Transforming the perioperative medicine care model: The Singapore experience.

More than 300 million surgeries are performed worldwide annually. Established perioperative centres in the UK, USA and Australia have demonstrated the impact of improving perioperative care in reducing costs, increasing patient satisfaction and improving population health. Likewise, the surgical burden of care in Asia is increasing, but with sociocultural, economic and epigenetic differences compared to the west. As Singapore's largest hospital, the Singapore General Hospital pre-admission perioperative clinic sees about 20,000 patients annually. We aim to illustrate Singapore General Hospital's perioperative model of care to contribute to the paucity of literature describing perioperative programme implementation within Asia, and to encourage the cross-sharing of perioperative practices internationally. Our perioperative framework navigates risk assessment, risk counselling, and mitigation of health, medical and functional risks to better patients' perioperative outcomes and population health. We have implemented evidence-based pathways for common conditions such as anaemia and malnutrition, including a multidisciplinary programme for the elderly to tackle frailty and reduce length of stay. We describe how we have enhanced local risk profiling with the Combined Assessment of Risk Encountered in Surgery surgical risk calculator derived locally using a gradient boosting machine learning model. Finally, we report clinical outcomes of these interventions and discuss further challenges and new initiatives at each tier of our perioperative model. Our perioperative care model provides a framework that other centres can adopt to promote value-driven care, while catering for differences in the Asian population, thereby promoting evidence-based improvements in the area of perioperative medicine.

Smoking Characteristics and Readiness-to-Quit Status Among Smokers Attending Preoperative Assessment Clinic - A Prospective Cohort Study.

BACKGROUND: Perioperative smoking is associated with an increased incidence of general postoperative morbidity and mortality. The perioperative period is recognized as an important "teachable moment" that can motivate patients to adopt health changing behaviors. OBJECTIVE: In this study, we aimed to determine the prevalence of smokers among elective surgical patients in an Asian tertiary hospital. We also investigated their smoking characteristics, previous quitting attempts, readiness-to-quit status as well as knowledge of smoking-related postoperative complications. METHODS: We conducted a single-center prospective cohort study among all patients who attended a preoperative assessment clinic within a 2-month period (August to September 2020) using a preoperative smoking questionnaire. RESULTS: A total of 3362 patients participated in the study, of which 348 (10.4%) were current smokers. More than half (65.6%) of the smokers had previously attempted to quit smoking, with most (78%) having made more than one attempt. Forty-nine percent of current smokers were in the pre-contemplation stage of quitting and thirty-one percent were in the contemplation stage. Only twenty-one percent were in the preparation stage of quitting. Thirty-eight percent of patients recognized the importance of smoking cessation perioperatively but only twenty-eight percent were confident of quitting perioperatively. Less than sixty percent of smokers were aware of at least one type of smoking-related postoperative complication. Less than half of the patients (45%) had ever received advice on perioperative smoking cessation from the surgeons. CONCLUSION: A thorough understanding of smokers' smoking characteristics, barriers to quit and readiness-to-quit status are crucial to establishing a successful multidisciplinary perioperative smoking cessation program. Counselling should address knowledge deficits and be tailored to a patient's stage-of-change in order to seize this precious perioperative "teachable moment".

Association of Multimorbidity With Frailty in Older Adults for Elective Non-Cardiac Surgery.

Introduction Frailty is associated with adverse surgical outcomes. While existing studies describe the prevalence of multimorbidity and frailty in the community, the surgical population may have more severe disease and significant surgical stress. This study aims to describe the distribution of frailty and multimorbidity in the older surgical population and examine if specific comorbidities are more strongly associated with frailty. Methods This is a single-centre retrospective cohort study using an electronic database in the preoperative evaluation clinic, conducted in Singapore General Hospital, Singapore. All patients above 70 years old going for elective non-cardiac surgery were included. Demographics and comorbidities were analysed for their association with frailty according to the Edmonton Frail Scale. Results A total of 1396 out of 1398 patients were analyzed. The overall incidence of frailty was 27.8% and multimorbidity was 63.4%. Factors independently associated with frailty were age (adjusted Odds Ratio [aOR] = 1.07), female gender (aOR = 1.67), type 2 diabetes mellitus (aOR = 1.69), chronic kidney disease (aOR = 1.47), end-stage renal failure (aOR = 3.58), history of cerebrovascular accident or transient ischemic attack (aOR = 1.87), moderate anaemia (aOR = 2.11), dementia (aOR = 6.38), depression (aOR = 3.82), and peptic ulcer disease (aOR = 1.98). The presence of multi-morbidity was significantly associated with frailty, with overall increasing strength of association. Conclusion As the number of comorbidities increases, the odds of frailty increase. Only a small proportion of those with multimorbidity accumulate enough biological deficits to develop frailty, putting them at higher risk than with solely multimorbidity or frailty. Dementia and depression are comorbidities with strong associations that have yet to see coordinated interventional efforts in the preoperative setting.

Advances in the research on the targets of anti-malaria actions of artemisinin.

