17, P < 0.001).CONCLUSIONA split-dose regimen of 2 L PEG/AA for an early morning colonoscopy was more effective and showed better compliance for diet restriction without any difference in satisfaction and discomfort. Introducing a split-dose regimen of 2 L PEG/AA to morning colonoscopy examinees is effective and tolerable in a comprehensive medical check-up setting.展开更多
Objective:To assess the effectiveness and adverse drug reactions of all-oral regimens for patients with multidrug-resistant tuberculosis.Methods:This retrospective study was conducted at 10 Programmatic Management of ...Objective:To assess the effectiveness and adverse drug reactions of all-oral regimens for patients with multidrug-resistant tuberculosis.Methods:This retrospective study was conducted at 10 Programmatic Management of Drug Resistant Tuberculosis sites in Punjab province of Pakistan.Patients receiving treatment for drug resistant tuberculosis from July 2019 to December 2020 with at least interim result i.e.6th month culture conversion or final outcomes(cured,complete,lost to follow-up,failure,death)available,were included in the study.Data was extracted from electronic data management system.For the reporting and management of adverse drug events,active tuberculosis drug safety monitoring and management was implemented across all sites.All the data was analyzed using SPSS version 22.Results:Out of 947 drug resistant tuberculosis patients included in this study,579(68%)of the patients had final outcomes available.Of these,384(67.9%)successfully completed their treatment.Out of 368(32%)patients who had their interim results available,all had their 6th month culture negative.Combining new medications was thought to result in serious adverse outcomes such as QT prolongation.However,this study did not record any severe adverse events among patients.Conclusions:All-oral regimens formulation guided by overall treatment effectiveness resulted in treatment outcomes comparable to those obtained with traditional injectable treatment.展开更多
文摘Background:The increasing incidence of cancers and infectious diseases worldwide presents a significant public health challenge that requires immediate intervention.Our strategy to tackle this issue involves the development of pharmaceutical formulations that combine phytopolyphenols(P),targeted drugs(T),and metal ions(M),collectively referred to as PTM regimens.The diverse pharmacological properties of PTM regimens are hypothesized to effectively reduce the risk factors associated with both cancers and infectious diseases.Methods:The effects of the pharmaceutical agents on the proliferation of cultured cancer cells and pathogens were assessed after 72 h and 48 h,respectively,using the MTT(3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide)assay and optical density at 600 nm(OD600).The synergistic effects of drug combinations were evaluated by combination index(CI),where CI<1 indicates synergism,CI=1 indicates addition,and CI>1 indicates antagonism.Efficacy index(EI)was also calculated.Assays of efflux pump ATPase activities were conducted using a colorimetric method.Results:This study evaluated the anticancer and antibacterial efficacy of PTM regimens that included phytopolyphenols(specifically curcumin(C)and green tea polyphenols(G)),repurposed drugs(memantine(Mem),thioridazine(TRZ),cisplatin(Cis),and 5-fluorouracil(5FU)),and ZnSO_(4)(Zn)across three cultured cancer cell lines and four cultured pathogens.The most effective regimens,GC·Mem·Zn and GC·TRZ·Zn,significantly enhanced the anticancer efficacy(EI)of cisplatin across the three cancer lines(OECM-1,A549 and DLD-1)by 7,11 and 21;7,9,and 17 fold,respectively,while the enhancements for 5-fluorouracil were 5,6 and 12;5,5 and 9 fold,respectively.Furthermore,these PTM regimens demonstrated substantial synergistic inhibition of Na^(+)-K^(+)-Mg^(2+)-ATPase and Mg^(2+)-ATPase in the cultured cancer cells,as well as a reduction in biofilm formation by the four cultured pathogens,suggesting their potential to address the challenges of multidrug resistance in cancers and infectious diseases.Conclusion:Given that all drugs incorporated in the PTM regimens have been clinically validated for safety and efficacy,particularly regarding their synergistic selective anticancer efficacy,inhibition of efflux pump ATPase,and antibiofilm formation of pathogens,these regimens may offer a promising therapeutic strategy to alleviate the severe side effects and drug resistance typically associated with chemotherapeutic agents.Further preclinical and clinical investigations are warranted.
文摘A clinical trial of nab-paclitaxel plus capecitabine as a first-line treatment for advanced biliary tract cancers was conducted.We analyzed the development of systemic therapy recommended by the National Comprehensive Cancer Network guidelines and the development of nab-paclitaxel combination chemotherapy for advanced biliary tract cancers(BTCs)and concluded that nab-paclitaxel plus capecitabine is a promising first-line regimen for advanced BTCs.
