Utilizing disease transmission and response capacities to optimize covid-19 control in Malaysia.

OBJECTIVES: Public Health Social Measures (PHSM) such as movement restriction movement needed to be adjusted accordingly during the COVID-19 pandemic to ensure low disease transmission alongside adequate health system capacities based on the COVID-19 situational matrix proposed by the World Health Organization (WHO). This paper aims to develop a mechanism to determine the COVID-19 situational matrix to adjust movement restriction intensity for the control of COVID-19 in Malaysia. METHODS: Several epidemiological indicators were selected based on the WHO PHSM interim guidance report and validated individually and in several combinations to estimate the community transmission level (CT) and health system response capacity (RC) variables. Correlation analysis between CT and RC with COVID-19 cases was performed to determine the most appropriate CT and RC variables. Subsequently, the CT and RC variables were combined to form a composite COVID-19 situational matrix (SL). The SL matrix was validated using correlation analysis with COVID-19 case trends. Subsequently, an automated web-based system that generated daily CT, RC, and SL was developed. RESULTS: CT and RC variables were estimated using case incidence and hospitalization rate; Hospital bed capacity and COVID-19 ICU occupancy respectively. The estimated CT and RC were strongly correlated [ρ = 0.806 (95% CI 0.752, 0.848); and ρ = 0.814 (95% CI 0.778, 0.839), p < 0.001] with the COVID-19 cases. The estimated SL was strongly correlated with COVID-19 cases (ρ = 0.845, p < 0.001) and responded well to the various COVID-19 case trends during the pandemic. SL changes occurred earlier during the increase of cases but slower during the decrease, indicating a conservative response. The automated web-based system developed produced daily real-time CT, RC, and SL for the COVID-19 pandemic. CONCLUSIONS: The indicators selected and combinations formed were able to generate validated daily CT and RC levels for Malaysia. Subsequently, the CT and RC levels were able to provide accurate and sensitive information for the estimation of SL which provided valuable evidence on the progression of the pandemic and movement restriction adjustment for the control of Malaysia.

Pharmacokinetic parameter driven outcomes model predicts a reduction in bleeding events associated with BAY 81-8973 versus antihemophilic factor (recombinant) plasma/albumin-free method in a Chinese healthcare setting.

BACKGROUND: Long-term prophylactic therapy is considered the standard of care for hemophilia A patients. This study models the long-term clinical and cost outcomes of two factor VIII (FVIII) products using a pharmacokinetic (PK) simulation model in a Chinese population. METHODS: Head-to-head PK profile data of BAY 81-8973 (KOVALTRY®) and antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM, ADVATE®) were applied to a two-state (alive and dead) Markov model to simulate blood FVIII concentrations at a steady state in prophylactically-treated patients with hemophilia A. Worsening of the Pettersson score was simulated and decline was associated with the probability of having orthopaedic surgery. The only difference between the compounds was FVIII concentration at a given time; each subject was treated with 25 IU/kg every 3 days. The model used a lifetime horizon, with cycle lengths of 1 year. RESULTS: Cumulative bleeding events, joint bleeding events, and major bleeding events were reduced by 19.3% for BAY 81-8973 compared to rAHF-PFM. Hospitalizations and hospitalization days were also reduced by 19.3% for BAY 81-8973 compared to rAHF-PFM. BAY 81-8973 resulted in both cost savings and a gain in quality adjusted life years (QALYs) compared to rAHF-PFM. CONCLUSION: Based on modeled head-to-head comparisons, differences in PK-properties between BAY 81-8973 and rAHF-PFM result in a reduced number of bleeding events, leading to reduced costs and increased quality of life for BAY 81-8973. These results should be used to inform clinical practice in China when caring for patients with severe hemophilia A.

Deciphering the behavior and potential mechanism of biochar at different pyrolysis temperatures to alleviate membrane biofouling.

