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  1. Kho AS, Ooi EH, Foo JJ, Ooi ET
    Comput Biol Med, 2021 01;128:104112.
    PMID: 33212331 DOI: 10.1016/j.compbiomed.2020.104112
    Infusion of saline prior to radiofrequency ablation (RFA) is known to enlarge the thermal coagulation zone. The abundance of ions in saline elevate the electrical conductivity of the saline-saturated region. This promotes greater electric current flow inside the tissue, which increases the amount of RF energy deposition and subsequently enlarges the coagulation zone. In theory, infusion of higher concentration of saline should lead to larger coagulation zone due to the greater number of ions. Nevertheless, existing studies on the effects of concentration on saline-infused RFA have been conflicting, with the exact role of saline concentration yet to be fully elucidated. In this paper, computational models of saline-infused RFA were developed to investigate the role of saline concentration on the outcome of saline-infused RFA. The elevation in tissue electrical conductivity was modelled using the microscopic mixture model, while RFA was modelled using the coupled dual porosity-Joule heating model. Results obtained indicated that the presence of a concentration threshold to which no further elevation in tissue electrical conductivity and enlargement in thermal coagulation can occur. This threshold was determined to be at 15% NaCl. Analysis of the Joule heating distribution revealed the presence of a secondary Joule heating site located along the interface between wet and dry tissue. This secondary Joule heating was responsible for the enlargement in coagulation volume and its rapid growth phase during ablation.
  2. Yap S, Ooi EH, Foo JJ, Ooi ET
    Comput Biol Med, 2021 04;131:104273.
    PMID: 33631495 DOI: 10.1016/j.compbiomed.2021.104273
    Radiofrequency ablation (RFA) is a thermal ablative treatment method that is commonly used to treat liver cancer. However, the thermal coagulation zone generated using the conventional RFA system can only successfully treat tumours up to 3 cm in diameter. Switching bipolar RFA has been proposed as a way to increase the thermal coagulation zone. Presently, the understanding of the underlying thermal processes that takes place during switching bipolar RFA remains limited. Hence, the objective of this study is to provide a comprehensive understanding on the thermal ablative effects of time-based switching bipolar RFA on liver tissue. Five switch intervals, namely 50, 100, 150, 200 and 300 s were investigated using a two-compartment 3D finite element model. The study was performed using two pairs of RF electrodes in a four-probe configuration, where the electrodes were alternated based on their respective switch interval. The physics employed in the present study were verified against experimental data from the literature. Results obtained show that using a shorter switch interval can improve the homogeneity of temperature distribution within the tissue and increase the rate of temperature rise by delaying the occurrence of roll-off. The coagulation volume obtained was the largest using switch interval of 50 s, followed by 100, 150, 200 and 300 s. The present study demonstrated that the transient thermal response of switching bipolar RFA can be improved by using shorter switch intervals.
  3. Yap S, Ooi EH, Foo JJ, Ooi ET
    Comput Biol Med, 2021 Jul;134:104488.
    PMID: 34020132 DOI: 10.1016/j.compbiomed.2021.104488
    Switching bipolar radiofrequency ablation (bRFA) is a cancer treatment technique that activates multiple pairs of electrodes alternately based on a predefined criterion. Various criteria can be used to trigger the switch, such as time (ablation duration) and tissue impedance. In a recent study on time-based switching bRFA, it was determined that a shorter switch interval could produce better treatment outcome than when a longer switch interval was used, which reduces tissue charring and roll-off induced cooling. In this study, it was hypothesized that a more efficacious bRFA treatment can be attained by employing impedance-based switching. This is because ablation per pair can be maximized since there will be no interruption to RF energy delivery until roll-off occurs. This was investigated using a two-compartment 3D computational model. Results showed that impedance-based switching bRFA outperformed time-based switching when the switch interval of the latter is 100 s or higher. When compared to the time-based switching with switch interval of 50 s, the impedance-based model is inferior. It remains to be investigated whether the impedance-based protocol is better than the time-based protocol for a switch interval of 50 s due to the inverse relationship between ablation and treatment efficacies. It was suggested that the choice of impedance-based or time-based switching could ultimately be patient-dependent.
  4. Kho ASK, Foo JJ, Ooi ET, Ooi EH
    Comput Methods Programs Biomed, 2020 Feb;184:105289.
    PMID: 31891903 DOI: 10.1016/j.cmpb.2019.105289
    BACKGROUND AND OBJECTIVE: The majority of the studies on radiofrequency ablation (RFA) have focused on enlarging the size of the coagulation zone. An aspect that is crucial but often overlooked is the shape of the coagulation zone. The shape is crucial because the majority of tumours are irregularly-shaped. In this paper, the ability to manipulate the shape of the coagulation zone following saline-infused RFA by altering the location of saline infusion is explored.

