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Lydia QN Liew,1 Lawrence SC Law,1 Edwin Seet,2 Fabio Di Piazza,3 Katherine E Liu,4 Ming Ann Sim,1 Vanessa TY Chua,1 Toby N Weingarten,5 Ashish K Khanna,6 Lian Kah Ti1,2 On behalf of the PRediction of Opioid-induced respiratory Depression In patients monitored by capnoGraphY (PRODIGY) Group Investigators1National University Hospital, Singapore, Singapore; 2National University of Singapore, Yong Loo Lin School of Medicine, Singapore; 3Medtronic Core Clinical Solutions, Study and Scientific Solutions, Rome, Italy; 4Patient Monitoring Clinical Research, Medtronic, Minneapolis, MN, USA; 5Departments of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA; 6Wake Forest School of Medicine, Winston-Salem, North Carolina, US & Outcomes Research Consortium, Cleveland, OH, USACorrespondence: Lian Kah Ti, Yong Loo Lin School of Medicine, National University of Singapore, 21 Lower Kent Ridge Road, Singapore, 119077, Singapore, Tel +65 6779 5555, Email lian_kah_ti@nuhs.edu.sgPurpose: 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 &boxh; 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.Keywords: opioids, oxygen desaturation index, respiratory depression, sleep apnea

Objective: Oropharyngeal dysphagia (dysphagia) is highly prevalent (up to 86%) in hospitalized patients with Alzheimer disease and related dementias (ADRD). This study aims to describe the management and clinical course of dysphagia in hospitalized patients with ADRD., Design: Prospective observational cohort study., Setting and Participants: The study was conducted across 10 hospitals within a large health system in New York. Participants were older adults with ADRD admitted to the medicine service and diagnosed with dysphagia to liquids on speech-language pathologist (SLP) assessment and were recruited between January and June 2023., Methods: Baseline characteristics [eg, dementia Functional Assessment Staging Tool (FAST)], dysphagia management (eg, prescribed diet), and clinical course (eg, dysphagia improvement, respiratory complications) were collected., Results: Of patients with ADRD and dysphagia (n = 62), the average age was 86.5 and 66.1% were FAST Stage 7. On admission, 48.4% had pneumonia, 79.0% had delirium, and 69.4% were made nil per os (NPO) for aspiration risk. Of those who received SLP reassessment after diet initiation (n = 25), 76% demonstrated dysphagia improvement; 75% of patients with FAST stage 7 demonstrated improvement. Respiratory complications occurred in 21.0% of patients on the following diets: NPO, nasogastric tube feeding, dysphagia diets, and comfort feeds. In univariate analyses, hospital-acquired dehydration, no dysphagia improvement, and delirium were associated with respiratory complications., Conclusions and Implications: The potential for dysphagia improvement in hospitalized patients with ADRD (even those with advanced dementia) highlights the critical need for standardizing reassessment. Further studies are needed to evaluate factors associated with respiratory complications in this population., Competing Interests: Disclosure The authors declare no conflicts of interest., (Copyright © 2024 Post-Acute and Long-Term Care Medical Association. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Patients with inflammatory bowel disease (IBD) receiving infliximab (IFX) commonly experience immunogenic loss of response (LOR) by formation of anti-drug antibodies (ADAs). An immunomodulator (IMM) used in combination with initial IFX induction is known to reduce ADA development and improve clinical outcomes. We aimed to assess the impact of reactively adding an IMM to patients on IFX monotherapy., Methods: We conducted a retrospective cohort study and systematic review with meta-analysis of patients with IBD demonstrating immunologic LOR, with or without clinical LOR, that had an IMM (azathioprine, 6-mercaptopurine, or methotrexate) reactively added (reactive combination therapy; rCT) to combat elevated ADAs and raise IFX level. Data were extracted for pooled effect size estimation using random-effects