Biofouling limits applications of membrane technology in wastewater treatment, but dosing additives to membrane tanks is an effective method to alleviate biofouling. In this study, biochar derived from corncob and pyrolyzed at 300, 500, and 700°C was dosed to determine the underlying anti-biofouling mechanism. The effects of the biochar on the membrane properties and foulant behavior were systematically investigated. The results showed that biochar delayed the occurrence of the fouling transition (0.5-3.0 h), and decreased the flux decline rate, thus achieving a higher water flux (3.1-3.7 times of the control group). Biochar altered membrane surface properties, and increased the membrane surface charge, roughness, and hydrophilicity, which all contributed to higher membrane permeability. Moreover, adding biochar reduced the number of foulants in the fouling layer, particularly protein substances. The flux model fit and the XDLVO theory further revealed the mitigating effect of biochar on membrane biofouling. At the initial intermediate-blocking stage, the effect of biochar on membrane fouling was determined by its properties, and adsorption capacity to the foulants, BC500 presented the best mitigation performance. At the later cake-filtration stage, the role of biochar in membrane fouling was strongly associated with protein content in the fouling layer, and the minimum rate of flux decline occurred in BC300. This study promotes the understanding and development of biochar to alleviate membrane biofouling.

Pathogen evolution, prevention/control strategy and clinical features of COVID-19: experiences from China.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported at the end of 2019 as a worldwide health concern causing a pandemic of unusual viral pneumonia and many other organ damages, which was defined by the World Health Organization as coronavirus disease 2019 (COVID-19). The pandemic is considered a significant threat to global public health till now. In this review, we have summarized the lessons learnt during the emergence and spread of SARS-CoV-2, including its prototype and variants. The overall clinical features of variants of concern (VOC), heterogeneity in the clinical manifestations, radiology and pathology of COVID-19 patients are also discussed, along with advances in therapeutic agents.

Clinical value of ankle flexion and extension exercises combined with a psychological intervention in knee osteoarthritis.

BACKGROUND: Considering the limited effectiveness of clinical interventions for knee osteoarthritis (KOA), it is necessary to continue to explore appropriate and effective treatment strategies to improve the condition of KOA patients. AIM: To clarify the influence of ankle flexion and extension exercises combined with a psychological intervention on the psychological status and activities of daily living (ADLs) of patients with KOA. METHODS: The research participants were 116 KOA patients admitted to The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine between May 2019 and May 2022, including 54 patients receiving routine treatment, care and psychological intervention (control group) and 62 patients additionally treated with ankle flexion and extension exercises (research group). The two groups were comparatively analyzed in terms of psychological status (Self-rating Anxiety/Depression Scale, SDS/SAS), ADLs, knee joint function (Lysholm Knee Scoring Scale), pain (Visual Analog Scale, VAS), fatigue (Multidimensional Fatigue Inventory, MFI), and quality of life (QoL; Short-Form 36 Item Health Survey, SF-36). RESULTS: After evaluation, it was found that the postinterventional SDS, SAS, VAS, and MFI scores in the research group were significantly reduced compared with the baseline (before the intervention) values and those of the control group, while the postinterventional Lysholm, ADL and SF-36 scores were markedly elevated. CONCLUSION: Therefore, ankle flexion and extension exercises are highly effective in easing negative psychological status, enhancing ADLs, daily living ability, knee joint function and QoL, and relieving pain and fatigue in KOA patients, thus warranting clinical promotion.

Cross-Reactive Profile Against Two Conserved Coronavirus Antigens in Sera from SARS-CoV-2 Hybrid and Vaccinated Immune Donors.

Since the beginning of the pandemic, the pre-existing immunity against SARS-CoV-2 has been postulated as one possible cause of asymptomatic infections. Later, various works reported that pre-existing immune response against the two structural conserved antigens: S2 subunit and the nucleocapsid protein, were associated to some level of asymptomatic profile in infected individuals. To explore the Ab background against these two antigens, in the context of vaccine-elicited and hybrid (natural infection plus vaccination induced) immunity of SARS-CoV-2, in this work, we tested sera from inactivated vaccine-immunized donors and from vaccinated and subsequent natural infected donors upon the Omicron variant wave in Guangdong province, China. Serum samples were collected from 27 COVID-19 convalescent, 25 SARS-CoV-2 vaccinated, and 10 negative donors. The IgG cross-reactivity response against these two antigens from another relevant human coronavirus (HCoV) was also evaluated. The findings indicate that IgG response against S2 and N protein was particularly higher in sera with hybrid immunity. The cross-reactive Abs were more significant against SARS-CoV-1, while a wide cross-reactivity was detected for N antigen for one human Alpha coronavirus HCoV-229E even in the negative control samples. The presence of cross-reactive Abs against the two conserved antigens N and S2, particularly in the context of hybrid immunity, could pave the way for future boosted vaccines carrying these conserved regions.