    METHODS: A 3D model of the liver tissue was developed. Saline infusion was described using the dual porosity model, while RFA was described using the electrostatic and bioheat transfer equations. Three infusion locations were investigated, namely at the proximal end, the middle and the distal end of the electrode. Investigations were carried out numerically using the finite element method.

    RESULTS: Results indicated that greater thermal coagulation was found in the region of tissue occupied by the saline bolus. Infusion at the middle of the electrode led to the largest coagulation volume followed by infusion at the proximal and distal ends. It was also found that the ability to delay roll-off, as commonly associated with saline-infused RFA, was true only for the case when infusion is carried out at the middle. When infused at the proximal and distal ends, the occurrence of roll-off was advanced. This may be due to the rapid and more intense heating experienced by the tissue when infusion is carried out at the electrode ends where Joule heating is dominant.

    CONCLUSION: Altering the location of saline infusion can influence the shape of the coagulation zone following saline-infused RFA. The ability to 'shift' the coagulation zone to a desired location opens up great opportunities for the development of more precise saline-infused RFA treatment that targets specific regions within the tissue.

  5. Kho ASK, Ooi EH, Foo JJ, Ooi ET
    Comput Methods Programs Biomed, 2021 Nov;211:106436.
    PMID: 34601185 DOI: 10.1016/j.cmpb.2021.106436
    BACKGROUND AND OBJECTIVE: Saline infusion is applied together with radiofrequency ablation (RFA) to enlarge the ablation zone. However, one of the issues with saline-infused RFA is backflow, which spreads saline along the insertion track. This raises the concern of not only thermally ablating the tissue within the backflow region, but also the loss of saline from the targeted tissue, which may affect the treatment efficacy.

    METHODS: In the present study, 2D axisymmetric models were developed to investigate how saline backflow influence saline-infused RFA and whether the aforementioned concerns are warranted. Saline-infused RFA was described using the dual porosity-Joule heating model. The hydrodynamics of backflow was described using Poiseuille law by assuming the flow to be similar to that in a thin annulus. Backflow lengths of 3, 4.5, 6 and 9 cm were considered.

    RESULTS: Results showed that there is no concern of thermally ablating the tissue in the backflow region. This is due to the Joule heating being inversely proportional to distance from the electrode to the fourth power. Results also indicated that larger backflow lengths led to larger growth of thermal damage along the backflow region and greater decrease in coagulation volume. Hence, backflow needs to be controlled to ensure an effective treatment of saline-infused RFA.

    CONCLUSIONS: There is no risk of ablating tissues around the needle insertion track due to backflow. Instead, the risk of underablation as a result of the loss of saline due to backflow was found to be of greater concern.

  6. Lim WTH, Ooi EH, Foo JJ, Ng KH, Wong JHD, Leong SS
    Ultrasound Med Biol, 2021 08;47(8):2033-2047.
    PMID: 33958257 DOI: 10.1016/j.ultrasmedbio.2021.03.030
    Early detection of chronic kidney disease is important to prevent progression of irreversible kidney damage, reducing the need for renal transplantation. Shear wave elastography is ideal as a quantitative imaging modality to detect chronic kidney disease because of its non-invasive nature, low cost and portability, making it highly accessible. However, the complexity of the kidney architecture and its tissue properties give rise to various confounding factors that affect the reliability of shear wave elastography in detecting chronic kidney disease, thus limiting its application to clinical trials. The objective of this review is to highlight the confounding factors presented by the complex properties of the kidney, in addition to outlining potential mitigation strategies, along with the prospect of increasing the versatility and reliability of shear wave elastography in detecting chronic kidney disease.
  7. Mak NL, Ooi EH, Lau EV, Ooi ET, Pamidi N, Foo JJ, et al.
    Comput Methods Programs Biomed, 2022 Dec;227:107195.
    PMID: 36323179 DOI: 10.1016/j.cmpb.2022.107195
    BACKGROUND AND OBJECTIVES: Thermochemical ablation (TCA) is a thermal ablation technique involving the injection of acid and base, either sequentially or simultaneously, into the target tissue. TCA remains at the conceptual stage with existing studies unable to provide recommendations on the optimum injection rate, and reagent concentration and volume. Limitations in current experimental methodology have prevented proper elucidation of the thermochemical processes inside the tissue during TCA. Nevertheless, the computational TCA framework developed recently by Mak et al. [Mak et al., Computers in Biology and Medicine, 2022, 145:105494] has opened new avenues in the development of TCA. Specifically, a recommended safe dosage is imperative in driving TCA research beyond the conceptual stage.