基金Supported by Beijing Medical Award Foundation of China,No.YXJL-2023-0638-0048.
文摘BACKGROUND Hepatic artery infusion chemotherapy(HAIC)is a widely used local therapeutic approach for intermediate to advanced-stage hepatocellular carcinoma(HCC),exhibiting considerable efficacy.However,the prevalence of postoperative pain highlights the importance of pain management.Owing to the limitations inherent in existing pain management strategies,this study investigates and assesses the analgesic effectiveness of a multimodal treatment protocol in mitigating pain after HAIC procedures.AIM To provide patients with a more comprehensive and effective pain management strategy.METHODS A total of 100 patients with primary HCC who underwent HAIC were randomly assigned to a control group(n=50)and a multimodal group(n=50).Baseline characteristics and perioperative data were collected.Upon enrollment,patients in the multimodal group received parecoxib(40 mg)30 minutes before HAIC,followed by 48 hours of patient-controlled analgesia with sufentanil.In contrast,the control group underwent standard preoperative preparation(psychological support)and received dezocine(5 mg)intraoperatively,with intravenous flurbiprofen(100 mg)administered every 12 hours for 48 hours postoperatively.RESULTS Compared to the control group,the multimodal analgesia group exhibited significantly lower resting and movement visual analog scale pain scores at postoperative 0,2,4,6,and 12 hours(P<0.05).Furthermore,the multimodal group experienced a reduced incidence of postoperative nausea and vomiting,as well as a lower overall frequency of adverse events,compared to the control group(P<0.05).Patient satisfaction was also significantly higher in the multimodal group than in the control group(P<0.05).CONCLUSION Our study demonstrates that multimodal analgesia is effective in reducing postoperative pain,minimizing adverse reactions,and improving patient satisfaction in HCC patients undergoing HAIC.This approach provides valuable clinical strategies for optimizing pain management in this patient population.
基金sponsored by Shanghai Roche Pharmaceuticals Ltd.
文摘Diffuse large B-cell lymphoma(DLBCL),the most common subtype of non-Hodgkin’s lymphoma(NHL)worldwide,accounts for 39% and 44% of nodal and extranodal NHL cases in China,respectively1.Standard first-line treatment for DLBCL is chemo-immunotherapy with rituximab,cyclophos-phamide,doxorubicin,vincristine,and prednisone,which cures 50%-60% of patients2.
基金This study was approved by the ethics committee of the First People’s Hospital of Fuzhou City(No.FZ202103).
文摘BACKGROUND Gastric cancer is one of the most common malignant tumors worldwide,with its incidence and mortality rates ranking among the highest in gastrointestinal cancers.The overexpression or gene amplification of human epidermal growth factor receptor 2(HER-2)occurs in approximately 15%-20%of gastric cancers and serves as a critical molecular target influencing prognosis and treatment out-comes.For patients with HER-2-positive gastric cancer,trastuzumab combined with platinum-based chemotherapy has been established as the standard first-line treatment.However,despite the demonstrated clinical benefits in prolonging survival,the overall efficacy remains limited.In recent years,with the successful application of immune checkpoint inhibitors(ICIs)in various malignant tumors,combining ICIs with existing standard treatment regimens has emerged as a promising approach to enhance the therapeutic efficacy of HER-2-positive gastric cancer.Nevertheless,the efficacy and prognostic factors of ICIs combined with trastuzumab and chemotherapy in HER-2-positive gastric cancer remain unclear.AIM To analyze the efficacy of ICIs combined with standard treatment regimens and the prognostic factors in patients with advanced HER-2-positive gastric cancer.METHODS Clinical data from 104 patients with advanced HER-2-positive gastric cancer who were treated at our hospital between March 2021 and May 2023 were retrospectively analyzed.Patients were divided into a control group(n=54,treated with trastuzumab combined with platinum-based chemotherapy as the standard regimen)and an observation group(n=50,treated with ICIs in addition to the standard regimen).The therapeutic efficacy,survival outcomes,and adverse reactions were compared between the two groups.Univariate and Cox multivariate analyses were performed to identify factors influencing patient prognosis.RESULTS With a median follow-up time of 14.6 months,there were no significant differences between the two groups in terms of objective response rate or disease control rate(P>0.05).The median progression-free survival(mPFS)and mPFS for patients with immunohistochemistry 3+in the observation group were significantly higher than those in the control group(P<0.05).Among patients in the observation group,those with positive programmed death-ligand 1(PD-L1)expression had a significantly higher mPFS than those with negative PD-L1 expression(P<0.05).Regarding adverse events,significant differences were observed between the two groups in hypothyroidism and neutropenia(P<0.05).Cox multivariate analysis showed that Eastern Cooperative Oncology Group(ECOG)performance status,peritoneal metastasis,positive programmed death-1 expression,and treatment regimen were independent factors influencing PFS(hazard ratio>1,P<0.05).CONCLUSION ICIs combined with standard treatment regimens for patients with advanced HER-2-positive gastric cancer demonstrate favorable clinical efficacy,significantly prolonging PFS with manageable safety.ECOG performance status,peritoneal metastasis,positive PD-L1 expression,and treatment regimen are independent factors influ-encing PFS,warranting increased clinical attention to patients exhibiting these factors.