Analysis of 86 fatal motorcycle frontal crashes in Chongqing, China.

OBJECTIVE: To analyze the injuries of motorcyclists involved in fatal motorcycle frontal crashes. METHODS: A survey group involving multi-discipline experts was built to randomly collect data on fatal motorcycle frontal collision accidents that occurred in Chongqing during 2006-2010. The sampled information included medical or autopsy reports, blood alcohol concentration (BAC) level, helmet use, accident witness, field sketch as well as field photos. The motorcyclist injuries were scored according to the Abbreviated Injury Scale (AIS) 2005. The involved riders with a BAC level larger than or equal to 20 mg/ml were attributed to alcohol use. Data were processed statistically with nonparametric test via software SPSS 11.0. RESULTS: A total of 86 fatal motorcycle frontal crashes were sampled and further analyzed. The age of motorcyclists enrolled in this investigation showed nominal distribution and the middle-aged (30-39 years) occupied the highest percentage of fatalities. There were only 14 motorcyclists (16.3%) wearing helmets at the moment of collision. And 12.8% of these motorcyclist crashes were attributable to alcohol use. Impact injury was the main fatal cause, accounting for 72% of motorcyclist deaths, followed by tumbling injury (26%) and run-over (2%). Respectively 84%, 22% and 19% of motorcyclists who sustained head, chest and abdominal trauma died. Extremity injury was the most frequently observed injury type. CONCLUSIONS: This investigation is helpful to build accident prevention programs and develop protection devices which may effectively mitigate injuries and prevent deaths following motorcycle frontal collision accidents. Further investigations on motorcycle collision accidents are still needed.

Comparison of surgical outcomes of sleep surgeries preoperatively evaluated with drug-induced sleep endoscopy and Müller's maneuver.

Objective The purpose of this study was to compare surgical outcomes for obstructive sleep apnea (OSA) when the procedure was based on the results of drug-induced sleep endoscopy (DISE) vs. the awake Müller's maneuver (MM). Methods Forty-seven patients with OSA who underwent sleep surgery were included. Patients were divided into 2 groups according to their preoperative upper airway evaluation method. Twenty-five patients received only MM for surgical decision making (MM group), and 22 patients received both MM and DISE (DISE group) for surgical decision making. Results The surgical success rate of the DISE group was higher than that of the MM group (59% vs. 36%), but the difference was not significant (p = 0.118). The differences between pre- and postoperative apnea-hypopnea index (AHI) values in both the MM and DISE group were highly significantly different (p < 0.001). Fifteen patients in the DISE group (68.2%) received multi-level surgery, while in the MM group only 7 patients (28%) received multi-level surgery. Patients with more severe OSA (AHI > 22 or lowest O2 saturation < 81%) had better surgical outcomes when their surgical procedures were based on the findings of DISE, rather than those of MM. Conclusion The results indicate that DISE provides no benefits with respect to surgical outcomes for patients with mild to moderate OSA; however, for patients with more severe OSA surgical procedures based on DISE result in better outcomes.

Cerebral blood flow in adolescents with drug-naive, first-episode major depressive disorder: An arterial spin labeling study based on voxel-level whole-brain analysis.

Purpose: The major depressive disorder (MDD) can be a threat to the health of people all over the world. Although governments have developed and implemented evidence-based interventions and prevention programs to prevent MDD and maintain mental health in adolescents, the number of adolescents with this condition has been on the rise for the past 10 years. Methods: A total of 60 adolescents were recruited, including 32 drug-naive adolescents with first-episode MDD and 28 healthy controls (HCs). Alterations in the intrinsic cerebral activity of the adolescents with MDD were explored using arterial spin labeling (ASL) while differences in the regional cerebral blood flow (rCBF) of the two groups were assessed based on voxel-based whole-brain analysis. Finally, correlations between the regional functional abnormalities and clinical variables were investigated for adolescents with MDD. Results: Compared with HCs, MDD patients had a lower rCBF in the left triangular part of the inferior frontal gyrus (IFGtriang) but a higher one in the right Precental gyrus (PreCG). Negative correlations were also noted between the CBF in the left IFGtriang and the Hamilton depression scale (HAMD) scores of MDD patients. Conclusion: Elucidating the neurobiological features of adolescent patients with MDD is important to adequately develop methods that can assist in early diagnosis, precaution and intervention.