    METHODS: The aforesaid computational TCA framework for sequential injection was applied and adapted to simulate TCA with simultaneous injection of acid and base at equimolar and equivolume. The developed framework, which describes the flow of acid and base, their neutralisation, the rise in tissue temperature and the formation of thermal damage, was solved numerically using the finite element method. The framework will be used to investigate the effects of injection rate, reagent concentration, volume and type (weak/strong acid-base combination) on temperature rise and thermal coagulation formation.

    RESULTS: A higher injection rate resulted in higher temperature rise and larger thermal coagulation. Reagent concentration of 7500 mol/m3 was found to be optimum in producing considerable thermal coagulation without the risk of tissue overheating. Thermal coagulation volume was found to be consistently larger than the total volume of acid and base injected into the tissue, which is beneficial as it reduces the risk of chemical burn injury. Three multivariate second-order polynomials that express the targeted coagulation volume as functions of injection rate and reagent volume, for the weak-weak, weak-strong and strong-strong acid-base combinations were also derived based on the simulated data.

    CONCLUSIONS: A guideline for a safe and effective implementation of TCA with simultaneous injection of acid and base was recommended based on the numerical results of the computational model developed. The guideline correlates the coagulation volume with the reagent volume and injection rate, and may be used by clinicians in determining the safe dosage of reagents and optimum injection rate to achieve a desired thermal coagulation volume during TCA.