Malaria has been a global epidemic health threat since ancient times. It still claims roughly half a million lives every year in this century. Artemisinin and its derivatives, are frontline antimalarial drugs known for their efficacy and low toxicity. After decades of wide use, artemisinins remain our bulwark against malaria. Here, we review decades of efforts that aim to understand the mechanism of action (MOA) of artemisinins, which help explain the specificity and potency of this anti-malarial drug. We summarize the methods and approaches employed to unravel the MOA of artemisinin over the last three decades, showing how the development of advanced techniques can help provide mechanistic insights and resolve some long-standing questions in the field of artemisinin research. We also provide examples to illustrate how to better repurpose artemisinins for anti-cancer therapies by leveraging on MOA. These examples point out a practical direction to engineer artemisinin for broader applications beyond malaria.

Assessment of predictive validity and feasibility of Edmonton Frail Scale in identifying postoperative complications among elderly patients: a prospective observational study.

Frailty is defined as diminished physiological reserve predisposing one to adverse outcomes when exposed to stressors. Currently, there is no standardized Frail assessment tool used perioperatively. Edmonton Frail Scale (EFS), which is validated for use by non-geriatricians and in selected surgical populations, is a candidate for this role. However, little evaluation of its use has been carried out in the Asian populations so far. This is a prospective observational study done among patients aged 70 years and above attended Preoperative Assessment Clinic (PAC) in Singapore General Hospital prior to major abdominal surgery from December 2017 to September 2018. The Comprehensive Complication Index (CCI) and Postoperative Morbidity Survey (POMS) were used to assess their postoperative morbidity respectively. Patient's acceptability of EFS was measured using the QQ-10 questionnaire and the inter-rater reliability of EFS was assessed by Kappa statistics and Bland Altman plot. The primary aim of this study is to assess if frailty measured by EFS is predictive of postoperative complications in elderly patients undergoing elective major abdominal surgery. We also aim to assess the feasibility of implementing EFS as a standard tool in the outpatient preoperative assessment clinic setting. EFS score was found to be a significant predictor of postoperative morbidity. (OR 1.35, p < 0.001) Each point increase in EFS score was associated with a 3 point increase in CCI score. (Coefficient b 2.944, p < 0.001) EFS score more than 4 has a fair predictability of both early and 30-day postoperative complications. Feasibility study demonstrated an overall acceptance of the EFS among our patients with good inter-rater agreement.

Refractory Lactic Acidosis and an Approach to its Management - A Case Report.

BACKGROUND: Lactic acidosis (LA) is a complication of diseases commonly seen in intensive care patients which carries an increased risk of mortality. It is classified by its pathophysiology; Type A results from tissue hypo-perfusion and hypoxia, and Type B results from abnormal metabolic activity in the absence of hypoxia. Reports of the co-occurrence of both types have been rarely reported in the literature relating to intensive care patients. This case report describes the challenging management of a patient diagnosed with both Type A and Type B LA. CASE PRESENTATION: A 55-year-old female with newly diagnosed diffuse large B-cell lymphoma (DLBCL) developed hospital-acquired pneumonia, respiratory failure, shock and intra-abdominal septicaemia from a bowel perforation. Blood gases revealed a mixed picture lactic acidosis. Correction of septic shock, respiratory failure and surgical repair caused initial improvement to the lactic acidosis, but this gradually worsened in the intensive care unit. Only upon starting chemotherapy and renal replacement therapy was full resolution of the lactic acidosis achieved. The patient was discharged but succumbed to her DLBCL several months later. CONCLUSION: Type A and Type B LA can co-occur, making management difficult. A systematic approach can help diagnose any underlying pathology and aid in early management.

Mechanistic Investigation of the Specific Anticancer Property of Artemisinin and Its Combination with Aminolevulinic Acid for Enhanced Anticolorectal Cancer Activity.

The antimalarial artemisinin (ART) possesses anticancer activity, but its underlying mechanism remains largely unclear. Using a chemical proteomics approach with artemisinin-based activity probes, we identified over 300 specific ART targets. This reveals an anticancer mechanism whereby ART promiscuously targets multiple critical biological pathways and leads to cancer cell death. The specific cytotoxicity of ART against colorectal cancer (CRC) cells rather than normal colon epithelial cells is due to the elevated capacity of heme synthesis in the cancer cells. Guided by this mechanism, the specific cytotoxicity of ART toward CRC cells can be dramatically enhanced with the addition of aminolevulinic acid (ALA), a clinically used heme synthesis precursor, to increase heme levels. Importantly, this novel ART/ALA combination therapy proves to be more effective than an ART monotherapy in a mouse xenograft CRC model. Thus, ART can be repurposed and potentiated by exploitation of its mechanism of action and the metabolic features of the CRC cells.

Artemisinin as an anticancer drug: Recent advances in target profiling and mechanisms of action.

