Inherent Risk Research Articles

Preliminary Results of a Phase 2 Study of IMM01 Combined with Azacitidine (AZA) As the First-Line Treatment in Adult Patients with Chronic Myelomonocytic Leukemia (CMML)

Background: Patients with Chronic Myelomonocytic Leukemia (CMML) have poor prognosis and an inherent risk for transformation to acute myeloid leukemia. IMM01 is a recombinant signal regulatory protein α (SIRPα) IgG1 fusion protein that exerts anti-tumor activity via blocking “Don't eat me” signal and activating the “Eat me” signal to induce strong antibody-dependent cellular phagocytosis (ADCP). Furthermore, IMM01 activated macrophages could process and present tumor antigen to T cells and elicit long-last tumor-specific T cell immune response. Methods : This is an open-label, multi-center, phase 2 study (NCT05140811) that evaluated safety and efficacy of IMM01 in combination with AZA as the first-line treatment in patients with newly diagnosed CMML. We enrolled patients aged 18 years or older with the diagnosis of CMML, including subtypes CMML-1 and 2, not eligible for stem cell transplant. Patients with treatment-naive CMML were administered intravenous IMM01 at a dosage of 2.0mg/kg/week and subcutaneous AZA at a dosage of 75 mg/m 2 on D1-7 per 28-day cycle. Safety was assessed by CTCAE V5.0 and efficacy by IWG 2006 (MDS) criteria. Results : Between August 4, 2022 and July 7, 2023, 24 patients were enrolled: median age was 62 years, 15 (62.5%) males, 18(75.0%) ECOG≥1. Additionally, 1(4.2%), 7(29.2%) and 16(66.7%) patients were intermediate risk(IR)-1, IR-2 and high risk(HR) by CPSS-mol classification, respectively. According to World Health Organization (WHO) classification of CMML, patients enrolled included CMML-1(50.0%) and CMML-2(50.0%). Majority of patients had poor baseline hematologic conditions with a median Hb of 69.5 (32, 132) g/L and a median PLT of 73.5 (5, 667)×10 9/L. By the data cut-off date of July 7, 2023, the median follow-up for the study was 4 months (95%CI:3.3-4.8). Among the 16 efficacy evaluable patients who received initial treatment ≥3 months, overall response rate (ORR) was 87.5% (14/16), including 25.0% (4/16) complete response (CR), 18.8% (3/16) marrow CR (mCR) with hematologic improvement (HI), 6.3% (1/16) HI and 37.5% (6/16) mCR alone. Among the 9 efficacy evaluable patients who received initial treatment ≥4 months, ORR was 88.9% (8/9), including 44.4% (4/9) CR, 11.1% (1/9) mCR with HI and 33.3% (3/9) mCR alone. The CR rate of IMM01 combined with AZA is increasing with longer treatment duration. The median duration of response (DoR) was not reached. NGS analysis of bone marrow collected from responders were included in this study. The most frequent treatment related adverse events (TRAEs) (≥20%) were lymphopenia (70.8%), leukopenia (70.8%), neutropenia (70.8%), thrombocytopenia (58.3%), infusion related reaction (33.3%), anemia (25.0%), pyrexia (25.0%), pneumonia (25.0%), constipation (20.8%), nausea (20.8%), vomiting (20.8%) and leukocytosis (20.8%). The most common ≥Grade 3 TRAEs (≥10%) included lymphopenia (66.7%), neutropenia (54.2%), leukopenia (54.2%), thrombocytopenia (54.2%), anemia (20.8%) and pneumonia (16.7%), all of which were commonly reported in AZA monotherapy studies for treatment naive MDS/CMML patients in China. The study is ongoing. Conclusions: Preliminary data showed that IMM01 (without a low-dose priming) combined with AZA were well tolerated. The combo, when compared to the historical data of AZA alone, showed exciting efficacy result for patients with treatment-naive CMML1-2.

