Predictors of unplanned hospital readmission after non-cardiac surgery in Singapore: a 2-year retrospective review.

INTRODUCTION: Unplanned hospital readmissions after surgery contribute significantly to healthcare costs and potential complications. Identifying predictors of readmission is inherently complex and involves an intricate interplay between medical factors, healthcare system factors and sociocultural factors. Therefore, the aim of this study was to elucidate the predictors of readmissions in an Asian surgical patient population. METHODS: A two-year single-institution retrospective cohort study of 2744 patients was performed in a university-affiliated tertiary hospital in Singapore, including patients aged 45 and above undergoing intermediate or high-risk non-cardiac surgery. Unadjusted analysis was first performed, followed by multivariable logistic regression. RESULTS: Two hundred forty-nine patients (9.1%) had unplanned 30-day readmissions. Significant predictors identified from multivariable analysis include: American Society of Anaesthesiologists (ASA) Classification grades 3 to 5 (adjusted OR 1.51, 95% CI 1.10-2.08, p = 0.01), obesity (adjusted OR 1.66, 95% CI 1.18-2.34, p = 0.04), asthma (OR 1.70, 95% CI 1.03-2.81, p = 0.04), renal disease (OR 2.03, 95% CI 1.41-2.92, p < 0.001), malignancy (OR 1.68, 95% CI 1.29-2.37, p < 0.001), chronic obstructive pulmonary disease (OR 2.46, 95% CI 1.19-5.11, p = 0.02), cerebrovascular disease (OR 1.73, 95% CI 1.17-2.58, p < 0.001) and anaemia (OR 1.45, 95% CI 1.07-1.96, p = 0.02). CONCLUSION: Several significant predictors of unplanned readmissions identified in this Asian surgical population corroborate well with findings from Western studies. Further research will require future prospective studies and development of predictive risk modelling to further address and mitigate this phenomenon.

Design, Synthesis and Anticancer Evaluation of Nitroimidazole Radiosensitisers.

The role of hypoxic tumour cells in resistance to radiotherapy, and in suppression of immune response, continues to endorse tumour hypoxia as a bona fide, yet largely untapped, drug target. Radiotherapy innovations such as stereotactic body radiotherapy herald new opportunities for classical oxygen-mimetic radiosensitisers. Only nimorazole is used clinically as a radiosensitiser, and there is a dearth of new radiosensitisers in development. In this report, we augment previous work to present new nitroimidazole alkylsulfonamides and we document their cytotoxicity and ability to radiosensitise anoxic tumour cells in vitro. We compare radiosensitisation with etanidazole and earlier nitroimidazole sulfonamide analogues and we identify 2-nitroimidazole and 5-nitroimidazole analogues with marked tumour radiosensitisation in ex vivo assays of surviving clonogens and with in vivo tumour growth inhibition.

Nocturnal Oxygen Desaturation Index Correlates with Respiratory Depression in Post-Surgical Patients Receiving Opioids - A Post-Hoc Analysis from the Prediction of Opioid-Induced Respiratory Depression in Patients Monitored by Capnography (PRODIGY) Study.

Purpose: Postoperative monitoring of respiratory status on general care wards typically consists of intermittent checks of oxyhemoglobin saturation and respiratory rate, allowing substantial unmonitored time for severe opioid induced respiratory depression (RD) to develop unnoticed. Oxygen desaturation index (ODI) can be computed solely by continuous pulse oximetry monitoring. In this post-hoc analysis, we evaluate whether nocturnal ODI correlates with RD. Patients and Methods: The PRODIGY trial (NCT02811302) was a multinational study conducted where adult patients receiving parenteral opioids on the general care floor were continuously monitored by blinded pulse oximetry and capnography monitoring to detect episodes of RD. An RD episode was defined as: respiratory rate ≤5 breaths/min (bpm) for ≥3 minutes, oxygen saturation (SpO2) ≤85% for ≥3 minutes, end-tidal carbon dioxide (EtCO2) ≤15 or ≥60 mm Hg for ≥3 minutes, apnea episode lasting >30 seconds, or any respiratory opioid-related adverse event. Data were used to calculate nocturnal (00:00 ─ 06:00) ODI4% based on desaturation episodes (4% decrease from mean oxyhemoglobin saturation in the past 120 seconds, lasting ≥10 seconds). Continuous monitoring began after a patient received parenteral opioids, allowing identification of potential RD and ODI4% episodes during opioid therapy. The average number of ODI4% episodes (≥1, ≥5, ≥10, ≥15 episodes/hour) were analyzed. Logistic regression and area under the receiver operating characteristic curve (AUC) were computed. Results: A final cohort of 1072 (out of 1335) patients had sufficient data, with 76% (N=817/1072) having ≥1 episode of ODI4%. Multivariable logistic regression showed that ODI4% was strongly associated with RD, with greater risk for higher ODI4% scores: ≥5 episodes/hour odds ratio 2.59 (95% CI 1.72-3.89, p<0.0001); ≥10 episodes/hour 3.39 (95% CI 1.80-6.39, p=0.0002); ≥15 episodes/hour 4.71 (95% CI 1.93-11.47, p=0.0006).There was no significant association between ODI4% and respiratory adverse events. Conclusion: Nocturnal ODI4% was highly correlated with RD among hospitalized patients receiving parenteral opioids. Patients with a high ODI4%, especially with ≥15 episodes/hour, are more likely to experience RD and should be evaluated for the need of closer monitoring after opioid administration.