  8. Tan ZQ, Ooi EH, Chiew YS, Foo JJ, Ng EYK, Ooi ET
    Ultrasonics, 2023 May;131:106961.
    PMID: 36812819 DOI: 10.1016/j.ultras.2023.106961
    Sonothrombolysis is a technique that utilises ultrasound waves to excite microbubbles surrounding a clot. Clot lysis is achieved through mechanical damage induced by acoustic cavitation and through local clot displacement induced by acoustic radiation force (ARF). Despite the potential of microbubble-mediated sonothrombolysis, the selection of the optimal ultrasound and microbubble parameters remains a challenge. Existing experimental studies are not able to provide a complete picture of how ultrasound and microbubble characteristics influence the outcome of sonothrombolysis. Likewise, computational studies have not been applied in detail in the context of sonothrombolysis. Hence, the effect of interaction between the bubble dynamics and acoustic propagation on the acoustic streaming and clot deformation remains unclear. In the present study, we report for the first time the computational framework that couples the bubble dynamic phenomena with the acoustic propagation in a bubbly medium to simulate microbubble-mediated sonothrombolysis using a forward-viewing transducer. The computational framework was used to investigate the effects of ultrasound properties (pressure and frequency) and microbubble characteristics (radius and concentration) on the outcome of sonothrombolysis. Four major findings were obtained from the simulation results: (i) ultrasound pressure plays the most dominant role over all the other parameters in affecting the bubble dynamics, acoustic attenuation, ARF, acoustic streaming, and clot displacement, (ii) smaller microbubbles could contribute to a more violent oscillation and improve the ARF simultaneously when they are stimulated at higher ultrasound pressure, (iii) higher microbubbles concentration increases the ARF, and (iv) the effect of ultrasound frequency on acoustic attenuation is dependent on the ultrasound pressure. These results may provide fundamental insight that is crucial in bringing sonothrombolysis closer to clinical implementation.
  9. Lim WTH, Ooi EH, Foo JJ, Ng KH, Wong JHD, Leong SS
    Ultrasonics, 2023 Aug;133:107046.
    PMID: 37247461 DOI: 10.1016/j.ultras.2023.107046
    The application of ultrasound shear wave elastography for detecting chronic kidney disease, namely renal fibrosis, has been widely studied. A good correlation between tissue Young's modulus and the degree of renal impairment has been established. However, the current limitation of this imaging modality pertains to the linear elastic assumption used in quantifying the stiffness of renal tissue in commercial shear wave elastography systems. As such, when underlying medical conditions such as acquired cystic kidney disease, which may potentially influence the viscous component of renal tissue, is present concurrently with renal fibrosis, the accuracy of the imaging modality in detecting chronic kidney disease may be affected. The findings in this study demonstrate that quantifying the stiffness of linear viscoelastic tissue using an approach similar to those implemented in commercial shear wave elastography systems led to percentage errors as high as 87%. The findings presented indicate that use of shear viscosity to detect changes in renal impairment led to a reduction in percentage error to values as low as 0.3%. For cases in which renal tissue was affected by multiple medical conditions, shear viscosity was found to be a good indicator in gauging the reliability of the Young's modulus (quantified through a shear wave dispersion analysis) in detecting chronic kidney disease. The findings show that percentage error in stiffness quantification can be reduced to as low as 0.6%. The present study demonstrates the potential use of renal shear viscosity as a biomarker to improve the detection of chronic kidney disease.
  10. Ooi EH, Lee KW, Yap S, Khattab MA, Liao IY, Ooi ET, et al.
    Comput Biol Med, 2019 03;106:12-23.
    PMID: 30665137 DOI: 10.1016/j.compbiomed.2019.01.003
    Effects of different boundary conditions prescribed across the boundaries of radiofrequency ablation (RFA) models of liver cancer are investigated for the case where the tumour is at the liver boundary. Ground and Robin-type conditions (electrical field) and body temperature and thermal insulation (thermal field) conditions are examined. 3D models of the human liver based on publicly-available CT images of the liver are developed. An artificial tumour is placed inside the liver at the boundary. Simulations are carried out using the finite element method. The numerical results indicated that different electrical and thermal boundary conditions led to different predictions of the electrical potential, temperature and thermal coagulation distributions. Ground and body temperature conditions presented an unnatural physical conditions around the ablation site, which results in more intense Joule heating and excessive heat loss from the tissue. This led to thermal damage volumes that are smaller than the cases when the Robin type or the thermal insulation conditions are prescribed. The present study suggests that RFA simulations in the future must take into consideration the choice of the type of electrical and thermal boundary conditions to be prescribed in the case where the tumour is located near to the liver boundary.
  11. Ooi EH, J Y Chia N, Ooi ET, Foo JJ, Liao IY, R Nair S, et al.
    Int J Hyperthermia, 2018 12;34(8):1142-1156.
    PMID: 29490513 DOI: 10.1080/02656736.2018.1437282
    A recent study by Ooi and Ooi (EH Ooi, ET Ooi, Mass transport in biological tissues: Comparisons between single- and dual-porosity models in the context of saline-infused radiofrequency ablation, Applied Mathematical Modelling, 2017, 41, 271-284) has shown that single-porosity (SP) models for describing fluid transport in biological tissues significantly underestimate the fluid penetration depth when compared to dual-porosity (DP) models. This has raised some concerns on whether the SP model, when coupled with models of radiofrequency ablation (RFA) to simulate saline-infused RFA, could lead to an underestimation of the coagulation size. This paper compares the coagulation volumes obtained following saline-infused RFA predicted based on the SP and DP models for fluid transport. Results showed that the SP model predicted coagulation zones that are consistently 0.5 to 0.9 times smaller than that of DP model. This may be explained by the low permeability value of the tissue interstitial space, which causes the majority of the saline to flow through the vasculature. The absence of fluid flow tracking in the vasculature in the SP model meant that any flow of saline into the vasculature is treated as losses and do not contribute to the saline penetration depth of the tissue. Comparisons with experimental results from the literature revealed that the DP models predicted coagulation zone sizes that are closer to the experimental values than the SP models. This supports the hypothesis that the SP model is a poor choice for simulating the outcome of saline-infused RFA.
  12. Mak NL, Ng WH, Ooi EH, Lau EV, Pamidi N, Foo JJ, et al.
    Comput Methods Programs Biomed, 2024 Jan;243:107866.
    PMID: 37865059 DOI: 10.1016/j.cmpb.2023.107866
    BACKGROUND AND OBJECTIVES: Thermochemical ablation (TCA) is a cancer treatment that utilises the heat released from the neutralisation of acid and base to raise tissue temperature to levels sufficient to induce thermal coagulation. Computational studies have demonstrated that the coagulation volume produced by sequential injection is smaller than that with simultaneous injection. By injecting the reagents in an ensuing manner, the region of contact between acid and base is limited to a thin contact layer sandwiched between the distribution of acid and base. It is hypothesised that increasing the frequency of acid-base injections into the tissue by shortening the injection interval for each reagent can increase the effective area of contact between acid and base, thereby intensifying neutralisation and the exothermic heat released into the tissue.