The Effect of Inflation and Rupiah Exchange Rate on Stock Prices with Dividends as Moderators

Objectives: The choice to pay dividends is a strategic one for every business. It's the foundation on which stock market investments are made. Dividends paid out by a firm are more highly valued by shareholders than capital profits. Due to the inherent risk associated with investing, investors would rather receive compensation in the now than in the future. The company's future success may be seen in its consistent dividend payments. The goal of this research was to examine the moderating role of dividends in a market vulnerable to inflation and the rupiah exchange rate. The focus is on dividend-paying firms trading on the IDX between 2013 and 2021.Methodology: The associative quantitative approach used here relies on previously collected data. The purposive sampling method was used in the sampling process. This study used 153 samples over 9 time periods, following the criteria. Both single- and multi-linear regression are used in the study.Finding: The findings in the study are inflation and rupiah exchange rates on stock prices have a negative effect and simultaneously affect stock prices while dividends per share can moderate the connection between inflation and stock prices.Conclusion: Both inflation and the rupiah exchange rate have been shown to have a negative effect on stock prices. Inflation has been shown to have a negative influence on stock prices while the rupiah exchange rate also has this effect. According to the findings of this journal, a combined effect of inflation and the value of the rupiah against other currencies may be seen in stock market prices. Furthermore, it has been shown that this effect can occur. The MRA research also shows that dividends per share have a moderating influence on the connection between inflation and stock prices, as well as the correlation between the rupiah exchange rate and stock prices.

Should dolutegravir always be withheld in people with HIV on dolutegravir with incident diabetes mellitus? a case report

Dolutegravir (DTG), an integrase strand transfer inhibitor is currently the recommended first and second line anti-retroviral therapy (ART) anchor agent by the World Health Organization due to its favorable side effect profile, high efficacy and genetic barrier to resistance.Despite its very good side effect profile, there have been multiple case reports of ART experienced patients developing hyperglycemia within weeks to a few months after switching to DTG preceded by weight loss. At population level, however, DTG as well as other integrase inhibitors have been demonstrated to have a reduced risk of incident diabetes mellitus (T2DM) compared to other HIV drug classes.Following multiple similar reports of accelerated hyperglycemia in Uganda during the first pilot year of DTG use, the Uganda Ministry of Health recommended withholding dolutegravir in all patients who develop diabetes. Whether this recommendation should be applied to all patients with incident T2DM remains to be demonstrated.We present a clinical case of an HIV positive ART naïve man who was diagnosed with T2DM after 36 weeks on DTG. We describe changes in blood glucose, glycated hemoglobin, insulin resistance and pancreatic beta cell function before and after withholding DTG. We demonstrated that he was phenotypically different from the reported cases of accelerated hyperglycemia and he continued to have worsening insulin resistance despite withholding DTG. His blood glucose improved with dietary T2DM management. It is possible he had an inherent risk of developing T2DM independent of his exposure to DTG. This put in question whether DTG should universally be withheld in PLHIV with incident T2DM in Uganda.

Crucial safety issues on Janus kinase inhibitors in rheumatoid arthritis might be associated with the lack of LDL-cholesterol management: a reasoned literature analysis.

This point of view explores the safety concerns of Janus kinase inhibitors (JAK-Is), used in treating rheumatoid arthritis (RA) and other rheumatologic conditions. Increasing evidence shows that JAK-Is may elevate the risk of venous thromboembolism (VTE), especially pulmonary embolism. This fact has prompted the European Medicines Agency to advise cautious use of these drugs in patients over 65, smokers, and those at risk of cardiovascular issues or cancer. The paper analyses the evidence on the association between VTE risk and RA and whether different JAK-Is pose different risks. It also probes the link between VTE, lipids, and JAK inhibition, noting that JAK-Is can alter HDL and LDL levels. On the other hand, some evidence indicates that tighter LDL-cholesterol control could mitigate VTE risk, particularly pulmonary embolism. Moreover, data from trials show little attention to treating this main cardiovascular and VTE risk factor in rheumatological patients. Although the lipid paradox theory emphasizes the U-shaped relationship between LDL cholesterol and cardiovascular risk in patients with RA, uncontrolled levels of clinically relevant LDL cholesterol remain closely linked to cardiovascular and VTE risk. In conclusion, high-potency statins could help to manage the increased cardiovascular and VTE risk concomitant to JAK-Is treatment in rheumatologic patients without depriving them of the best therapeutic choice and, in addition, reducing the inherent risk associated with the disease.