Association Between Race and Opioid-Induced Respiratory Depression: An International Post Hoc Analysis of the Prediction of Opioid-induced Respiratory Depression In Patients Monitored by Capnography Trial.

BACKGROUND: Opioid-induced respiratory depression (OIRD) is common on the medical and surgical wards and is associated with increased morbidity and health care costs. While previous studies have investigated risk factors for OIRD, the role of race remains unclear. We aim to investigate the association between race and OIRD occurrence on the medical/surgical ward. METHODS: This is a post hoc analysis of the PRediction of Opioid-induced respiratory Depression In patients monitored by capnoGraphY (PRODIGY) trial; a prospective multinational observational blinded study of 1335 general ward patients who received parenteral opioids and underwent blinded capnography and oximetry monitoring to identify OIRD episodes. For this study, demographic and perioperative data, including race and comorbidities, were analyzed and assessed for potential associations with OIRD. Univariable χ 2 and Mann-Whitney U tests were used. Stepwise selection of all baseline and demographic characteristics was used in the multivariable logistic regression analysis. RESULTS: A total of 1253 patients had sufficient racial data (317 Asian, 158 Black, 736 White, and 42 other races) for inclusion. The incidence of OIRD was 60% in Asians (N = 190/317), 25% in Blacks (N = 40/158), 43% in Whites (N = 316/736), and 45% (N = 19/42) in other races. Baseline characteristics varied significantly: Asians were older, more opioid naïve, and had higher opioid requirements, while Blacks had higher incidences of heart failure, obesity, and smoking. Stepwise multivariable logistic regression revealed that Asians had increased risk of OIRD compared to Blacks (odds ratio [OR], 2.49; 95% confidence interval [CI], 1.54-4.04; P = .0002) and Whites (OR, 1.38; 95% CI, 1.01-1.87; P = .0432). Whites had a higher risk of OIRD compared to Blacks (OR, 1.81; 95% CI, 1.18-2.78; P = .0067). The model's area under the curve was 0.760 (95% CI, 0.733-0.787), with a Hosmer-Lemeshow goodness-of-fit test P value of .23. CONCLUSIONS: This post hoc analysis of PRODIGY found a novel association between Asian race and increased OIRD incidence. Further study is required to elucidate its underlying mechanisms and develop targeted care pathways to reduce OIRD in susceptible populations.

Novel local anesthesia technique 'NATURE ' (Nerves And Transversalis-fascia Using RopivacainE) to improve outcomes during endo-laparoscopic inguinal hernia repair.