models, and ADA and IFX trough levels were compared pre- and post-IMM initiation., Results: We identified 6 patients who received rCT due to rising ADA titers and low IFX levels. Median ADA titer decreased from 506 ng/mL (interquartile range (IQR) [416-750]) to 76.5 ng/mL (IQR [25.8-232]), an 85% decrease (p = 0.031). Median IFX trough increased from 0.4 µg/mL (IQR [0.4-0.48]) to 8.25 µg/mL (IQR [3.7-9.6]), a 20.6-fold increase (p = 0.038). Meta-analysis pooled effect size of 7 studies with 89 patients showed an 87% ADA titer reduction [95% confidence interval (CI) = 72-94%], 6.7-fold increased IFX trough (95% CI = 2.4-18.7), and 76% clinical remission rescue rate (95% CI = 59-93%)., Conclusions: These results suggest rCT is a valid rescue strategy in patients with immunogenic LOR to IFX to reduce ADA titers, restore therapeutic IFX levels, and recapture clinical remission of IBD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: A secondary loss of response (LOR) to infliximab (IFX) therapy for inflammatory bowel disease (IBD) is typically associated with low IFX trough levels, often with high levels of neutralizing antibodies to IFX (ATI). A small subset of patients on long-term therapy experience a "nonimmune" LOR, without ATI and with desired IFX trough levels ≥5 μg/mL, regarded as a LOR to the mechanism of action of IFX. However, this currently accepted IFX goal level is largely derived from observations of patients within the first year of therapy and may not apply to those on treatment beyond 1 year., Methods: Retrospective review of all IBD patients receiving IFX infusions for ≥12 months with at least 1 IFX trough and ATI measurement beyond 12 months was conducted. Chart review of all patients with absent ATI and an IFX trough ≥5 μg/mL classifies as LOR versus non-LOR based on physician assessment, with a comparison of IFX troughs between the two groups., Results: Of 167 patients using IFX ≥12 months, 13 (7.8%) experienced a nonimmune secondary LOR. The mean duration of IFX use was over 3 years for both LOR and non-LOR patients. The mean IFX trough for those with LOR was greater than for those without LOR, 18.5 μg/mL versus 13.1 μg/mL, p = 0.110., Conclusion: Our results did not demonstrate lower IFX levels among patients experiencing secondary nonimmune LOR on long-term therapy. Our results do not redefine the therapeutic IFX goal levels for those patients on long-term therapy and suggest that underdosing of IFX is not the cause of secondary LOR., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Uveal melanoma (UM) is the deadliest form of eye cancer in adults. Inactivating mutations and/or loss of expression of the gene encoding BRCA1-associated protein 1 (BAP1) in UM tumors are associated with an increased risk of metastasis. To investigate the mechanisms underlying this risk, we explored the functional consequences of BAP1 deficiency. UM cell lines expressing mutant BAP1 grew more slowly than those expressing wild-type BAP1 in culture and in vivo. The ability of BAP1 reconstitution to restore cell proliferation in BAP1-deficient cells required its deubiquitylase activity. Proteomic analysis showed that BAP1-deficient cells had decreased phosphorylation of ribosomal S6 and its upstream regulator, p70S6K1, compared with both wild-type and BAP1 reconstituted cells. In turn, expression of p70S6K1 increased S6 phosphorylation and proliferation of BAP1-deficient UM cells. Consistent with these findings, BAP1 mutant primary UM tumors expressed lower amounts of p70S6K1 target genes, and S6 phosphorylation was decreased in BAP1 mutant patient-derived xenografts (PDXs), which grew more slowly than wild-type PDXs in the liver (the main metastatic site of UM) in mice. BAP1-deficient UM cells were also more resistant to amino acid starvation, which was associated with diminished phosphorylation of S6. These studies demonstrate that BAP1 deficiency slows the proliferation of UM cells through regulation of S6 phosphorylation. These characteristics may be associated with metastasis by ensuring survival during amino acid starvation.