A Theoretical Review of the Internal Control Measures in Preventing E-Banking Frauds in the Nigerian Banking Sector

The developments in the field of information technology have changed banking business and the manner in which its customers transact significantly, bringing about more reliance on electronic banking transactions fondly referred to as “e-banking transactions”. This has also changed the kind of risk both the banks and its customers are faced with, resulting in some significant losses reported; and calling for the need for sound internal control systems that can be applied on e-banking activities to reduce losses and inherent risk. This paper is a theoretical review of the expected characteristics of the internal control system required to combat e-banking fraud in the Nigerian Banking Sector. Related concepts, theories and studies around internal control and electronic banking and fraud were reviewed. To reduce the losses attributed to e-banking frauds, the internal control system over e-banking transactions and activities should not be postmortem like the traditional banking services, but among others, be online real-time, generating alerts as transactions occur, having a combination of proactive and reactive techniques and should automatically generate audit trails. The paper recommends that the Central Bank of Nigeria (CBN) as the apex regulator of the sector should biannually review the controls put in place by the banks to check e-banking transactions for adequacy, and apply appropriate sanctions where necessary. Technology is constantly evolving, hence, the need for consistent review of processes and procedures by the banks, who should continuously sensitize its customers on safeguarding access credentials, while creating avenues for immediate reporting and account restriction in the event of suspicious activities.

Risk Contagion of Local Government Implicit Debt Integrating Complex Network and Multi-Subject Coordination

This article analyzes the risk contagion mechanism of local government implicit debt from the perspective of multi-subject collaboration, considering interaction effects among different influencing factors. On this basis, with the help of complex network theory and mean field theory, a risk contagion model of local government implicit debt is constructed, and then the evolution characteristics and control strategies for risk contagion of local government implicit debt are analyzed theoretically and simulated. The main findings obtained from the study are: (1) A scale-free network is not conducive to the risk contagion of local government implicit debt, while the opposite is true for a random network. (2) Information openness accuracy and information disclosure strategy both exhibit a positive “U” shaped relationship with the risk contagion of local government implicit debt. Debt management level, emotional tendency, risk preference level, credit policy robustness, accountability mechanism soundness, and perfection of laws and regulations are all negatively correlated with the risk contagion of local government implicit debt. (3) In order to effectively reduce the risk contagion intensity of local government implicit debt, local governments at all levels should continuously strengthen their debt management capabilities and information openness, and the central government should continuously improve accountability mechanisms, laws, and regulations. At the same time, financial institutions and the media should actively play the role of “stabilizers”. However, the local government implicit debt risk is an inherent risk, and its control focus should be on reducing rather than eliminating the risk.

Peranan Risk Based Audit Pada Bagian Kredit Dalam Mengevaluasi Proses Kredit

This study aims to determine how the application of Risk-Based Audit on the credit department of PT. BPR Bank Kertiawan in order to improve the efficiency and effectiveness of the entity's internal audit. The results showed that the key business process credit at PT. BPR Bank Kertiawan which has a high risk is the Credit Analysis section which affects the credit take over process and the making of a Credit Agreement and its supporting documents so that for further examination, SKAI will focus on the Credit Analysis section which has a high inherent risk

Electric vehicle fire risk assessment framework using Fault Tree Analysis.

In the near future, the rapid adoption of electric vehicles is inevitable, driven by environmental concerns and climate change awareness. However, this progressive trend also brings forth safety concerns and hazards, notably regarding the risk of EV fires, which have garnered significant media attention. This necessitates the need to study for comprehensive fire risk assessment strategies aimed at preventing and mitigating such incidents. This study presents a framework for assessing fire risks in EVs using Fault Tree Analysis (FTA). By integrating disparate data sources into a unified dataset, the proposed methodology offers a holistic approach to understanding potential hazards. The study embarked on a comprehensive exploration of EV fire causes through qualitative FTA. Through this approach, the work discerned five major causes: human factors, vehicle factors, management factors, external factors, and unknown factors. Using a meticulous weighted average approach, the annual EV fire frequency for each country was deduced, revealing an average annual EV fire rate of 2.44 × 10 -4 fires per registered EV. This metric provides a significant benchmark, reflecting both the probability and inherent risk of such incidents. However, uncertainties in data quality and reporting discrepancies highlight the imperative of continued research. As EV adoption surges, this study underscores the importance of comprehensive, data-driven insights for proactive risk management, emphasizing the necessity for vigilant and adaptive strategies. The findings emphasize the pivotal role of this assessment in shaping response strategies, particularly for first responders dealing with EV fires. In essence, this research not only elevates the understanding of EV fire risks but also offer a foundation for future safety measures and policies in the domain.