To mask or not to mask: Debunking the myths of mask-wearing during COVID-19 across cultures.

Mask-wearing is the simplest yet most effective preventive behavior during COVID-19. However, it has sparked great controversy, particularly in America. Little is known about what psychosocial factors predict people's decision to mask. This research challenges three myths about mask-wearing. First, does mask-wearing provide a false sense of security? Second, is knowledge of COVID-19 a more robust predictor than political ideology of mask-wearing behavior? Third, does resistance to masks reflect anti-authoritarianism or a lack of trust in government? With nationally representative samples across two cultures (N = 1,121), findings reveal a significant positive correlation between mask-wearing and other preventive behaviors. Moreover, knowledge of COVID-19 and trust in government significantly predicted mask-wearing. Implications of the results are also discussed in the cross-cultural context. Critically, findings could provide practical implications for public education and policymaking by uncovering how to more effectively promote compliance with recommended preventive behaviors during our ongoing struggle with COVID-19.

Virus removal by membrane bioreactors: A review of mechanism investigation and modeling efforts.

The increasing pressure on the global water supply calls for more advanced solutions with higher efficiency and better sustainability, leading to the promptly developing water reclamation and reuse schemes including treatment technologies and risk management strategies where microbial safety is becoming a crucial aspect in the interest of public health. Backed up by the development of membrane technology, membrane bioreactors (MBR) have received substantial attention for their superiority over conventional treatment methods in many ways and are considered promising in the water reclamation realm. This review paper provides an overview of the efforts made to manage and control the potential waterborne viral disease risks raised by the use of effluent from MBR treatment processes, including the mechanisms involved in the virus removal process and the attempts to model the dynamics of the removal process. In principle, generalized and integrated virus removal models that provide insight into real-time monitoring are urgently needed for advanced real-time control purpose. Future studies of approaches that can well handle the inherent uncertainty and nonlinearity of the complex removal process are crucial to the development and promotion of related technologies.

Hepatic Arterial Infusion Chemotherapy with Modified FOLFOX as an Alternative Treatment Option in Advanced Hepatocellular Carcinoma Patients with Failed or Unsuitability for Transarterial Chemoembolization.

OBJECTIVE: This study aimed to assess the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) with modified FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) as an alternative treatment option in advanced hepatocellular carcinoma (HCC) patients with failed or unsuitability for transarterial chemoembolization (TACE). MATERIALS AND METHODS: From September 2018 to January 2020, 87 advanced HCC patients who progressed on TACE or were not eligible for TACE received HAIC treatment with modified FOLFOX. The primary endpoint was overall survival (OS) and secondary endpoints included progression-free survival (PFS), tumor response assessed by Response Evaluation Criteria in Solid Tumors 1.1, and adverse events graded according to CTCAE 5.0. Based on prognostic factors determined by multivariate analysis, a nomogram was developed to predict patient survival. RESULTS: The median OS and PFS were 9.0 months (95%CI 7.6-10.4) and 3.7 months (95%CI 3.1-4.3), respectively. The objective response rate was 13.8%, with a disease control rate of 48.3%. Grade 3 adverse events were observed, such as infection (9.2%), thrombocytopenia (5.7%), hyperbilirubinemia (3.4%), abdominal pain (2.3%) and alanine aminotransferase increase (2.3%). Albumin, AST, and extrahepatic metastasis were incorporated to construct a new nomogram that could stratify patients into three prognostic subgroups, including low-, intermediate-, and high-risk groups, with significant differences in 9-month OS rates (71%, 42% and 6%, respectively; p< 0.001). The nomogram was better than the Okuda, AJCC, and CLIP staging systems for OS prediction. CONCLUSION: These findings support the feasibility of HAIC with modified FOLFOX as an alternative treatment strategy for advanced HCC when TACE is ineffective or unsuitable.

