Multimodal intrathecal analgesia (MITA) with morphine for reducing postoperative opioid use and acute pain following hepato-pancreato-biliary surgery: A multicenter retrospective study.

INTRODUCTION: The optimal analgesic modality for patients undergoing hepato-pancreato-biliary (HPB) surgery remains unknown. The analgesic effects of a multimodal intrathecal analgesia (MITA) technique of intrathecal morphine (ITM) in combination with clonidine and bupivacaine compared to ITM alone have not been investigated in these patients. METHODS: We performed a multicenter retrospective study of patients undergoing complex HPB surgery who received ITM, bupivacaine, and clonidine (MITA group) or ITM-only (ITM group) as part of their perioperative analgesia strategy. The primary outcome was the unadjusted oral morphine equivalent daily dose (oMEDD) in milligrams on postoperative day 1. After adjusting for age, body mass index, hospital allocation, type of surgery, operation length, and intraoperative opioid use, postoperative oMEDD use was investigated using a bootstrapped quantile regression model. Other prespecified outcomes included postoperative pain scores, opioid-related adverse events, major complications, and length of hospital stay. RESULTS: In total, 118 patients received MITA and 155 patients received ITM-only. The median (IQR) cumulative oMEDD use on postoperative day 1 was 20.5 mg (8.6:31.0) in the MITA group and 52.1 mg (18.0:107.0) in the ITM group (P < 0.001). There was a variation in the magnitude of the difference in oMEDD use between the groups for different quartiles. For the MITA group, on postoperative day 1, patients in the 25th percentile required 14.0 mg less oMEDD (95% CI: -25.9 to -2.2; P = 0.025), patients in the 50th percentile required 27.8 mg less oMEDD (95% CI: -49.7 to -6.0; P = 0.005), and patients in the 75th percentile required 38.7 mg less oMEDD (95% CI: -72.2 to -5.1; P = 0.041) compared to patients in the same percentile of the ITM group. Patients in the MITA group had significantly lower pain scores in the postoperative recovery unit and on postoperative days 1 to 3. The incidence of postoperative respiratory depression was low (<1.5%) and similar between groups. Patients in the MITA group had a significantly higher incidence of postoperative hypotension requiring vasopressor support. However, no significant differences were observed in major postoperative complications, or the length of hospital stay. CONCLUSION: In patients undergoing complex HPB surgery, the use of MITA, consisting of ITM in combination with intrathecal clonidine and bupivacaine, was associated with reduced postoperative opioid use and resulted in superior postoperative analgesia without risk of respiratory depression when compared to patients who received ITM alone. A randomized prospective clinical trial investigating these two intrathecal analgesic techniques is justified.

Exploring and Expanding Supererogatory Acts: Beyond Duty for a Sustainable Future.

Supererogation has gained attention as a means of explaining the voluntary behaviours of individuals and organizations that are done for the benefit of others and which go above what is required of legislation and what may be expected by society. Whilst the emerging literature has made some significant headway in exploring supererogation as an ethical lens for the study of business there remain several important issues that require attention. These comprise, the lack of primary evidence upon which such examinations have been made, attention has been given to only singular pro-social acts of organizations, and the focus has been upon the actions of large organizations. Furthermore, Heyd's (Supererogation, Cambridge University Press, 1982) original taxonomy of six supererogatory acts, comprising Moral Heroism, Beneficence, Volunteering, Favour, Forgiveness and Forbearance, has been considered to be complete and other forms of supererogatory acts have not yet been explored. In order to address these gaps this study poses the research questions: First, it studies how a single, contemporary SME performs multiple supererogatory acts in its attempts to address its social and environmental goals that go beyond CSR. Second, it seeks to gain a deeper theoretical understanding of Heyd's (Supererogation, Cambridge University Press, 1982) taxonomy of six forms of supererogation through the capture of primary data. This research makes a three-year case study examination of a single SME that has been formally recognized for its work in addressing social and environmental issues at local, national and global levels. Primary data are acquired of the supererogatory acts that it performs through a three-year participant observation case study, utilizing 61 interviews and 3 focus groups with internal and external stakeholders. In doing so, it addresses the empirical limitations of the extant research, substantiates each of the forms that supererogatory acts may take, and makes a contribution to the theory of supererogation by identifying a further class of act that is 'Sharing'.

Discontinuation of nucleot(s)ide analogue therapy in HBeAg-negative chronic hepatitis B: a meta-analysis.

BACKGROUND AND AIMS: Sustained virological suppression and hepatitis B surface antigen (HBsAg) loss have been described after nucleot(s)ide analogue (NA) discontinuation for patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). We performed a meta-analysis of the clinical outcomes after NA discontinuation for HBeAg-negative CHB. METHODS: Studies involving NA cessation in HBeAg-negative CHB individuals with a median follow-up of ≥12 months were included. Participants were HBeAg-negative at the time of NA initiation. Random effects meta-analyses were performed for the following clinical outcomes: (1) virological relapse (VR) at 6 and 12 months; (2) clinical relapse (CR) at 6 and 12 months and (3) HBsAg loss. Effect of other variables was estimated using subgroup analysis and meta-regression. Studies including patients stopping entecavir (ETV) and/or tenofovir disoproxil fumarate (TDF) were considered separately to studies including patients stopping older generation NA. RESULTS: N=37 studies met inclusion criteria. Cumulative incidence of VR and CR after stopping ETV/TDF was 44% and 17% at 6 months and 63% and 35% at 12 months. Similar relapse rates were observed after stopping older NAs. Among patients stopping ETV/TDF, TDF cessation was associated with increased CR rates at 6 months versus ETV. There was an association between follow-up ≥4 years and HBsAg loss rates when stopping older NAs. Hepatic decompensation and hepatocellular carcinoma were rare but occurred more frequently in studies including cirrhotic individuals. CONCLUSION: VR is common after NA discontinuation, however, CR was only seen in one-third of patients at 12 months. Stopping NA therapy can be followed by HBsAg clearance, and rates are higher with longer follow-up.