文摘Oral anticoagulation therapy with warfarin is used to prevent and treat venous and arterial thrombosis and embolism. Its narrow therapeutic index should be monitored carefully in order to reach the desired outcomes. The complexity of the pharmacokinetic and pharmacodynamics profile of warfarin makes it a challenge to use during treatment. Its manufacturing characteristics play a key role in its dosage. The aim of this study is to examine and evaluate the effect of two different warfarin regimens in Chinese patients. A cross-sectional study design was adopted. Medical records of all patients （n = 368） who received warfarin therapy in cardio-thoracic surgery wards between Sep. 2008 and Dec. 2009 were reviewed. Details of antithrombotic results of international normalized ratio （INR） monitoring were obtained. Statistical analysis was performed to assess factors predictive of INR therapeutic range at patients＇ discharge time according to different warfarin regimens （2.5 mg in China and 3.0 mg in USA）. The patients＇ mean age was （48.23~12.96） years. The percentage of patients within the INR therapeutic range in the group treated with 2.5 mg warfarin （35.17%） was much lower than that in group treated with 3.0 mg warfarin （47.72%）. Therefore, a significance difference was observed （P = 0.032〈0.05）. In this study, statistical values have shown that most of the patients were related to medical case requesting INR target range of 1.8-2.2 and 2.0-2.5, respectively. There was a statistically significant difference between the two groups. The study showed that the 2.5 mg-warfarin regimen was less suitable than the 3.0 mg-warfarin regimen. Medication regimen should be simplified as much as possible, especially during different treatment period.
基金supported by PRIN 2012 project titled "Advanced processes to convert organic wastes in innovative, sustainable and useful products" co-financed by the Italian Minister of University and Scientific Research (MIUR).
文摘Biowaste valorization through anaerobic digestion is an attractive option to achieve both climate protection goals and renewable energy production.In this paper,a complete set of batch trials was carried out on kitchen waste to investigate the effects of mild thermal pretreatment,temperature regimen and substrate/inoculum ratio.Thermal pretreatment was effective in the solubilisation of macromolecular fractions,particularly carbohydrates.The ability of the theoretical methodologies in estimating hydrogen and methane yields of complex substrates was evaluated by comparing the experimental results with the theoretical values.Despite the single batch configuration,a significant initial hydrogen production was observed,prior to methane yield.Main pretreatment effect was the gain in hydrogen production;the extent was highly variable according to the other parameters values.High hydrogen yields,up to 113 mL H2/g VSfed,were related to the prompt transformation of soluble sugars.Thermophilic regimen resulted,as expected,in faster digestions(up to 78 mL CH4/gVS/day) and sorted out pH inhibition.The relatively low methane yields(342-398 mL CH4/g VSfed) were the result of the consistent lignocellulosic content and low lipid content.Thermal pretreatment proved to be a promising option for the enhancement of hydrogen production in food waste dark fermentation.