Towards a risk-adjusted tourism and travel competitiveness index

The concept of Tourism Destinations Competitiveness has evolved from a price-focused perspective to the consideration of multiple factors including sustainability, residents’ well-being, or destination image. Regardless of the version used, it is expected that a competitive destination should be able to convert its advantageous position into economic returns. However, the pandemic has come to upset the foundations of the sector, since many of the destinations traditionally classified as highly competitive have also been the most affected by the pandemic. In this paper, we propose to review the notion of competitiveness by considering properly the dimension of inherent risk, using specific composite indexes, and adjusting conventional competitiveness indicators including these dimensions. We revise the results of these new adjusted by risk competitiveness indexes for the organization for economic cooperation and development (OECD) and OECD partner countries. Among other relevant points, the findings indicate relevant changes in rankings when we explicitly include risk in the competitiveness calculations.

EXPLORING INVESTOR ENGAGEMENT WITH CRYPTOCURRENCY INVESTMENTS IN SRI LANKA

This research paper explores the dynamics of investor engagement in cryptocurrencies within the context of Sri Lanka, a country marked by economic distress and growing interest in the digital economy. Cryptocurrencies, characterized by their decentralized nature and potential for high returns, have gained significant traction globally. This study employs an exploratory research methodology to delve into the demographic details, investment behaviour, and strategies of cryptocurrency users in Sri Lanka. Through convenience sampling, the study identifies and surveys 35 cryptocurrency users. The research findings reveal that the cryptocurrency market in Sri Lanka is predominantly male dominated, with the majority falling within the 21-30 age group and holding Bachelors degrees. Participants are primarily employed in the self-employed or private sectors. Their investment horizons vary, with a notable percentage investing for 3-5 years, followed by 1-2 years and less than a year. A significant portion of respondents has experienced fraud within the cryptocurrency space, emphasizing the need for cautious investment practices. Investment levels among participants vary, with the largest proportion having invested more than 500,000 LKR. However, a substantial number of investors have portfolios exceeding 1,000,000 LKR, highlighting the diversity of investment sizes. Profitability in cryptocurrency investments is mixed, with a substantial proportion achieving significant profits, while others report substantial losses. This underscores the inherent risk in cryptocurrency investments, with a notable percentage of participants experiencing financial setbacks. KEYWORDS: Cryptocurrency, Investments, Profitability, Financial setbacks.

Mechanism and evolution trend of digital green fusion in China's regional advanced manufacturing industry

This paper has observed pivotal changes in innovative frameworks at the intersection of the digital revolution and sustainable initiatives. Within Industry 4.0, the fusion between intelligent manufacturing and green innovation has become a central driver for sustainability. Integrating these two pivotal forces to harness their collective efficiency is crucial. However, current literature offers limited insights into their combined impact, and the direction of their evolving trends still needs to be defined. Considering this, the research elucidates the core concepts and traits of digital-green fusion (DGF) within regional advanced manufacturing (RAMIDGF). Moreover, this research proposes a double-helix fusion mechanism model. Utilizing data from the advanced manufacturing sectors in six key Chinese urban clusters, this paper adopts a comprehensive analytical toolkit that includes the Coupling Modified Model, Kernel Density Estimation, Markov Chain algorithms, and the Dagum Gini Coefficient for trend analysis. The findings indicate that between 2009 and 2021, RAMIDGF exhibited a trend of initial growth followed by a decline, showing a strong correlation with per capita GDP (RGDP). The principal source of variation in RAMIDGF stems from differences between urban agglomerations, with the Yangtze River Delta and the Beijing-Tianjin-Hebei clusters exhibiting transitional behavior and a ‘ladder-type trend’ in RAMIDGF. As metropolitan clusters become more economically integrated, the probability of transitional behavior in RAMIDGF heightens. However, achieving elevated leapfrog development proves challenging, with an inherent risk of decline. Spatial spillover implications, agglomeration characteristics, and club convergence tendencies mark the RAMIDGF process. These findings expand upon new paradigms for regional sustainable development, offering novel avenues for realizing high-quality growth.