This research, using data from the Community Criminal Courts where a majority of elderly offenders are tried and sentenced, investigates the socio-economic profile of elderly offenders and the factors influencing their criminal motivation in Singapore. It revisits conceptualizations of offending in older age which until now has received scant attention even in Asian societies where ties to conventional institutions are thought to be "protective." The majority of elderly offenders in this study were "revolving door prisoners" and were never in possession of any efficacious social capital that would have prevented them from committing a crime or enabled their re-entry process, a problem compounded by the study's findings that almost 70% of the sampled offenders had experienced mental health issues. This would have spelled adverse consequences for their desistance and, conversely, their recidivist behavior, a finding that was consistent with many other studies that had examined the association between psychosis and crime., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The views expressed in this publication are those of the authors and do not necessarily represent the views or official policy of the State Courts.

Most uveal melanoma cases harbor activating mutations in either GNAQ or GNA11. Despite activation of the mitogen-activated protein kinase (MAPK) signaling pathway downstream of Gαq/11, there are no effective targeted kinase therapies for metastatic uveal melanoma. The human genome encodes numerous understudied kinases, also called the "dark kinome". Identifying additional kinases regulated by Gαq/11 may uncover novel therapeutic targets for uveal melanoma. In this study, we treated GNAQ-mutant uveal melanoma cell lines with a Gαq/11 inhibitor, YM-254890, and conducted a kinase signaling proteomic screen using multiplexed-kinase inhibitors followed by mass spectrometry. We observed downregulated expression and/or activity of 22 kinases. A custom siRNA screen targeting these kinases demonstrated that knockdown of microtubule affinity regulating kinase 3 (MARK3) and serine/threonine kinase 10 (STK10) significantly reduced uveal melanoma cell growth and decreased expression of cell cycle proteins. Additionally, knockdown of MARK3 but not STK10 decreased ERK1/2 phosphorylation. Analysis of RNA-sequencing and proteomic data showed that Gαq signaling regulates STK10 expression and MARK3 activity. Our findings suggest an involvement of STK10 and MARK3 in the Gαq/11 oncogenic pathway and prompt further investigation into the specific roles and targeting potential of these kinases in uveal melanoma., Competing Interests: Conflict of interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A. E. A. has an ownership interest in patent number 9880150 and a pending patent, PCT/US22/76492. No potential conflicts of interest were disclosed by the other authors. M. A. D. has been a consultant to Roche/Genentech, Array, Pfizer, Novartis, BMS, GSK, Sanofi-Aventis, Vaccinex, Apexigen, Eisai, Iovance, and ABM Therapeutics, and he has been the PI of research grants to MD Anderson by Roche/Genentech, GSK, Sanofi-Aventis, Merck, Myriad, Oncothyreon, ABM Therapeutics, and LEAD Pharma. J. S. G. has been a consultant for Domain Pharmaceuticals, Pangea Therapeutics, and io9, and is the founder of Kadima Pharmaceuticals, all unrelated to the current study. All other authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Post-anaesthesia care unit (PACU) delirium affects 5%-45% of patients after surgery and is associated with postoperative delirium and increased mortality. Up to 40% of PACU delirium is preventable, but it remains under-recognised due to a lack of awareness of its diagnosis. The nursing delirium screening scale (Nu-DESC) has been validated for diagnosing PACU delirium, but is not routinely used locally. This study aimed to use Nu-DESC to establish the incidence and risk factors of PACU delirium in patients undergoing non-cardiac surgery in the surgical population., Methods: We conducted an audit of eligible patients undergoing major surgery in three public hospitals in Singapore over 1 week. Patients were assessed for delirium 30-60 min following their arrival in PACU using Nu-DESC, with a total score of ≥2 indicative of delirium., Results: A total of 478 patients were assessed. The overall incidence rate of PACU delirium was 18/478 (3.8%), and the incidence was 9/146 (6.2%) in patients aged > 65 years. Post-anaesthesia care unit delirium was more common in females, patients with malignancy and those who underwent longer operations. Logistic regression analysis showed that the use of bispectral index (P < 0.001) and the presence of malignancy (P < 0.001) were significantly associated with a higher incidence of PACU delirium., Conclusion: In this first local study, the incidence of PACU delirium was 3.8%, increasing to 6.2% in those aged > 65 years. Understanding these risk factors will form the basis for which protocols can be established to optimise resource management and prevent long-term morbidities and mortality in PACU delirium., Competing Interests: None

Background: Vaccination continues to be the key public health measure for preventing severe COVID-19 outcomes. Certain groups may be at higher risk of incomplete vaccine schedule, which may leave them vulnerable to COVID-19 hospitalisation and death., Aim: To identify the sociodemographic and clinical predictors for not receiving a scheduled COVID-19 vaccine after previously receiving one., Methods: We conducted two retrospective cohort studies with ≥3.7 million adults aged ≥18 years in Scotland. Multivariable logistic regression was used to estimate adjusted odds ratios (aOR) of not receiving a second, and separately a third dose between December 2020 and May 2022. Independent variables included sociodemographic and clinical factors., Results: Of 3,826,797 people in the study population who received one dose, 3,732,596 (97.5%) received two doses, and 3,263,153 (86.5%) received all doses available during the study period. The most strongly associated predictors for not receiving the second dose were: being aged 18-29 (reference: 50-59 years; aOR:4.26; 95% confidence interval (CI):4.14-4.37); hospitalisation due to a potential vaccine related adverse event of special interest (AESI) (reference: not having a potential AESI, aOR:3.78; 95%CI: 3.29-4.35); and living in the most deprived quintile (reference: least deprived quintile, aOR:3.24; 95%CI: 3.16-3.32). The most strongly associated predictors for not receiving the third dose were: being 18-29 (reference: 50-59 years aOR:4.44; 95%CI: 4.38-4.49), living in the most deprived quintile (reference: least deprived quintile aOR:2.56; 95%CI: 2.53-2.59), and Black, Caribbean, or African ethnicity (reference: White ethnicity aOR:2.38; 95%CI: 2.30-2.46). Pregnancy, previous vaccination with mRNA-1273, smoking history, individual and household severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positivity, and having an unvaccinated adult in the household were also associated with incomplete vaccine schedule., Conclusion: We observed several risk factors that predict incomplete COVID-19 vaccination schedule. Vaccination programmes must take immediate action to ensure maximum uptake, particularly for populations vulnerable to severe COVID-19 outcomes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

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., (© 2023. The Author(s).)