基金supported by the National Natural Science Foundation of China (Nos.51579099,51521006,and 51508186)the Program for Changjiang Scholars and Innovative Research Team in University (No.IRT-13R17)the Hunan Provincial Natural Science Foundation of China (No.2016JJ3076)
文摘Due to the wide use of silver nanoparticles(AgNPs) in various fields, it is crucial to explore the potential negative impacts on the aquatic environment of AgNPs entering into the environment in different ways. In this study, comparative experiments were conducted to investigate the toxicological impacts of polyvinylpyrrolidone-coated silver nanoparticles(PVP-AgNPs) with two kinds of dosing regimens, continuous and one-time pulsed dosing, in different exposure media(deionized water and XiangJiang River water). There were a number of quite different experimental results(including 100% mortality of zebrafish,decline in the activity of enzymes, and lowest number and length of adventitious roots) in the one-time pulsed dosing regimen at high PVP-AgNP concentration exposure(HOE)compared to the three other treatments. Meanwhile, we determined that the concentration of leached silver ions from PVP-AgNPs was too low to play a role in zebrafish death. Those results showed that HOE led to a range of dramatic ecosystem impacts which were more destructive than those of other treatments. Moreover, compared with the continuous dosing regimen, despite the fact that higher toxicity was observed for HOE, there was little difference in the removal of total silver from the aquatic environment for the different dosing regimens. No obvious differences in ecological impacts were observed between different water columns under low concentration exposure. Overall, this work highlighted the fact that the toxicity of Ag NPs was impacted by different dosing regimens in different exposure media, which may be helpful for assessments of ecological impacts on aquatic environments.
基金supported by grants from the Natural Science Foundation of Jiangsu Province (BL2013017)the Suzhou Science and Technology Bureau (SYS201156) to Dr. Feng Qian+1 种基金the Suzhou Health and Family Planning Commission (LCZX201413) to Ming Lithe Key National Science and Technology Program in the Thirteen Five-Year Plan Period of China (2017ZX10201102-007-002)
文摘Little is known about the prevalence of drug-resistant mutations in HIV-1-positive individuals in Suzhou, China. To elucidate the transmitted drug resistance(TDR) and acquired drug resistance mutation(ADR) profiles, we collected blood specimens from 127 drug-naive and 117 first-line drugtreated HIV-1-infected individuals sampled from 2014 to 2016 in Suzhou. We successfully amplified po/fragments from 100 drug-naive and 20 drug-treated samples. We then determined the drugresistant mutations to protease(PR) and reverse-transcriptase(RT) inhibitors according to the Stanford drug resistance database. Overall, 11 and 13 individuals had transmitted(drug-naive group) and acquired(treated group) resistance mutations, respectively. Six transmitted drugresistant mutations were found, including two mutations(L33F and L76V) in the protease region and four(K70N/E and V179D/E) in the RT region. Only L76 V was a major mutation, and K70N/E and V179D/E are known to cause low-level resistance to RT inhibitors. All 13 treated participants who had major drug resistance mutations demonstrated intermediate to high resistance to efavirenz and nevirapine, and six had a treatment duration of less than three months. No major mutations to RT inhibitors were found, implying that the epidemic of transmitted resistance mutations was not significant in this area. Our results suggest that more frequent virus load and drug resistance mutation tests should be conducted for individuals receiving antiretroviral treatment, especially for newly treated patients. Our research provides insights into the occurrence of HIV-1 drug resistance in Suzhou and will help to optimize the treatment strategy for this population.
基金supported by the China Mega-Project for Infectious Disease(2014ZX10004002-004-001)National Natural Science Foundation of China(31500152)+1 种基金National Key Technology R&D Program(2014BAI13B04)National program on key research project of china(2016YFD0500400)
文摘Post-exposure prophylaxis（PEP） has proved to be the most important measure for rabies prevention and control. There is little information regarding adverse reactions to the Essen and 2-1-1 regimens in preschool children（aged 0-6）. We reexamined the outcomes of 1,109 preschool children who were vaccinated using SPEEDA under the Essen regimen between January 2011 and December 2012 and 1,267 preschool children under the 2-1-1 regimen between January 2013 and December 2014. We find that, in preschool children, the febrile reaction after the first 2-dose injection in the 2-1-1 regimen was significantly higher than that induced by the first 1-dose in the Essen procedure. Thus, we recommend that the Essen regimen should still be used for rabies PEP in preschool children.