Cardiovascular risk in a contemporary cohort of patients with myeloproliferative neoplasms’

BackgroundMyeloproliferative neoplasms (MPNs) are a group of disorders of clonal haemopoiesis associated with an inherent risk of arterial and venous thrombotic complications. The prevalence of thrombotic complications and the impact of cardiovascular risk factors (CVRFs) in contemporary patient cohorts within the current era of MPN treatments have not been completely defined. ObjectivesWe aim to characterise the cardiovascular risk of patients with MPN by identifying the prevalence of CVRFs and describing the pattern of thrombotic events. We also aim to utilise the QRISK3 algorithm, which is a validated model used to estimate an individual's risk of developing cardiovascular disease, to further phenotype this cohort of patients. MethodsWe perform a retrospective analysis on a single-centre cohort of 438 patients with MPN. ResultsMPN patients continue to carry a high burden of vascular morbidity with a prevalence of arterial thrombotic events in 15.8 % (69/438) and venous thrombotic events in 13.2 % (58/438) of the cohort. The novel use of the QRISK3 algorithm, which showed a mean score of 13.7 % across the MPN population, provides further evidence to suggest an increased cardiovascular risk in MPN patients. ConclusionWith an increased risk of cardiovascular disease in patients with MPN, we propose an integrated approach between primary and specialised healthcare services using risk stratification tools such as QRISK3, which will allow aggressive optimisation of CVRFs to prevent thrombosis and reduce the overall morbidity and mortality in patients with MPN.

How Important Is a Lesser Metatarsal Osteotomy in Preventing Second Hammertoe Recurrence?

Hammertoes with greater preoperative transverse plane deformity are more likely to recur after corrective surgery; however, it is unclear whether this represents an inherent (fixed, non-modifiable) risk, or whether steps can be taken intraoperatively to mitigate this risk. In this study, we examined whether transverse plane transposition and/or shortening of the 2nd metatarsal during 2nd hammertoe surgery influenced recurrence. We performed a secondary analysis of pre-existing data from patients that had previously undergone 2nd hammertoe surgery at our institution between January 1, 2011 and December 31, 2013. One hundred two patients (137 toes) were followed for a mean 28 ± 7.8 months postoperatively. Thirty-seven toes required, at the surgeon's discretion, an additional/concomitant Weil metatarsal osteotomy. Magnitude of transverse plane transposition and shortening of the 2nd metatarsal, and joint angular measurements were obtained from the 2nd metatarsophalangeal joint on weightbearing AP radiographs preoperatively and at 6-10 weeks postoperatively. Cox regression analysis was used to identify predictors of hammertoe recurrence using these new variables and a set of known predictors. In the final regression model, failure to establish a satisfactory postoperative metatarsal parabola (i.e., long 2nd metatarsal; Nilsonne values < -4mm, multivariate hazards ratio [HR] 1.96, P=0.097), and intraoperative lateral transposition of the metatarsal head (multivariate HR 3.45, P=0.028) seemed to confer additional risk for hammertoe recurrence. We conclude that shortening osteotomies may be assistive in some individuals, while further inquiry is still needed to determine whether similar benefits can be derived from medial head transposition in medial toe deformities. Level of Clinical Evidence: 3, comparative study Classification: Forefoot Reconstruction.

Prey selection along a predators' body size gradient evidences the role of different trait-based mechanisms in food web organization.

An increase in prey richness, prey size and predator trophic position with predator body size has been consistently reported as prime features of food web organization. These trends have been explained by non-exclusive mechanisms. First, the increase in energy demand with body size determines that larger predators must reduce prey selectivity for achieving the required number of resources, being consumption relationships independent of prey traits. Second, when consumption is restricted by gape limitation, small predators are constrained to select among small prey. However, this selection weakens over large predators, which progressively consume more and larger prey. Finally, the optimal foraging mechanism predicts that larger predators optimize their diet by selecting only large prey with high energy reward. Each one of these mechanisms can individually explain the increase in prey richness, prey size and predator trophic position with predator body size but their relative importance or the direct evidence for their combined role was seldom considered. Here we use the community assembly by trait selection (CATS) theory for evaluating the support for each one of these mechanisms based on the prey selection patterns that they predict. We analyzed how prey body size and trophic guild determine prey selection by predators of increasing body size in a killifish guild from a temporary pond system. Results support the combination of the three mechanisms to explain the structural trends in our food web, although their strength is contingent on prey trophic group. Overall, high energy prey are preferred by larger predators, and small predators select small prey of all trophic status. However, large predators prefer large primary producers and avoid large carnivorous prey, probably because of the inherent risk of consuming other carnivorous. Our study provides a mechanistic understanding of how predator traits determine the selection of prey traits affecting food web assembly.