Uveal melanoma (UM) displays a high frequency of metastasis; however, effective therapies for metastatic UM are limited. Identifying unique metabolic features of UM may provide a potential targeting strategy. A lipid metabolism protein expression signature was induced in a normal choroidal melanocyte (NCM) line transduced with GNAQ (Q209L), a driver in UM growth and development. Consistently, UM cells expressed elevated levels of fatty acid synthase (FASN) compared to NCMs. FASN upregulation was associated with increased mammalian target of rapamycin (mTOR) activation and sterol regulatory element-binding protein 1 (SREBP1) levels. FASN and mTOR inhibitors alone significantly reduced UM cell growth. Concurrent inhibition of FASN and mTOR further reduced UM cell growth by promoting cell cycle arrest and inhibiting glucose utilization, TCA cycle metabolism, and de novo fatty acid biosynthesis. Our findings indicate that FASN is important for UM cell growth and co-inhibition of FASN and mTOR signaling may be considered for treatment of UM.

Background: NC-6300 is a novel epirubicin (EPI) drug conjugated polymeric micelle developed using cutting-edge micellar nanoparticle technology. The nanoparticle epirubicin conjugates EPI to a polymer via a pH-sensitive linker which enables the selective EPI release into tumor. Tumor activity was observed in a monotherapy phase Ib trial, where two of two patients with angiosarcoma achieved a partial response. To further explore the activity of NC-6300 in angiosarcoma, an expansion cohort was undertaken., Methods: Ten patients with angiosarcoma were enrolled in the expansion cohort. Patients were dosed using the recommended dose of 150 mg/m2 intravenously (IV) once every 3 weeks. The primary endpoint was progression-free survival., Results: The most common adverse events (AEs) of any grade, regardless of the causal relationship with NC-6300, were neutropenia (90%), fatigue, and thrombocytopenia (60% each) and nausea (50%). The most common grades 3 and 4 AEs were neutropenia (80%), thrombocytopenia (40%), and anemia and leukopenia (20% each). The median progression-free survival (mPFS) for all subjects was 5.4 months. The mPFS was 3.8 months in subjects with prior anthracycline treatment and 8.2 months in subjects without prior anthracycline treatment., Conclusion: NC-6300 was well tolerated, showing promising activity in angiosarcoma patients without prior anthracycline treatment. NC-6300 warrants further investigation (ClinicalTrials.gov Identifier: NCT03168061)., (© The Author(s) 2022. Published by Oxford University Press.)

BRCA1-associated protein 1 (BAP1) is a tumor suppressor gene that is mutated in cancer, including uveal melanoma. Loss-of-function BAP1 mutations are associated with uveal melanoma metastasis and poor prognosis, but the mechanisms underlying these effects remain unclear. Upregulation of cell-cell adhesion proteins is involved with collective migration and metastatic seeding of cancer cells. Here, we show that BAP1 loss in uveal melanoma patient samples is associated with upregulated gene expression of multiple cell adhesion molecules (CAM), including E-cadherin (CDH1), cell adhesion molecule 1 (CADM1), and syndecan-2 (SDC2). Similar findings were observed in uveal melanoma cell lines and single-cell RNA-sequencing data from uveal melanoma patient samples. BAP1 reexpression in uveal melanoma cells reduced E-cadherin and CADM1 levels. Functionally, knockdown of E-cadherin decreased spheroid cluster formation and knockdown of CADM1 decreased growth of BAP1-mutant uveal melanoma cells. Together, our findings demonstrate that BAP1 regulates the expression of CAMs which may regulate metastatic traits., Implications: BAP1 mutations and increased metastasis may be due to upregulation of CAMs., (©2022 American Association for Cancer Research.)

Background: Telemedicine is increasingly being leveraged, as the need for remote access to health care has been driven by the rising chronic disease incidence and the COVID-19 pandemic. It is also important to understand patients' willingness to pay (WTP) for telemedicine and the factors contributing toward it, as this knowledge may inform health policy planning processes, such as resource allocation or the development of a pricing strategy for telemedicine services. Currently, most of the published literature is focused on cost-effectiveness analysis findings, which guide health care financing from the health system's perspective. However, there is limited exploration of the WTP from a patient's perspective, despite it being pertinent to the sustainability of telemedicine interventions., Objective: To address this gap in research, this study aims to conduct a systematic review to describe the WTP for telemedicine interventions and to identify the factors influencing WTP among patients with chronic diseases in high-income settings., Methods: We systematically searched 4 databases (PubMed, PsycINFO, Embase, and EconLit). A total of 2 authors were involved in the appraisal. Studies were included if they reported the WTP amounts or identified the factors associated with patients' WTP, involved patients aged ≥18 years who were diagnosed with chronic diseases, and were from high-income settings., Results: A total of 11 studies from 7 countries met this study's inclusion criteria. The proportion of people willing to pay for telemedicine ranged from 19% to 70% across the studies, whereas the values for WTP amounts ranged from US $0.89 to US $821.25. We found a statistically significant correlation of age and distance to a preferred health facility with the WTP for telemedicine. Higher age was associated with a lower WTP, whereas longer travel distance was associated with a higher WTP., Conclusions: On the basis of our findings, the following are recommendations that may enhance the WTP: exposure to the telemedicine intervention before assessing the WTP, the lowering of telemedicine costs, and the provision of patient education to raise awareness on telemedicine's benefits and address patients' concerns. In addition, we recommend that future research be directed at standardizing the reporting of WTP studies with the adoption of a common metric for WTP amounts, which may facilitate the generalization of findings and effect estimates., (©Valerie Chua, Jin Hean Koh, Choon Huat Gerald Koh, Shilpa Tyagi. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 13.04.2022.)