BACKGROUND: The use of local anaesthesia infiltration techniques may attenuate pain following endo-laparoscopic inguinal hernia surgery. We aim to reduce post-operative pain and the subsequent need for analgesia using a novel technique of local anaesthesia infiltration 'NATURE' (Nerves And Transversalis-fascia Using RopivacainE). METHODS: This is a retrospective study of patients who underwent endo-laparoscopic inguinal hernia repair in two institutions in Singapore. Patients who received the local anaesthesia according to the new technique (intervention group) were compared to patients who received local anaesthesia only over their surgical incisions (control group). RESULTS: Data on 97 patients were analysed. There were 50 (51.5%) patients in the intervention group and 47 (48.5%) patients in the control group. No significant differences were observed in the two patient population's baseline characteristics, operative time and cumulative need for medications. The intervention group reported lower pain levels immediately after surgery (1.4 ± 1.7 versus 2.4 ± 1.9, p<0.01) and at 4 hours post-surgery (0.9 ± 1.1 versus 1.4 ± 1.2, p = 0.02). They also had lower levels of post-operative complications (4% versus 21.3%, p = 0.03). CONCLUSION: Infiltration of local anaesthesia at specific anatomical locations during endo-laparoscopic inguinal hernia surgery can be effective in minimising post-operative pain. Prospective randomised controlled trials are needed to further substantiate this technique.

The neglected perioperative population of undiagnosed diabetics - a retrospective cohort study.

BACKGROUND: Diabetes is known to increase morbidity and 30-day mortality in adults undergoing non-cardiac surgery, but longer term outcomes are less studied. This study was done to explore how undiagnosed and known diabetes affect 30-day and one-year morbidity and mortality outcomes. The secondary aim was to study the prevalence of undiagnosed diabetics in our perioperative Asian surgical population. METHODS: A retrospective cohort study of 2106 patients aged > 45 years undergoing non-cardiac surgery in a single tertiary hospital was performed. Undiagnosed diabetics were identified (HbA1c ≥6.5% or fasting blood glucose ≥126 mg/dL) and relevant demographic, clinical and surgical data were analyzed to elicit the relationship to adverse outcomes. Univariate analysis was first performed to identify significant variables with p-values ≤0.1, which were then analyzed using multiple logistic regression to calculate the adjusted odds ratio. RESULTS: The prevalence of undiagnosed diabetes was 7.4%. The mean and median HbA1c of known diabetics were 7.9 and 7.5%, while the mean and median HbA1c for undiagnosed diabetics were 7.2 and 6.8% respectively. 36.4% of known diabetics and 20.5% of undiagnosed diabetics respectively had a random blood glucose > 200 mg/dL. Undiagnosed diabetics had a three-fold increase in 1-year mortality compared to non-diabetics (adjusted OR 3.46(1.80-6.49) p < 0.001) but this relationship was not significant between known and non-diabetics. Compared to non-diabetics, known diabetics were at increased risks of new-onset atrial fibrillation (aOR 2.48(1.01-6.25) p = 0.047), infection (aOR 1.49(1.07-2.07) p = 0.017), 30-day readmission (aOR 1.62(1.17-2.25) p = 0.004) and 30-day mortality (aOR 3.11(1.16-8.56) p = 0.025). CONCLUSIONS: Although undiagnosed diabetics have biochemically less severe disease compared to known diabetics at the point of testing, they are at a one-year mortality disadvantage which is not seen among known diabetics. This worrying trend highlights the importance of identifying and treating diabetes. Congruent to previous studies, known diabetics have higher morbidity and 30-day mortality compared to non-diabetics.

Identification of Small-Molecule Positive Modulators of Calcitonin-like Receptor-Based Receptors.

Class B G protein-coupled receptors are highly therapeutically relevant but challenges remain in identifying suitable small-molecule drugs. The calcitonin-like receptor (CLR) in particular is linked to conditions such as migraine, cardiovascular disease, and inflammatory bowel disease. The CLR cannot act as a cell-surface receptor alone but rather must couple to one of three receptor activity-modifying proteins (RAMPs), forming heterodimeric receptors for the peptides adrenomedullin and calcitonin gene-related peptide. These peptides have extended binding sites across their receptors. This is one reason why there are few small-molecule ligands that can modulate these receptors. Here we describe small molecules that are able to positively modulate the signaling of the CLR with all three RAMPs but are not active at the related calcitonin receptor. These compounds were selected from a ß-arrestin recruitment screen, coupled with rounds of medicinal chemistry to improve their activity. Translational potential is shown as the compounds can positively modulate cAMP signaling in a vascular cell line model. Binding experiments do not support an extracellular domain binding site; however, molecular modeling reveals potential allosteric binding sites in multiple receptor regions. These are the first small-molecule positive modulators described for the CLR:RAMP complexes.

Factors predicting one-year post-surgical mortality amongst older Asian patients undergoing moderate to major non-cardiac surgery - a retrospective cohort study.