Dynamics of HBV surface antigen related end points in chronic hepatitis B infection: a systematic review and meta-analysis.

BACKGROUND: In chronic hepatitis B (CHB) treatment, hepatitis B surface antigen (HBsAg) is regarded as a promising clinical end point associated with long-term clinical outcomes. We performed a meta-analysis to characterize the dynamics and influencing factors of HBsAg. METHODS: Literature search was conducted through PubMed from January 1995 to May 2015 for papers reporting HBsAg in patients receiving various antiviral treatments. We conducted weighted linear regression to select for potential influencing factors on maximum HBsAg loss percentage, and subgroup analysis to calculate the pooled estimates of maximum HBsAg loss and seroconversion percentage following treatment of interferon (IFN), nucleoside analogue (NUC) or combination therapies (NUC+IFN), respectively. Study heterogeneity was assessed through sensitivity test and I-square statistics. RESULTS: We collected data from 24 papers involving 6,674 adult CHB patients. In most studies, average HBsAg level decreased during treatment but relapsed after treatment cessation, while HBsAg loss or seroconversion percentage continued to increase or remained stable after treatment cessation. No strong relationship was observed between maximum HBsAg change and its baseline level. The pooled estimates of maximum HBsAg loss percentage for IFN (5.3%, 2.7-7.9%) and NUC+IFN (5.2%, 3.1-7.4%) were significantly higher than that of NUC (0.93%, 0.29-1.6%). Higher maximum HBsAg loss percentage is associated with longer peak time. Pooled maximum HBsAg seroconversion percentage estimates were 1.6%, 0.56% and 6.2% for IFN, NUC and NUC+IFN. CONCLUSIONS: With respect to HBsAg lowering, this meta-analysis confirmed the importance of longer treatment duration and addition of IFN, which revealed the potential value of immune-based therapies.

Redox-based electron exchange capacity of biowaste-derived biochar accelerates syntrophic phenol oxidation for methanogenesis via direct interspecies electron transfer.

In this study, six different types of biochar (based on two feedstocks and three pyrolytic temperatures) were prepared as individual additives for both syntrophic phenol degradation and methanogenesis promotion. The results showed that for phenol degradation, the addition of biochar (15 g/L) shortened the methanogenic lag time from 15.0 days to 1.1-3.2 days and accelerated the maximum CH4 production rate from 4.0 mL/d to 10.4-13.9 mL/d. Microbial community analysis revealed that the electro-active Geobacter was enriched (from 3.8-7.7% to 11.1-23.1%), depending on the type of biochar that was added. This indicates a potential shift of syntrophic phenol metabolism from a thermodynamically unfavorable pathway with H2 as the interspecies electron transfer mediator to direct interspecies electron transfer (DIET). Integrated analysis of methanogenesis dynamics and the electrochemical properties of biochar showed that compared with electrical conductivity, the electron exchange capacity of biochar was more likely to dominate the DIET process, which was due to the presence of redox-active organic functional groups in biochar. The removal of biochar from the anaerobic system generally prolonged the lag time, revealing the importance of adsorption capacity of biochar to mitigate bio-toxicity of phenol to microbial activity.

Redox-active biochar facilitates potential electron tranfer between syntrophic partners to enhance anaerobic digestion under high organic loading rate.

Sawdust-based biochar prepared (SDBC) at three pyrolytic temperatures were compared as additives to mesophilic anaerobic digestion (AD). SDBC prepared at 500 °C performed better in enhancing CH4 production than other SDBCs. Analyzing the crucial electro-chemical characteristics of the SDBCs revealed that the excellent electron transfer capacity of SDBC was significant to stimulate methanogenesis promotion. A long-term semi-continuous operation further confirmed that adding SDBC to AD system increased the maximum organic loading rate (OLR) from 6.8 g VS/L/d to 16.2 g VS/L/d, which attributed to the extremely low volatile fatty acids (VFA) accumulation. Microbial community succession analysis found that SDBC addition altered both bacterial and archaea structure greatly. More importantly, the syntrophic and electro-active partners of Petrimonas and Methanosarcina synergistically enriched under high OLR condition were responsible for the high-efficient VFA degradation, which suggested that SDBC likely acted as redox-active mediator to facilitate direct interspecies electron transfer between the syntrophic partners for high-efficient syntrophic methanogenesis process.