Introduction: Post-anaesthesia care unit (PACU) delirium is a potentially preventable condition that results in a significant long-term effect. In a multicentre prospective cohort study, we investigate the incidence and risk factors of postoperative delirium in elderly patients undergoing major non-cardiac surgery., Methods: Patients were consented and recruited from 4 major hospitals in Singapore. Research ethics approval was obtained. Patients older than 65 years undergoing non-cardiac surgery >2 hours were recruited. Baseline perioperative data were collected. Preoperative baseline cognition was obtained. Patients were assessed in the post-anaesthesia care unit for delirium 30-60 minutes after arrival using the Nursing Delirium Screening Scale (Nu-DESC)., Results: Ninety-eight patients completed the study. Eleven patients (11.2%) had postoperative delirium. Patients who had PACU delirium were older (74.6±3.2 versus 70.6±4.4 years, P =0.005). Univariate analysis showed those who had PACU delirium are more likely to be ASA 3 (63.6% vs 31.0%, P =0.019), had estimated glomerular filtration rate (eGFR) of >60mL/min/1.73m2 (36.4% vs 10.6%, P =0.013), higher HbA1C value (7.8±1.2 vs 6.6±0.9, P =0.011), raised random blood glucose (10.0±5.0mmol/L vs 6.5±2.4mmol/L, P =0.0066), and moderate-severe depression (18.2% vs 1.1%, P=0.033). They are more likely to stay longer in hospital (median 8 days [range 4-18] vs 4 days [range 2-8], P=0.049). Raised random blood glucose is independently associated with increased PACU delirium on multivariate analysis.

Effective therapeutic options are still lacking for uveal melanoma (UM) patients who develop metastasis. Metastatic traits of UM are linked to BRCA1-associated protein 1 (BAP1) mutations. Cell metabolism is re-programmed in UM with BAP1 mutant UM, but the underlying mechanisms and opportunities for therapeutic intervention remain unclear. BAP1 mutant UM tumors have an elevated glycolytic gene expression signature, with increased expression of pyruvate dehydrogenase (PDH) complex and PDH kinase (PDHK1). Furthermore, BAP1 mutant UM cells showed higher levels of phosphorylated PDHK1 and PDH that was associated with an upregulated glycolytic profile compared to BAP1 wild-type UM cells. Suppressing PDHK1-PDH phosphorylation decreased glycolytic capacity and cell growth, and induced cell cycle arrest of BAP1 mutant UM cells. Our results suggest that PDHK1-PDH phosphorylation is a causative factor of glycolytic phenotypes found in BAP1 mutant UM and propose a therapeutic opportunity for BAP1 mutant UM patients., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Metastatic uveal melanoma (UM) responds poorly to targeted therapies and immune checkpoint inhibitors. Loss of BRCA1-associated protein 1 (BAP1) via inactivating mutations in the BAP1 gene is associated with UM progression. Thus, molecular alterations caused by BAP1 dysfunction may be novel therapeutic targets for metastatic UM. Here, we found that phosphorylation of AMP-dependent kinase (AMPK) was elevated in BAP1-altered (or mutant) compared to BAP1-unaltered (or wild-type [WT]) UM tumors. As a readout of AMPK pathway activation, phosphorylation of an AMPK downstream effector, acetyl-CoA-carboxylase (ACC), was also elevated. BAP1 re-expression in BAP1-null UM cell lines decreased phospho-AMPK (pAMPK) and phospho-ACC (pACC) levels. AMPK phosphorylation is mediated by calcium/calmodulin dependent protein kinase kinase 2 (CaMKK2) and potentially liver kinase B1 (LKB1) in BAP1 mutant UM cells. Knockdown of AMPKα1/2 reduced the viability of BAP1 mutant UM cells, indicating a survival function of AMPK in BAP1 mutant UM. Our data suggest that the AMPK pathway is an important mechanism mediating the survival of BAP1 mutant UM. Targeting the AMPK pathway may be a novel therapeutic strategy for metastatic UM., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