文摘AIM: To compare two different anti-vascular endothelial growth factor(anti-VEGF) treatment regimens'-a priori pro re nata(PRN) and PRN regimen following^(th)e loading phaseanatomical and functional results in neovascular agerelated macular degeneration(n AMD) patients. METHODS: Totally 544 n AMD patients followed and treated with aflibercept(n=135) and ranibizumab(n=409)at 9 different centers between 2013 and 2015 were enrolled into^(th)is retrospective multicenter study. Patients with initial best corrected visual acuity(BCVA) interval of 1.3-0.3(log MAR) and a minimum follow-up of 12 mo were included. Patients under two different regimens-a priori pro re nata(1+PRN) or 3 consecutive intravitreal injections followed by a PRN regimen(3+PRN)-were compared in BCVA at 3^(th), 6^(th) and 12^(th) months, and in central macular^(th)ickness(CMT) at 6^(th) and 12^(th) months. The total study group, intravitreal ranibizumab(IVR) and intravitreal aflibercept(IVA) groups were evaluated separately. RESULTS: The mean CMT decreased in^(th)e 1+PRN(n=101) regimen from 407 to 358 and 340 μm and in^(th)e 3+PRN(n=443) group from 398 to 318 and finally to 310 μm at months 6 and 12, respectively. Anatomically,^(th)e CMT reduction at 6^(th) month(48.5 vs 76.4;P<0.05) was statistically significant in favor of 3+PRN group. BCVA changed in 1+PRN group from 0.77 to 0.78, 0.75 and 0.75;in 3+PRN group from 0.81 to 0.69, 0.72, and 0.76 at months 3, 6, and 12, respectively. Visual gain was statistically better in 3+PRN group at 3^(th) month(-0.01 vs 0.12;P<0.001). In IVR group, CMT reduction was in greater in 3+PRN at 6^(th)(44 vs 72) and 12^(th) month(61 vs 84), but statistically insignificant. The 3+PRN group revealed statistically better visual results at 3^(th) month(-0.02 vs 0.11, P<0.05). In IVA group, although statistically insignificant, CMT reduction(61 vs 89, 6^(th) month;85 vs 97, 12^(th) month) and visual gain(0.02 vs 0.16;0.02 vs 0.14;0.05 vs 0.11) was found in favor of 3+PRN group at all visits.CONCLUSION: The loading dose of anti-VEGF treatments in n AMD leads to significantly better anatomical and functional results, regardless of the agent, specially in early follow-up interval.
文摘For drugs obeying parallel first-order and Michaelis-Menten elimination kinetics,mathematical analysis concerning the optimum dosage regimen of intravenous infusion is conducted and following equations are derived:where Xo is the intravenous loading dose,Cb the plasma concentration level desired in clinical therapy,V the apparent distribution volume,k0 the rate constant of intravenouns infusion,K the first－order elimination rate constant,Vm the theoretical maximum rate of the Michaelis－Menten elimination process,Km the Michaelis constant.From this dosage regimen,plasma level maintains a constant Cb during the administration period.When K=0 the dosage regimen above is also suitable for drugs obeying Michaelis-Menten elimination kinetics.
基金supported by National Natural Science Foundation of China (32172759)Shaanxi Provincial Science and Technology Department (2022QFY11-05,2021KJXX-97,2021TD-30).
文摘Background Body phosphorus metabolism exhibits a circadian rhythm over the 24-h daily cycle.The egg laying behavior makes laying hens a very special model for investigating phosphorus circadian rhythms.There is lack of information about the impact of adjusting phosphate feeding regimen according to daily rhythm on the phosphorus homeostasis and bone remodeling of laying hens.Methods and results Two experiments were conducted.In Exp.1,Hy-Line Brown laying hens(n=45)were sampled according the oviposition cycle(at 0,6,12,and 18 h post-oviposition,and at the next oviposition,respectively;n=9 at each time point).Diurnal rhythms of body calcium/phosphorus ingestions and excretions,serum calcium/phosphorus levels,oviduct uterus calcium transporter expressions,and medullary bone(MB)remodeling were illustrated.In Exp.2,two diets with different phosphorus levels(0.32%and 0.14%non-phytate phosphorus(NPP),respectively)were alternately presented to the laying hens.Briefly,four phosphorus feeding regimens in total(each included 6 replicates of 5 hens):(1)fed 0.32%NPP at both 09:00 and 17:00;(2)fed 0.32%NPP at 09:00 and 0.14%NPP at 17:00;(3)fed 0.14%NPP at 09:00 and 0.32%NPP at 17:00;(4)fed 0.14%NPP at both 09:00 and 17:00.As a result,the regimen fed 0.14%NPP at 09:00 and 0.32%NPP at 17:00,which was designed to strengthen intrinsic phosphate circadian rhythms according to the findings in Exp.1,enhanced(P<0.05)MB remodeling(indicated by histological images,serum markers and bone mineralization gene expressions),elevated(P<0.05)oviduct uterus calcium transportation(indicated by transient receptor potential vanilloid 6 protein expression),and subsequently increased(P<0.05)eggshell thickness,eggshell strength,egg specific gravity and eggshell index in laying hens.Conclusions These results underscore the importance of manipulating the sequence of daily phosphorus ingestion,instead of simply controlling dietary phosphate concentrations,in modifying the bone remodeling process.Body phosphorus rhythms will need to be maintained during the daily eggshell calcification cycle.