BACKGROUND: While short-term perioperative outcomes have been well studied in Western surgical populations, the aim of this study is to look at the one-year perioperative mortality and its associated factors in an Asian surgical population after non-cardiac surgery. METHODS: A retrospective cohort study of 2163 patients aged above 45 undergoing non-cardiac surgery in a university-affiliated tertiary hospital from January to July 2015 was performed. Relevant demographic, clinical and surgical data were analysed to elicit their relationship to mortality at one year after surgery. A univariate analysis was first performed to identify significant variables with p-values ≤ 0.2, which were then analysed using Firth multiple logistic regression to calculate the adjusted odds ratio. RESULTS: The one-year mortality in our surgical population was 5.9%. The significant factors that increased one-year mortality include smoking (adjusted OR 2.17 (1.02-4.45), p = 0.044), anaemia (adjusted OR 1.32 (1.16-1.47), p < 0.001, for every 1 g/dL drop in haemoglobin level), lower BMI (adjusted OR 0.93 (0.87-0.98), p = 0.005, for every 1 point increase in BMI), Malay and Indian ethnicity (adjusted OR 2.68 (1.53-4.65), p = 0.001), peripheral vascular disease (adjusted OR 4.21 (1.62-10.38), p = 0.004), advanced age (adjusted OR 1.04 (1.01-1.06), p = 0.004, for every one year increase in age), emergency surgery (adjusted OR 2.26 (1.29-3.15), p = 0.005) and malignancy (adjusted OR 3.20 (1.85-5.52), p < 0.001). CONCLUSIONS: Our study shows that modifiable risk factors such as malnutrition, anaemia and smoking which affect short term mortality extend beyond the immediate perioperative period into longer term outcomes. Identification and optimization of this subset of patients are therefore vital. Further similar large studies should be done to develop a risk scoring system for post-operative long-term outcomes. This would aid clinicians in risk stratification, counselling and surgical planning, which will help in patients' decision making and care planning.

Hypoxia-selective radiosensitisation by SN38023, a bioreductive prodrug of DNA-dependent protein kinase inhibitor IC87361.

DNA-dependent protein kinase (DNA-PK) plays a key role in repair of radiation-induced DNA double strand breaks (DSB) by non-homologous end-joining. DNA-PK inhibitors (DNA-PKi) are therefore efficient radiosensitisers, but normal tissue radiosensitisation represents a risk for their use in radiation oncology. Here we describe a novel prodrug, SN38023, that is metabolised to a potent DNA-PKi (IC87361) selectively in radioresistant hypoxic cells. DNA-PK inhibitory potency of SN38023 was 24-fold lower than IC87361 in cell-free assays, consistent with molecular modelling studies suggesting that SN38023 is unable to occupy one of the predicted DNA-PK binding modes of IC87361. One-electron reduction of the prodrug by radiolysis of anoxic formate solutions, and by metabolic reduction in anoxic HCT116/POR cells that overexpress cytochrome P450 oxidoreductase (POR), generated IC87361 efficiently as assessed by LC-MS. SN38023 inhibited radiation-induced Ser2056 autophosphorylation of DNA-PK catalytic subunit and radiosensitised HCT116/POR and UT-SCC-54C cells selectively under anoxia. SN38023 was an effective radiosensitiser in anoxic HCT116 spheroids, demonstrating potential for penetration into hypoxic tumour tissue, but in spheroid co-cultures of high-POR and POR-null cells it showed no evidence of bystander effects resulting from local diffusion of IC87361. Pharmacokinetics of IC87361 and SN38023 at maximum achievable doses in NIH-III mice demonstrated sub-optimal exposure of UT-SCC-54C tumour xenografts and did not provide significant tumour radiosensitisation. In conclusion, SN38023 has potential for exploiting hypoxia for selective delivery of a potent DNA-PKi to the most radioresistant subpopulation of cells in tumours. However, prodrugs providing improved systemic pharmacokinetics and that release DNA-PKi that elicit bystander effects are needed to maximise therapeutic utility.

Hypoxia-Activated Prodrugs of PERK Inhibitors.