With labour markets already polarised in industrialised economies, if Covid-19 worsens this polarity, young people could be more severely affected. This is because their entry into a post-pandemic economy has ramifications for their divergent or convergent career trajectories far into the future. Therefore, on the premise that work life is central to quality of life, this article assesses the effects of low wage and Covid-19 on the psychological outlook of young people in Singapore. We found that Covid-19 did worsen polarisation. On average, higher wage workers telecommuted more and had more work, but low wage young workers bore the brunt of earnings loss and job disruption. Low wage respondents also experienced poorer psychological well-being, even after adverse child experiences, highest educational qualification and occupation type were controlled for. However, higher wage workers might be more psychologically affected by the Covid-19 impacts. This might be because low earning workers are more accustomed to employment instability. These findings suggest the urgency of policy attention to help low wage young workers recover from Covid-19., (© The International Society for Quality-of-Life Studies (ISQOLS) and Springer Nature B.V. 2022.)

Cancer cell metabolism is a targetable vulnerability; however, a precise understanding of metabolic heterogeneity is required. Inactivating mutations in BRCA1-associated protein 1 (BAP1) are associated with metastasis in uveal melanoma (UM), the deadliest adult eye cancer. BAP1 functions in UM remain unclear. UM patient sample analysis divided BAP1 mutant UM tumors into two subgroups based on oxidative phosphorylation (OXPHOS) gene expression suggesting metabolic heterogeneity. Consistent with patient data, transcriptomic analysis of BAP1 mutant UM cell lines also showed OXPHOS high or OXPHOS low subgroups. Integrated RNA sequencing, metabolomics, and molecular analyses showed that OXPHOS high BAP1 mutant UM cells utilize glycolytic and nucleotide biosynthesis pathways, whereas OXPHOS low BAP1 mutant UM cells employ fatty acid oxidation. Furthermore, the two subgroups responded to different classes of metabolic suppressors. Our findings indicate that targeting cancer metabolism is a promising therapeutic option for BAP1 mutant UM; however, tailored approaches may be required due to metabolic heterogeneities.

Uveal melanoma is a rare cancer in adults, but its treatment is one of the clinical unmet needs in the melanoma field. Metastatic disease develops in approximately 50% of patients and is associated with poor survival due to the lack of effective treatment options. It provides a paradigm for cancers that show evidence of aberrant G protein-coupled receptor signaling, tumor dormancy, and liver-selective metastatic tropism and are associated with the loss of the BAP1 tumor suppressor. At the Melanoma Research Foundation CURE OM Science Meeting at the Society for Melanoma Research Meeting held in Utah on November 20, 2019, clinicians and researchers presented findings from their studies according to three themes within uveal melanoma: (i) ongoing clinical trials, (ii) molecular determinants, and (iii) novel targets that could be translated into clinical trials. This meeting underscored the high interest in the uveal melanoma research field and the unmet need for effective treatment strategies for late-stage disease. Findings from ongoing clinical trials are promising, and multiple studies show how novel combinatorial strategies increase response rates. Novel targets and tumor vulnerabilities identified bioinformatically or through high-throughput screens also reveal new opportunities to target uveal melanoma. The future directions pursued by the uveal melanoma research field will likely have an impact on other cancer types that harbor similar genetic alterations and/or show similar biological properties., (©2020 American Association for Cancer Research.)

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.

Frequent GNAQ and GNA11 mutations in uveal melanoma hyperactivate the MEK-ERK signaling pathway, leading to aberrant regulation of cyclin-dependent kinases (CDK) and cell-cycle progression. MEK inhibitors (MEKi) alone show poor efficacy in uveal melanoma, raising the question of whether downstream targets can be vertically inhibited to provide long-term benefit. CDK4/6 selective inhibitors are FDA-approved in patients with estrogen receptor (ER)-positive breast cancer in combination with ER antagonists/aromatase inhibitors. We determined the effects of MEKi plus CDK4/6 inhibitors (CDK4/6i) in uveal melanoma. In vitro , palbociclib, a CDK4/6i, enhanced the effects of MEKi via downregulation of cell-cycle proteins. In contrast, in vivo CDK4/6 inhibition alone led to cytostasis and was as effective as MEKi plus CDK4/6i treatment at delaying tumor growth. RNA sequencing revealed upregulation of the oxidative phosphorylation (OxPhos) pathway in both MEKi-resistant tumors and CDK4/6i-tolerant tumors. Furthermore, oxygen consumption rate was increased following MEKi + CDK4/6i treatment. IACS-010759, an OxPhos inhibitor, decreased uveal melanoma cell survival in combination with MEKi + CDK4/6i. These data highlight adaptive upregulation of OxPhos in response to MEKi + CDK4/6i treatment in uveal melanoma and suggest that suppression of this metabolic state may improve the efficacy of MEKi plus CDK4/6i combinations., (©2020 American Association for Cancer Research.)