    METHODS: To verify this hypothesis, a computational model was developed to simulate the thermochemical processes involved during TCA with sequential injection. Four major processes that take place during TCA were considered, i.e., the flow of acid and base, their neutralisation, the release of exothermic heat and the formation of thermal damage inside the tissue. Equimolar acid and base at 7.5 M was injected into the tissue intermittently. Six injection intervals, namely 3, 6, 15, 20, 30 and 60 s were investigated.

    RESULTS: Shortening of the injection interval led to the enlargement of coagulation volume. If one considers only the coagulation volume as the determining factor, then a 15 s injection interval was found to be optimum. Conversely, if one places priority on safety, then a 3 s injection interval would result in the lowest amount of reagent residue inside the tissue after treatment. With a 3 s injection interval, the coagulation volume was found to be larger than that of simultaneous injection with the same treatment parameters. Not only that, the volume also surpassed that of radiofrequency ablation (RFA); a conventional thermal ablation technique commonly used for liver cancer treatment.

    CONCLUSION: The numerical results verified the hypothesis that shortening the injection interval will lead to the formation of larger thermal coagulation zone during TCA with sequential injection. More importantly, a 3 s injection interval was found to be optimum for both efficacy (large coagulation volume) and safety (least amount of reagent residue).

  13. Lu G, Ou J, Ji J, Ren Z, Hu X, Wang C, et al.
    Front Microbiol, 2019;10:1416.
    PMID: 31281304 DOI: 10.3389/fmicb.2019.01416
    Getah virus (GETV) is a mosquito-borne virus that was first determined in Malaysia in 1955, and can infect humans and multiple other mammals. GETV infection in horses has been reported in Japan and India, and causes great economic losses. In China, GETV has been identified in mosquitoes, pigs, foxes, and cattle with a wide geographical distribution, but has not been detected in horses. In August 2018, a sudden onset of fever was observed in racehorse in an equestrian training center in Guangdong Province in southern China. Blood samples were collected from the sick horse, and PCR/RT-PCR analysis was performed to screen for equine viral pathogens associated with fever. The results indicated that the samples were GETV RNA positive. After RT-PCR, sequencing, and assembly, the genome of the first Chinese horse-derived GETV strain, GZ201808, was obtained. Compared with the genome sequences of other GETV strains, twelve unique nucleotide substitutions were observed in GZ201808. The genome of GZ201808 had the highest genetic identity (99.6%) with AH9192, which was detected in pigs in China in 2017. Phylogenetic analysis indicated that GZ201808 clustered in Group III, and was located in an independent branch distant from other horse-derived GETV strains, indicating a unique evolutionary pattern of GZ201808. This study first determined and described the disease course of horse infected with GETV in China, sequenced and characterized the genome of the field horse-derived GETV strain, and therefore presented an unequivocal report of GETV infection in horses in China.
  14. Yao S, Chong SL, Allen JC, Dang H, Ming M, Chan LCN, et al.
    Transl Pediatr, 2023 Mar 31;12(3):344-353.
    PMID: 37035406 DOI: 10.21037/tp-22-443
    BACKGROUND: To study the association in moderate and severe pediatric traumatic brain injury (TBI) between hyperglycemia, hyperlactatemia, acidosis and unfavorable outcome, as assessed by Pediatric Cerebral Performance Category (PCPC) on discharge from the pediatric intensive care unit (PICU).

    METHODS: Children <16 years old with TBI and Glasgow Coma Scale (GCS) ≤13 in an Asian multi-center PICU TBI cohort from January 2014 to October 2017 were included in this study. We defined unfavorable outcome as PCPC ≥3-moderate disability, severe disability, vegetative state, and death. We performed logistic regression to investigate the association between metabolic changes with unfavorable outcome. We divided hyperglycemia (glucose >11.1 mmol/L) during PICU admission into early-onset (within 24 h), late-onset (beyond 48 h) and persistent (throughout first 72 h).