Artemisinin and its derivatives (collectively termed as artemisinins) are among the most important and effective antimalarial drugs, with proven safety and efficacy in clinical use. Beyond their antimalarial effects, artemisinins have also been shown to possess selective anticancer properties, demonstrating cytotoxic effects against a wide range of cancer types both in vitro and in vivo. These effects appear to be mediated by artemisinin-induced changes in multiple signaling pathways, interfering simultaneously with multiple hallmarks of cancer. Great strides have been taken to characterize these pathways and to reveal their anticancer mechanisms of action of artemisinin. Moreover, encouraging data have also been obtained from a limited number of clinical trials to support their anticancer property. However, there are several key gaps in knowledge that continue to serve as significant barriers to the repurposing of artemisinins as effective anticancer agents. This review focuses on important and emerging aspects of this field, highlighting breakthroughs in unresolved questions as well as novel techniques and approaches that have been taken in recent studies. We discuss the mechanism of artemisinin activation in cancer, novel and significant findings with regards to artemisinin target proteins and pathways, new understandings in artemisinin-induced cell death mechanisms, as well as the practical issues of repurposing artemisinin. We believe these will be important topics in realizing the potential of artemisinin and its derivatives as safe and potent anticancer agents.

Mapping sites of aspirin-induced acetylations in live cells by quantitative acid-cleavable activity-based protein profiling (QA-ABPP).

Target-identification and understanding of mechanism-of-action (MOA) are challenging for development of small-molecule probes and their application in biology and drug discovery. For example, although aspirin has been widely used for more than 100 years, its molecular targets have not been fully characterized. To cope with this challenge, we developed a novel technique called quantitative acid-cleavable activity-based protein profiling (QA-ABPP) with combination of the following two parts: (i) activity-based protein profiling (ABPP) and iTRAQ™ quantitative proteomics for identification of target proteins and (ii) acid-cleavable linker-based ABPP for identification of peptides with specific binding sites. It is known that reaction of aspirin with its target proteins leads to acetylation. We thus applied the above technique using aspirin-based probes in human cancer HCT116 cells. We identified 1110 target proteins and 2775 peptides with exact acetylation sites. By correlating these two sets of data, 523 proteins were identified as targets of aspirin. We used various biological assays to validate the effects of aspirin on inhibition of protein synthesis and induction of autophagy which were elicited from the pathway analysis of Aspirin target profile. This technique is widely applicable for target identification in the field of drug discovery and biology, especially for the covalent drugs.

A quantitative chemical proteomics approach to profile the specific cellular targets of andrographolide, a promising anticancer agent that suppresses tumor metastasis.

Drug target identification is a critical step toward understanding the mechanism of action of a drug, which can help one improve the drug's current therapeutic regime and expand the drug's therapeutic potential. However, current in vitro affinity-chromatography-based and in vivo activity-based protein profiling approaches generally face difficulties in discriminating specific drug targets from nonspecific ones. Here we describe a novel approach combining isobaric tags for relative and absolute quantitation with clickable activity-based protein profiling to specifically and comprehensively identify the protein targets of andrographolide (Andro), a natural product with known anti-inflammation and anti-cancer effects, in live cancer cells. We identified a spectrum of specific targets of Andro, which furthered our understanding of the mechanism of action of the drug. Our findings, validated through cell migration and invasion assays, showed that Andro has a potential novel application as a tumor metastasis inhibitor. Moreover, we have unveiled the target binding mechanism of Andro with a combination of drug analog synthesis, protein engineering, and mass-spectrometry-based approaches and determined the drug-binding sites of two protein targets, NF-κB and actin.

Analysis of anterior segment dynamics using anterior segment optical coherence tomography before and after laser peripheral iridotomy.

OBJECTIVE: To evaluate changes in the speed of pupil constriction and in anterior segment parameters after laser peripheral iridotomy (LPI) in patients with angle closure using anterior segment optical coherence tomography. METHODS: In this prospective observational study, videos of pupil and anterior segment changes in response to illumination were captured with real-time video recording using anterior segment optical coherence tomography and were analyzed frame by frame before and after LPI. Customized software was used to measure the speed of pupil constriction and changes in anterior chamber depth and anterior chamber area, as well as iris thickness at 750 µm from the scleral spur, at the sphincter muscle region (0.75 mm from the pupillary margin), and at the mid-iris location (half the distance between the scleral spur and the pupillary margin). Pupil diameter, angle opening distance, and trabecular-iris space area at 500 µm from the scleral spur were determined. The speed of pupil constriction was defined as the rate of pupil diameter change in response to illumination. RESULTS: Twenty-nine patients were included. Most were Chinese (26 of 29 [90%]) and female (18 of 29 [62%]). The anterior chamber area, angle opening distance at 500 µm from the scleral spur, and trabecular-iris space area at 500 µm from the scleral spur were significantly higher after LPI (P < .001). A significant increase was observed in the speed of pupil constriction after LPI (P < .005). In response to illumination, the rate of change in iris thickness at the sphincter muscle region and at 750 µm from the scleral spur was faster after LPI (P < .05). Similarly, an increase was observed in the speed of change of angle-opening distance at 500 µm from the scleral spur in response to illumination after LPI (P < .05). CONCLUSIONS: In patients with angle closure, changes in dynamic iridopupillary behavior are observed after LPI. The speed of pupillary constriction is faster after LPI.