Bromodomain and extraterminal protein inhibitors (BETi) are epigenetic therapies aimed to target dysregulated gene expression in cancer cells. Despite early successes of BETi in a range of malignancies, the development of drug resistance may limit their clinical application. Here, we evaluated the mechanisms of BETi resistance in uveal melanoma, a disease with little treatment options, using two approaches: a high-throughput combinatorial drug screen with the clinical BET inhibitor PLX51107 and RNA sequencing of BETi-resistant cells. NF-κB inhibitors synergistically sensitized uveal melanoma cells to PLX51107 treatment. Furthermore, genes involved in NF-κB signaling were upregulated in BETi-resistant cells, and the transcription factor CEBPD contributed to the mechanism of resistance. These findings suggest that inhibitors of NF-κB signaling may improve the efficacy of BET inhibition in patients with advanced uveal melanoma. SIGNIFICANCE: These findings provide evidence that inhibitors of NF-κB signaling synergize with BET inhibition in in vitro and in vivo models, suggesting a clinical utility of these targeted therapies in patients with uveal melanoma., (©2019 American Association for Cancer Research.)

Alterations in transcriptional programs promote tumor development and progression and are targetable by bromodomain and extraterminal (BET) protein inhibitors. However, in a multi-site clinical trial testing the novel BET inhibitor, PLX51107, in solid cancer patients, liver metastases of uveal melanoma (UM) patients progressed rapidly following treatment. Mechanisms of resistance to BET inhibitors in UM are unknown. We show that fibroblast growth factor 2 (FGF2) rescued UM cells from growth inhibition by BET inhibitors, and FGF2 effects were reversible by FGF receptor (FGFR) inhibitors. BET inhibitors also increased FGFR protein expression in UM cell lines and in patient tumor samples. Hepatic stellate cells (HSCs) secrete FGF2, and HSC-conditioned medium provided resistance of UM cells to BET inhibitors. PLX51107 was ineffective in vivo, but the combination of a FGFR inhibitor, AZD4547, and PLX51107 significantly suppressed the growth of xenograft UM tumors formed from subcutaneous inoculation of UM cells with HSCs and orthotopically in the liver. These results suggest that co-targeting of FGFR signaling is required to increase the responses of metastatic UM to BET inhibitors., (© 2019 The Authors. Published under the terms of the CC BY 4.0 license.)

Purpose of Review: Currently, there are no U.S. Food and Drug Administration-approved or effective treatment options for advanced-stage uveal melanoma. In this article, we focus on therapeutic targets in pathways/mechanisms associated with common mutations in uveal melanoma. We review the challenges associated with targeting of these pathways and novel treatment strategies., Recent Findings: Common mutations that promote uveal melanoma initiation and progression include alterations in G protein subunit alpha q/11 (GNAQ/GNA11) and breast cancer gene 1-associated protein 1 (BAP1). Mutant GNAQ/GNA11 induces constitutive activation of tumorigenic pathways such as extracellular signal-regulated kinase (ERK)1/2 and yes-associated protein. Inhibition of mitogen-activated protein kinase kinase (MEK) downstream of ERK1/2, however, was shown in trials to have limited clinical benefit. Recent reports suggested that combination therapies of MEK inhibition and modulators of mechanisms of drug resistance may improve tumor responses to MEK inhibitors. BAP1 has been shown to be involved in modulating chromatin dynamics and deubiquitination of proteins. Hence, epigenetic inhibitors are being investigated in BAP1 mutant uveal melanoma. However, other functions of BAP1, such as in DNA damage repair and cell cycle regulation, indicate additional targets for treatment of BAP1 mutant uveal melanoma. In addition, the frequent delayed development of uveal melanoma macrometastases is likely due to cellular dormancy mechanisms. Nuclear receptor subfamily 2, group F, member 1 and transforming growth factor beta 2 were among factors that have been shown in other cancers to induce dormant phenotypes., Summary: Findings from studies in uveal melanoma and in other cancers provide evidence for potential strategies that may be tested preclinically and clinically in advanced-stage uveal melanoma to improve treatment outcome and overall survival of patients.

Porcine reproductive and respiratory syndrome (PRRS) is a disease characterised by late-term reproductive failure in sows and gilts, and respiratory problems in piglets and growing pigs. In this study, 240 sera were collected from four farms that had been practicing different PRRS vaccination regime for more than a year and vaccinations were done at 2 months before sampling. Fifteen sera samples from four age groups: sows, growers, weaners and piglets were collected from each farm and analysed using IDEXX PRRS X3 ELISA for PRRSV antibodies. Pooled serum samples were tested by using nested-PCR that enable the differentiation of Type I and Type II PRRSV. Out of 80 pooled serum samples, none were positive for PRRSV indicating all age groups were not viraemic after vaccination. Results by ELISA test showed all the farms were seropositive for PRRS. ELISA testing showed no significant difference between the farms except for Farm B which practised whole herd US MLV vaccination. Farm B showed significantly lower (p<0.05) S/P ratio in their piglet, grower and sow groups which suggest there was low virus circulation in herd. Farm A which practised US MLV on sow was the only farm found to have seronegative status in their weaners. Data indicates PRRS MLV vaccination will not cause viraemia post four weeks vaccination and whole herd MLV vaccination may help to reduce virus circulation in PRRS endemic farm.