SAT206 A Case Of Parathyroid Carcinoma Presenting As A Parathyroid Adenoma

Abstract Disclosure: P. Subarajan: None. A. Boutsicaris: None. C.A. Poku: None. N. Lopez: None. Distinguishing between parathyroid adenoma (PA) and parathyroid cancer (PC) in patients with primary hyperparathyroidism (PHPT) can be difficult to determine before pathology results. Estimates vary between studies, but roughly 85% of cases of PHPT are PAs. We present a case of a PC that presented clinically as a PA. A 59 year old female presented to Endocrinology for hypercalcemia that was incidentally noted to be 13.8 and 12.8 on initial recheck. Endocrinology completed a secondary workup of the hypercalcemia which noted a PTH of 147 in the setting of a calcium (Ca) of 12.6. Lab review showed that her corrected Ca had been elevated over the preceding 2 years. She had a replete 25-OH vitamin D of 43 and a GFR of 29. A neck ultrasound revealed a 2.1 cm mass suspicious for a parathyroid mass. A sestamibi scan was consistent with increased focal uptake at the inferior pole of the right thyroid lobe. She had renal dysfunction, hypercalcemia and newly diagnosed osteoporosis which prompted referral to endocrine surgery. Intraoperatively, an enlarged right inferior parathyroid gland and a large mass encompassing the inferior thyroid pole extending into the anterior mediastinum with lymphadenopathy were noted. En Bloc resection was completed and final pathology was consistent with high grade parathyroid carcinoma infiltrating the adjacent thyroid gland. Genetic testing for HPT-JT was negative and ultrasound monitoring has remained negative. PC is rare and typically has a clinical presentation and course that sets it apart from PA. The PTH is typically 3-10 times above the upper limit of normal in PC and only 1-2 times above the upper limit of normal in PA. As a result of the variation in PTH, serum Ca is more elevated in PC than PA. PC patients typically present with a parathyrotoxicosis that is profound. A palpable neck mass can be present in 40-70% of individuals with PC. Our patient had an equivocal presentation that appeared more consistent with PA, which can be problematic when deciding on the optimal surgical approach. Amino-PTH is hypersecreted in PC and reacts with 3rd generation PTH assays, but not second generation assays. Clinically, using a third/second generation PTH assay ratio &amp;gt;1 can support a possible clinical suspicion of PC over PA. En Bloc resection is the surgical approach of choice for suspected PC. En Bloc resection may not always be done for a patient with a presentation and evaluation consistent with PA: data shows that only 12.5% of PC patients underwent En Bloc resection, as opposed to 78.6% who underwent parathyroidectomy alone. This puts patients at risk of requiring repeat surgical intervention and poses a higher risk for recurrence. It brings to question whether every PA should be addressed with an En Bloc resection to avoid this inherent risk. This case adds to the literature of PC presenting as PA and supports the argument for standard En Bloc resection in all cases. Presentation: Saturday, June 17, 2023

Approach to suspected donor-derived infections.

Prevention of donor-derived disease among pediatric solid organ transplant recipients requires judicious risk-benefit assessment. Comprehensive guidelines outline specific donor risk factors and post-transplant monitoring strategies to prevent and mitigate transmission of HIV, hepatitis B, and hepatitis C. However, elimination of unanticipated donor-derived infections remains challenging. The objectives of this review are to (1) define risk of anticipated vs. unanticipated disease transmission events in pediatric solid organ transplant recipients; (2) discuss donor presentations that confer greater risk of unanticipated disease transmission; (3) develop a matrix for consideration of donor acceptance; and (4) discuss limitations and future directions for donor screening. Although solid organ transplant confers inherent risk of infection transmission, the risk of significant disease transmission events may be mitigated by a comprehensive approach including donor assessment, consideration of recipient need, post-transplant monitoring, and early intervention.

Incidents relating to paediatric regional anaesthesia in the first 8000 cases reported to webAIRS.