    RESULTS: Among the 305 children analyzed, 136 (44.6%) had unfavorable outcome. Children with unfavorable outcome were more likely to have early hyperglycemia (75/136, 55.1% vs. 33/169, 19.5%; P<0.001), high lactate levels >2.0 mmol/L (74/136, 54.4% vs. 56/169, 32.5%; P<0.001) and initial acidosis (85/136, 62.5% vs. 78/169, 56.1%; P=0.003) compared to those with favorable outcome. After adjusting for gender, GCS ≤8 and presence of polytrauma, early hyperglycemia [adjusted odds ratio (aOR) =3.68, 95% CI: 2.12-6.39, P<0.001] and late hyperglycemia (aOR =13.30, 95% CI: 1.64-107.8, P=0.015] were independently associated with unfavorable outcome. All children with persistent hyperglycemia died.

    CONCLUSIONS: We described unfavorable outcome in pediatric TBI especially with persistent hyperglycemia. Future trials should investigate the causal relationship between glycemic trends, early intervention and outcome in this cohort.

  15. Chong SL, Dang H, Ming M, Mahmood M, Zheng CQS, Gan CS, et al.
    Pediatr Crit Care Med, 2021 Apr 01;22(4):401-411.
    PMID: 33027240 DOI: 10.1097/PCC.0000000000002575
    OBJECTIVES: Traumatic brain injury remains an important cause of death and disability. We aim to report the epidemiology and management of moderate to severe traumatic brain injury in Asian PICUs and identify risk factors for mortality and poor functional outcomes.

    DESIGN: A retrospective study of the Pediatric Acute and Critical Care Medicine Asian Network moderate to severe traumatic brain injury dataset collected between 2014 and 2017.

    SETTING: Patients were from the participating PICUs of Pediatric Acute and Critical Care Medicine Asian Network.

    PATIENTS: We included children less than 16 years old with a Glasgow Coma Scale less than or equal to 13.

    INTERVENTIONS: None.

    MEASUREMENTS AND MAIN RESULTS: We obtained data on patient demographics, injury circumstances, and PICU management. We performed a multivariate logistic regression predicting for mortality and poor functional outcomes. We analyzed 380 children with moderate to severe traumatic brain injury. Most injuries were a result of road traffic injuries (174 [45.8%]) and falls (160 [42.1%]). There were important differences in temperature control, use of antiepileptic drugs, and hyperosmolar agents between the sites. Fifty-six children died (14.7%), and 104 of 324 survivors (32.1%) had poor functional outcomes. Poor functional outcomes were associated with non-high-income sites (adjusted odds ratio, 1.90; 95% CI, 1.11-3.29), Glasgow Coma Scale less than 8 (adjusted odds ratio, 4.24; 95% CI, 2.44-7.63), involvement in a road traffic collision (adjusted odds ratio, 1.83; 95% CI, 1.04-3.26), and presence of child abuse (adjusted odds ratio, 2.75; 95% CI, 1.01-7.46).

    CONCLUSIONS: Poor functional outcomes are prevalent after pediatric traumatic brain injury in Asia. There is an urgent need for further research in these high-risk groups.

  16. Yang HK, Ji J, Han SU, Terashima M, Li G, Kim HH, et al.
    Lancet Gastroenterol Hepatol, 2021 02;6(2):120-127.
    PMID: 33253659 DOI: 10.1016/S2468-1253(20)30315-0
    BACKGROUND: Peritoneal recurrence of gastric cancer after curative surgical resection is common and portends a poor prognosis. Early studies suggest that extensive intraoperative peritoneal lavage (EIPL) might reduce the risk of peritoneal recurrence and improve survival. We aimed to evaluate the survival benefit of EIPL in patients with gastric cancer undergoing curative gastrectomy.