Avoiding health worker infection and containing the coronavirus disease 2019 pandemic: Perspectives from the frontline in Wuhan.

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused great public concern worldwide due to its high rates of infectivity and pathogenicity. The Chinese government responded in a timely manner, alleviated the dilemma, achieved a huge victory and lockdown has now been lifted in Wuhan. However, the outbreak has occurred in more than 200 other countries. Globally, as of 9:56 am CEST on 19 May 2020, there have been 4,696,849 confirmed cases of COVID-19, including 315,131 deaths, reported to Word Health Organization (WHO). The spread of COVID-19 overwhelmed the healthcare systems of many countries and even crashed the fragile healthcare systems of some. Although the situation in each country is different, health workers play a critical role in the fight against COVID-19. In this review, we highlight the status of health worker infections in China and other countries, especially the causes of infection in China and the standardised protocol to protect health workers from the perspective of an anaesthesiologist, in the hope of providing references to reduce medical infections and contain the COVID-19 epidemic.

Biofiltration treatment of odors from municipal solid waste treatment plants.

An in situ compost biofilter was established for the treatment of odors from biostabilization processing of municipal solid waste. The concentrations of total volatile organic compounds (VOCs) in odors and their components were measured. Biofilter media was characterized in terms of total carbon (TC), total nitrogen (TN), total phosphorus (TP), organic matter (OM), pH value and determination of bacterial colony structure. Gas chromatography-mass spectrometry (GC-MS) analysis showed that the main components of the produced gas were benzene, toluene, ethylbenzene and xylene (BTEX) along with other alkanes, alkenes, terpenes, and sulphur compounds. The compost biofilter had remarkable removal ability for alkylated benzenes (>80%), but poor removal for terpenes ( approximately 30%). Total VOC concentrations in odors during the biostabilization process period ranged from 0.7 to 87 ppmv, and the VOC removal efficiency of the biofilter varied from 20% to 95%. After about 140 days operation, TN, TC, TP and OM in compost were kept almost stable, but the dissolved N, NH(4)-N and NO(3)-N experienced an increase of 44.5%, 56.2% and 76.3%, respectively. Dissolved P decreased by 27.3%. The pH value experienced an increase in the early period and finally varied from 7.38 to 8.08. Results of bacterial colony in packing material indicated that bacteria and mold colony counts increased, but yeasts and actinomyces decreased along with biofilter operation, which were respectively, 3.7, 3.4, 0.04 and 0.07 times of their initial values.

New perspectives on treatment strategies for patient with acute myeloid leukemia and complex karyotype abnormalities after percutaneous coronary intervention: A case report.

RATIONALE: Acute myeloid leukemia (AML), in patients with coronary heart disease (CHD) and treated percutaneous coronary intervention (PCI), is rarely seen in clinic. There are few similar cases reported, and there are no evidence-based medicine guidelines for the treatment. PATIENT CONCERNS: A 52-year-old man was diagnosed with coronary atherosclerotic heart disease in November 2011, and received a stent placement in the left anterior descending coronary artery 1 year later. One day after the surgery, his laboratory tests showed pancytopenia. DIAGNOSES: Based on precise diagnosis of leukemia, namely cell morphology, immunology, cytogenetics, and molecular biological typing, the patient was diagnosed with AML-M2. INTERVENTIONS: The patient received idarubicin with cytarabine in 1st cycles, and single cytarabine regimen was used in 2nd and 3rd cycles for the accumulative toxicity of idarubicin in postinduction chemotherapy. Meanwhile, staged-treatment strategy was implemented by using antiplatelet drugs during different chemotherapy phases, and personalized pharmaceutical care on the basis of the recognition of potential adverse effects of chemotherapy regimen. OUTCOMES: Until now, the disease-free survival in the patient has been over 6 years, and he is still followed up in clinic. LESSONS: Although leukemia accompanied with coronary heart disease, even after receiving the coronary stenting therapy is rarely seen in clinic, the treatment with antiplatelet drugs for post chemotherapy patients with coronary disease is necessary. Clinical pharmacists are supposed to be more proficient in developing personalized drug treatment strategies, especially maintaining the balance between the effect and the risk in difficult and complex cases.