文摘Objective This study aimed to compare the current Essen rabies post-exposure immunization schedule(0-3-7-14-28)in China and the simple 4-dose schedule(0-3-7-14)newly recommended by the World Health Organization in terms of their safety,efficacy,and protection.Methods Mice were vaccinated according to different immunization schedules,and blood was collected for detection of rabies virus neutralizing antibodies(RVNAs)on days 14,21,28,35,and 120after the first immunization.Additionally,different groups of mice were injected with lethal doses of the CVS-11 virus on day 0,subjected to different rabies immunization schedules,and assessed for morbidity and death status.In a clinical trial,185 rabies-exposed individuals were selected for post-exposure vaccination according to the Essen schedule,and blood was collected for RVNAs detection on days 28and 42 after the first immunization.Results A statistically significant difference in RVNAs between mice in the Essen and 0-3-7-14 schedule groups was observed on the 35th day(P<0.05).The groups 0-3-7-14,0-3-7-21,and 0-3-7-28 showed no statistically significant difference(P>0.05)in RVNAs levels at any time point.The post-exposure immune protective test showed that the survival rate of mice in the control group was 20%,whereas that in the immunization groups was 40%.In the clinical trial,the RVNAs positive conversion rates on days 28(14 days after 4 doses)and 42(14 days after 5 doses)were both 100%,and no significant difference in RVNAs levels was observed(P>0.05).Conclusion The simple 4-dose schedule can produce sufficient RVNAs levels,with no significant effect of a delayed fourth vaccine dose(14–28 d)on the immunization potential.
文摘To evaluate the effectiveness and tolerability of a split-dose 2 L polyethylene glycol (PEG)/ascorbic acid (AA) regimen for healthy examinees who visited for comprehensive medical check-up in the early morning.METHODSFrom February 2015 to March 2015, examinees of average risk who were scheduled for a colonoscopy in the morning were retrospectively enrolled.RESULTSThe 189 examinees were divided into split-dose and non-split-dose groups. The adequacy of bowel preparation for the split-dose group vs the non-split-dose group was 96.8% vs 85.2%, respectively, P < 0.001, and the compliance of the last meal restriction was 74.6% vs 58.2%, respectively, P < 0.001. The sleep disturbance (P < 0.001) was more prevalent in the split-dose group, however the willingness to repeat the same preparation method (P = 0.243) was not different in both groups. The split-dose regimen was the most important factor influencing adequate bowel preparation in multivariate analysis (HR = 10.89, 95%CI: 6.53-18.17, P < 0.001).CONCLUSIONA split-dose regimen of 2 L PEG/AA for an early morning colonoscopy was more effective and showed better compliance for diet restriction without any difference in satisfaction and discomfort. Introducing a split-dose regimen of 2 L PEG/AA to morning colonoscopy examinees is effective and tolerable in a comprehensive medical check-up setting.
文摘Objective:To assess the effectiveness and adverse drug reactions of all-oral regimens for patients with multidrug-resistant tuberculosis.Methods:This retrospective study was conducted at 10 Programmatic Management of Drug Resistant Tuberculosis sites in Punjab province of Pakistan.Patients receiving treatment for drug resistant tuberculosis from July 2019 to December 2020 with at least interim result i.e.6th month culture conversion or final outcomes(cured,complete,lost to follow-up,failure,death)available,were included in the study.Data was extracted from electronic data management system.For the reporting and management of adverse drug events,active tuberculosis drug safety monitoring and management was implemented across all sites.All the data was analyzed using SPSS version 22.Results:Out of 947 drug resistant tuberculosis patients included in this study,579(68%)of the patients had final outcomes available.Of these,384(67.9%)successfully completed their treatment.Out of 368(32%)patients who had their interim results available,all had their 6th month culture negative.Combining new medications was thought to result in serious adverse outcomes such as QT prolongation.However,this study did not record any severe adverse events among patients.Conclusions:All-oral regimens formulation guided by overall treatment effectiveness resulted in treatment outcomes comparable to those obtained with traditional injectable treatment.