    METHODS: In this open-label, phase 3, multicentre randomised trial, patients aged 21-80 years with cT3 or cT4 gastric cancer undergoing curative resection were enrolled at 22 centres from South Korea, China, Japan, Malaysia, Hong Kong, and Singapore. Patients were randomly assigned to receive surgery and EIPL (EIPL group) or surgery alone (standard surgery group) via a web-based programme in random permuted blocks in varying block sizes of four and six, assuming equal allocation between treatment groups. Randomisation was stratified according to study site and the sequence was generated using a computer program and concealed until the interventions were assigned. After surgery in the EIPL group, peritoneal lavage was done with 1 L of warm (42°C) normal 0·9% saline followed by complete aspiration; this procedure was repeated ten times. The primary endpoint was overall survival. All analyses were done assuming intention to treat. This trial is registered with ClinicalTrials.gov, NCT02140034.

    FINDINGS: Between Sept 16, 2012, and Aug 3, 2018, 800 patients were randomly assigned to the EIPL group (n=398) or the standard surgery group (n=402). Two patients in the EIPL group and one in the standard surgery group withdrew from the trial immediately after randomisation and were excluded from the intention-to-treat analysis. At the third interim analysis on Aug 28, 2019, the predictive probability of overall survival being significantly higher in the EIPL group was less than 0·5%; therefore, the trial was terminated on the basis of futility. With a median follow-up of 2·4 years (IQR 1·5-3·0), the two groups were similar in terms of overall survival (hazard ratio 1·09 [95% CI 0·78-1·52; p=0·62). 3-year overall survival was 77·0% (95% CI 71·4-81·6) for the EIPL group and 76·7% (71·0-81·5) for the standard surgery group. 60 adverse events were reported in the EIPL group and 41 were reported in the standard surgery group. The most common adverse events included anastomotic leak (ten [3%] of 346 patients in the EIPL group vs six [2%] of 362 patients in the standard surgery group), bleeding (six [2%] vs six [2%]), intra-abdominal abscess (four [1%] vs five [1%]), superficial wound infection (seven [2%] vs one [<1%]), and abnormal liver function (six [2%] vs one [<1%]). Ten of the reported adverse events (eight in the EIPL group and two in the standard surgery group) resulted in death.

    INTERPRETATION: EIPL and surgery did not have a survival benefit compared with surgery alone and is not recommended for patients undergoing curative gastrectomy for gastric cancer.

    FUNDING: National Medical Research Council, Singapore.

  17. Maiwall R, Sarin SK, Kumar S, Jain P, Kumar G, Bhadoria AS, et al.
    Liver Int, 2017 Oct;37(10):1497-1507.
    PMID: 28393476 DOI: 10.1111/liv.13443
    BACKGROUND AND AIM: There is limited data on predictors of acute kidney injury in acute on chronic liver failure. We developed a PIRO model (Predisposition, Injury, Response, Organ failure) for predicting acute kidney injury in a multicentric cohort of acute on chronic liver failure patients.

    PATIENTS AND METHODS: Data of 2360 patients from APASL-ACLF Research Consortium (AARC) was analysed. Multivariate logistic regression model (PIRO score) was developed from a derivation cohort (n=1363) which was validated in another prospective multicentric cohort of acute on chronic liver failure patients (n=997).

    RESULTS: Factors significant for P component were serum creatinine[(≥2 mg/dL)OR 4.52, 95% CI (3.67-5.30)], bilirubin [(<12 mg/dL,OR 1) vs (12-30 mg/dL,OR 1.45, 95% 1.1-2.63) vs (≥30 mg/dL,OR 2.6, 95% CI 1.3-5.2)], serum potassium [(<3 mmol/LOR-1) vs (3-4.9 mmol/L,OR 2.7, 95% CI 1.05-1.97) vs (≥5 mmol/L,OR 4.34, 95% CI 1.67-11.3)] and blood urea (OR 3.73, 95% CI 2.5-5.5); for I component nephrotoxic medications (OR-9.86, 95% CI 3.2-30.8); for R component,Systemic Inflammatory Response Syndrome,(OR-2.14, 95% CI 1.4-3.3); for O component, Circulatory failure (OR-3.5, 95% CI 2.2-5.5). The PIRO score predicted acute kidney injury with C-index of 0.95 and 0.96 in the derivation and validation cohort. The increasing PIRO score was also associated with mortality (P

  18. Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, Abdellatif M, Abdoli A, Abel S, et al.
    Autophagy, 2021 Jan;17(1):1-382.
    PMID: 33634751 DOI: 10.1080/15548627.2020.1797280
    In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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