Uveal melanoma is the most common primary intraocular malignant tumor in adults and arises from the transformation of melanocytes in the uveal tract. Even after treatment of the primary tumor, up to 50% of patients succumb to metastatic disease. The liver is the predominant organ of metastasis. There is an important need to provide effective treatment options for advanced stage uveal melanoma. To provide the preclinical basis for new treatments, it is important to understand the molecular underpinnings of the disease. Recent genomic studies have shown that mutations within components of G protein-coupled receptor (GPCR) signaling are early events associated with approximately 98% of uveal melanomas. Implications: This review discusses the alterations in GPCR signaling components (GNAQ and GNA11), dysregulated GPCR signaling cascades, and viable targeted therapies with the intent to provide insight into new therapeutic strategies in uveal melanoma. Mol Cancer Res; 15(5); 501-6. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Patients with metastatic uveal melanoma usually die within 1 year of diagnosis, emphasizing an urgent need to develop new treatment strategies. The liver is the most common site of metastasis. Mitogen-activated protein kinase kinase (MEK) inhibitors improve survival in V600 BRAF-mutated cutaneous melanoma patients but have limited efficacy in patients with uveal melanoma. Our previous work showed that hepatocyte growth factor (HGF) signaling elicits resistance to MEK inhibitors in metastatic uveal melanoma. In this study, we demonstrate that expression of two BH3-only family proteins, Bim-EL and Bmf, contributes to HGF-mediated resistance to MEK inhibitors. Targeting HGF/cMET signaling with LY2875358, a neutralizing and internalizing anti-cMET bivalent antibody, and LY2801653, a dual cMET/RON inhibitor, overcomes resistance to trametinib provided by exogenous HGF and by conditioned medium from primary hepatic stellate cells. We further determined that activation of PI3Kα/γ/δ isoforms mediates the resistance to MEK inhibitors by HGF. Combination of LY2801653 with trametinib decreases AKT phosphorylation and promotes proapoptotic PARP cleavage in metastatic uveal melanoma explants. Together, our data support the notion that selectively blocking cMET signaling or PI3K isoforms in metastatic uveal melanoma may break the intrinsic resistance to MEK inhibitors provided by factors from stromal cells in the liver. Mol Cancer Ther; 16(3); 516-28. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Hydrogel nanocomposites containing silver nanoparticles of size 15⁻21 nm were prepared by diffusion and in-situ chemical reduction in chemically crosslinked polymers based on N -acryloyl- N '-ethyl piperazine (AcrNEP) and N -isopropylacrylamide (NIPAM). The polymer chains of the hydrogel network offered control and stabilization of silver nanoparticles without the need for additional stabilizers. The presence of silver nanoparticles and their size was quantified by UV-Vis absorption spectroscopy and scanning electron microscopy. The nanocomposite hydrogels were responsive to pH and temperature changes of the external environment. The equilibrium weight swelling ratio of the hydrogel nanocomposite was lower in comparison with the precursor hydrogel. Silver nanoparticles present in the nanocomposite offered additional physical crosslinking which influenced media diffusion and penetration velocity. The release of silver nanoparticles from the hydrogel matrix in response to external pH changes was studied. The rate of release of silver nanoparticles was higher in a solution of pH 2.5 due to maximum swelling caused by ionization of the gel network. No significant release of nanoparticles was observed in a solution of pH 7.

This study examined the ethnic differences in stressors, risk, and protective factors among people who attempted suicide in Singapore. A retrospective chart review of 626 attempted suicide cases at a hospital in Singapore between 2004 and 2006 collected information on diagnosis according to DSM-IV-TR criteria. Chi-square tests was used to compare the sociodemographic characteristics, stressors, risk factors, and protective factors among Chinese, Malay, Indian, and other ethnic groups. Logistic regression was used to determine the odds ratios of having two or more stressors, risk factors, or protective factors for the four ethnic groups. Women were more likely than men to attempt suicide, although they also were more likely to have two or more suicide protective factors than men. In general, older people were more likely to have two or more suicide risk factors than the younger groups. Ethnic differences were found in history of psychiatric illnesses and unemployment among the risk factors, and for most of the protective factors, but none of the stressors. Indians were more likely to have two or more protective factors than were Chinese (OR of 7.74, 95% CI [1.04, 8.72]. Future suicide prevention programs should target young adults and strengthen the protective factors among different ethnic groups., (© The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)