Tumour hypoxia plays an important role in tumour progression and resistance to therapy. Under hypoxia unfolded proteins accumulate in the endoplasmic reticulum (ER) and this stress is relieved through the protein kinase R-like ER kinase (PERK) signalling arm of the unfolded protein response (UPR). Targeting the UPR through PERK kinase inhibitors provides tumour growth inhibition, but also elicits on-mechanism normal tissue toxicity. Hypoxia presents a target for tumour-selective drug delivery using hypoxia-activated prodrugs. We designed and prepared hypoxia-activated prodrugs of modified PERK inhibitors using a 2-nitroimidazole bioreductive trigger. The new inhibitors retained PERK kinase inhibitory activity and the corresponding prodrugs were strongly deactivated. The prodrugs were able to undergo fragmentation following radiolytic reduction, or bioreduction in HCT116 cells, to release their effectors, albeit inefficiently. We examined the effects of the prodrugs on PERK signalling in hypoxic HCT116 cells. This study has identified a 2-substituted nitroimidazole carbamate prodrug with potential to deliver PERK inhibitors in a hypoxia-selective manner.

Next-Generation Hypoxic Cell Radiosensitizers: Nitroimidazole Alkylsulfonamides.

Innovations in the field of radiotherapy such as stereotactic body radiotherapy, along with the advent of radio-immuno-oncology, herald new opportunities for classical oxygen-mimetic radiosensitizers. The role of hypoxic tumor cells in resistance to radiotherapy and in suppression of immune response continues to endorse tumor hypoxia as a bona fide, yet largely untapped, drug target. Only nimorazole is used clinically as a radiosensitizer, and there is a dearth of new radiosensitizers in development. Here we present a survey of novel nitroimidazole alkylsulfonamides and document their cytotoxicity and ability to radiosensitize anoxic tumor cells in vitro. We use a phosphate prodrug approach to increase aqueous solubility and to improve tumor drug delivery. A 2-nitroimidazole and a 5-nitroimidazole analogue demonstrated marked tumor radiosensitization in either ex vivo assays of surviving clonogens or tumor regrowth delay.

Chemical Space Mimicry for Drug Discovery.

We describe a new library generation method, Machine-based Identification of Molecules Inside Characterized Space (MIMICS), that generates sets of molecules inspired by a text-based input. MIMICS-generated libraries were found to preserve distributions of properties while simultaneously increasing structural diversity. Newly identified MIMICS-generated compounds were found to be bioactive as inhibitors of specific components of the unfolded protein response (UPR) and the VEGFR2 pathway in cell-based assays, thus confirming the applicability of this methodology toward drug design applications. Wider application of MIMICS could facilitate the efficient utilization of chemical space.

Synthesis and in vitro and in vivo evaluation of antimalarial polyamines.

We recently reported that 1,14-diphenylacetamide derivatives of spermine exhibit potent nM in vitro growth inhibition properties of Plasmodium falciparum. In an effort to expand the structure-activity relationship of this compound class towards malaria, we have prepared and biologically tested a library that includes benzamide and 3-phenylpropanamide 'capping acid' groups, and polyamines that include spermine (PA3-4-3) and chain extended analogues PA3-8-3 and PA3-12-3. 2-Hydroxy and 2,5-dimethoxy analogues were typically found to exhibit the most potent activity towards the dual drug resistant strain K1 of P. falciparum with IC50's in the range of 1.3-9.5 nM, and selectivity indices (SI) of 42,300 to 4880. In vivo evaluation of three analogues against Plasmodium berghei was undertaken, with one demonstrating a modest 27.9% reduction in parasitaemia.

Discovery and preliminary structure-activity relationship analysis of 1,14-sperminediphenylacetamides as potent and selective antimalarial lead compounds.

Screening of synthesized and isolated marine natural products for in vitro activity against four parasitic protozoa has identified the ascidian metabolite 1,14-sperminedihomovanillamide (orthidine F, 1) as being a non-toxic, moderate growth inhibitor of Plasmodium falciparum (IC(50) 0.89 µM). Preliminary structure-activity relationship investigation identified essentiality of the spermine polyamine core and the requirement for 1,14-disubstitution for potent activity. One analogue, 1,14-spermine-di-(2-hydroxyphenylacetamide) (3), exhibited two orders of magnitude increased anti-P. f activity (IC(50) 8.6 nM) with no detectable in vitro toxicity. The ease of synthesis of phenylacetamido-polyamines, coupled with potent nM levels of activity towards dual drug resistant strains of P. falciparum makes this compound class of interest in the development of new antimalarial therapeutics.