Regional anaesthesia is an essential tool in the armamentarium for paediatric anaesthesia. While largely safe and effective, a range of serious yet preventable adverse events can occur. Incidence and risk factors have been described, but few detailed case series exist relating to paediatric regional anaesthesia. Across Australia and New Zealand, a web-based anaesthesia incident reporting system enables voluntary reporting of detailed anaesthesia-related events in adults and children. From this database, all reports involving paediatric regional anaesthesia (age less than 17 years) were retrieved. Perioperative events and their outcomes were reviewed and analysed. When offered, the reported contributing or alleviating factors relating to the case and its management were noted. This paper provides a summary of these reports alongside an evidence review to support safe practice. Of 8000 reported incidents, 26 related to paediatric regional anaesthesia were identified. There were no deaths or reports of permanent harm. Nine reports of local anaesthetic systemic toxicity were included, seven equipment and technical issues, six errors in which regional anaesthesia made an indirect contribution and four logistical and communication issues. Most incidents involved single-shot techniques or a neuraxial approach. Common themes included variable local anaesthetic dosing, cognitive overload, inadequate preparation and communication breakdown. Neonates, infants and medically complex children were disproportionately represented, highlighting their inherent risk profile. A range of preventable incidents are reported relating to patient, systems and human factors, demonstrating several areas for improvement. Risk stratification, application of existing dosing and administration guidelines, and effective teamwork and communication are encouraged to ensure safe regional anaesthesia in the paediatric population.

Myocardial stretch-induced compliance is abrogated under ischemic conditions and restored by cGMP/PKG-related pathways.

Introduction: Management of acute myocardial infarction (MI) mandates careful optimization of volemia, which can be challenging due to the inherent risk of congestion. Increased myocardial compliance in response to stretching, known as stretch-induced compliance (SIC), has been recently characterized and partly ascribed to cGMP/cGMP-dependent protein kinase (PKG)-related pathways. We hypothesized that SIC would be impaired in MI but restored by activation of PKG, thereby enabling a better response to volume loading in MI. Methods: We conducted experiments in ex vivo rabbit right ventricular papillary muscles under ischemic and non-ischemic conditions as well as pressure-volume hemodynamic evaluations in experimental in vivo MI induced by left anterior descending artery ligation in rats. Results: Acutely stretching muscles ex vivo yielded increased compliance over the next 15min, but not under ischemic conditions. PKG agonists, but not PKC agonists, were able to partially restore SIC in ischemic muscles. A similar effect was observed with phosphodiesterase-5 inhibitor (PDE5i) sildenafil, which was amplified by joint B-type natriuretic peptide or nitric oxide donor administration. In vivo translation revealed that volume loading after MI only increased cardiac output in rats infused with PDE5i. Contrarily to vehicle, sildenafil-treated rats showed a clear increase in myocardial compliance upon volume loading. Discussion: Our results suggest that ischemia impairs the adaptive myocardial response to acute stretching and that this may be partly prevented by pharmacological manipulation of the cGMP/PKG pathway, namely, with PDE5i. Further studies are warranted to further elucidate the potential of this intervention in the clinical setting of acute myocardial ischemia.

Climate Change Risk Disclosures and Audit Fees: A Text Analytics Assessment

ABSTRACT In this paper, we first conduct a longitudinal study of public companies’ climate change risk disclosures from 2005 to 2019. Results indicate that although the number of firms disclosing climate change risks increased over time, disclosure length and disclosure clarity did not improve consistently during the study period. It seems that firms temporarily adjusted their disclosure behaviors around 2010 to satisfy the SEC’s 2010 guidance regarding climate change disclosures. From that point forward, however, companies’ disclosure length and clarity declined. Climate change and disclosures in a client’s environment can elevate both inherent risk and audit risk. Accordingly, the second part of the study empirically examines whether climate change risk disclosures are embedded into the auditors’ risk model and associated audit prices. Results suggest that audit fees are significantly associated with climate change risk disclosure length and clarity, and lower climate change risk disclosure clarity is associated with higher audit fees.

DNA recognition and induced genome modification by a hydroxymethyl-γ tail-clamp peptide nucleic acid

Peptide nucleic acids (PNAs) can target and stimulate recombination reactions in genomic DNA. We have reported that γPNA oligomers possessing the diethylene glycol γ-substituent show improved efficacy over unmodified PNAs in stimulating recombination-induced gene modification. However, this structural modification poses a challenge because of the inherent racemization risk in O-alkylation of the precursory serine side chain. To circumvent this risk and improve γPNA accessibility, we explore the utility of γPNA oligomers possessing the hydroxymethyl-γ moiety for gene-editing applications. We demonstrate that a γPNA oligomer possessing the hydroxymethyl modification, despite weaker preorganization, retains the ability to form a hybrid with the double-stranded DNA target of comparable stability and with higher affinity than that of the diethylene glycol-γPNA. When formulated into poly(lactic-co-glycolic acid) nanoparticles, the hydroxymethyl-γPNA stimulates higher frequencies (≥ 1.5-fold) of gene modification than the diethylene glycol γPNA in mouse bone marrow cells.