Treatment of Peripheral Arterial Occlusive Disease around the Globe: Malta.

INTRODUCTION: Malta is a small island in the middle of the Mediterranean with a population of 514,564 inhabitants and is served by one public tertiary hospital, Mater Dei Hospital. The Vascular unit was set up in 2007. The aim of this review is to analyse the work related to peripheral arterial occlusive disease (PAOD) in Malta with an in-depth focus on amputations and revascularisation procedures since the introduction of the Vascular unit. METHOD: Various sources of data have been interrogated to address this subject. Population and prevalence data on obesity and type II diabetes mellitus from 2003 to 2019 was obtained from the National Statistics Office, the World Health Organization, and the International Diabetes Federation, respectively. The Maltese Vascular Register (MaltaVasc), and in-hospital reports from 2003 to 2019 was used to obtain data on revascularisation procedures, major amputations and minor amputation rates in Malta. RESULTS: Malta has one of the highest rates of obesity in Europe. In 2015, the prevalence rate was 30.6%. Similarly, data from the International Diabetes Federation Atlas showed that the prevalence rate of T2DM among adults was 14% in 2017. There was a mean of 33 open/hybrid procedures per 100,000 population (28-38, 95% confidence interval) between 2005 and 2009 and a mean of 57 endovascular procedures per 100,000 population (46-68, 95% confidence interval) during the same time-period. From 2009 to 2019, there was a mean of 16 major amputations and 78 minor amputations per 100,000 population. CONCLUSION: A significant reduction in major amputation rates with an increase in minor amputation rates and revascularisation rates has been noted since the establishment of the vascular unit in Malta. During this period, there has been an increase in prevalence in obesity and T2DM together with an aging population.

Bivalirudin as an Alternative Anticoagulant for Cardiopulmonary Bypass During Adult Cardiac Surgery-A Change in Practice.

The referral of patients for open heart surgery, presenting with a history of heparin hypersensitivity instigated a multidisciplinary effort to find an alternative anticoagulant to heparin. The various options mentioned in the literature call for changes in the routine practice of open heart surgery on cardiopulmonary bypass. These changes involve mostly the perfusion setup and conduct on bypass and to a lesser extent the anesthetic and surgical practice. Nevertheless, the different professions involved in the cardiac surgical firm discussed the proposed changes in a multidisciplinary effort. A new protocol was drafted, endorsed, and executed. The authors highlight these changes and their successful use in the subsequent case study.

Urgent Coronary Artery Bypass Surgery in a Patient with Postinfarction Angina and Active Myelomonocytic Leukaemia.

Chronic myelomonocytic leukaemia (CMML) is a myelodysplastic/myeloproliferative neoplasm affecting the production and differentiation of the monocyte cell lineage. Cardiac surgery in the context of CMML poses challenges that are not routinely encountered. This is the first reported case in the literature of a patient with active CMML undergoing urgent on-pump coronary artery bypass grafting. A 68-year-old Caucasian man with a history of hypertension, hyperlipidaemia, hypothyroidism, and hypercholesterolaemia, who had been diagnosed by the haematologists with CMML a few months earlier but had remained untreated, underwent urgent surgical coronary revascularisation because of postinfarction angina following a non-ST elevation myocardial infarction associated with troponin I rise. The patient had fulminant postoperative myelomonocytic leukaemoid reaction, with a clinical picture of severe systemic inflammatory response syndrome and multiple organ dysfunction syndrome. This led to extensive vasodilation and heart failure that resulted in the death of the patient. Various authors have suggested different techniques and treatment options, each attempting to mitigate the effect of the postoperative inflammatory response. However, this is a high-risk endeavour with a myriad of inflammatory signals mobilised into action because of the surgical insult. Off-pump surgery or preoperative pharmacological attenuation of CMML activity might have dampened this response and resulted in a positive outcome for the patient.

Cell-based therapies for cardiac repair: a meeting report on scientific observations and European regulatory viewpoints.

In the past decade, novel cell-based products have been studied in patients with acute and chronic cardiac disease to assess whether these therapies are efficacious in improving heart function and preventing the development of end-stage heart failure. Cardiac indications studied include acute myocardial infarction (AMI), refractory angina, and chronic heart failure (CHF). Increased clinical activity, experience, and multiple challenges faced by developers have been recognized at the regulatory level. In May 2014, the Committee for Advanced Therapies (CAT) discussed in an expert meeting various cell-based medicinal products developed for cardiac repair, with a focus on non-manipulated bone marrow cells, sorted bone marrow or apheresis, and expanded cells, applied to patients with AMI or CHF. The intention was to share information, both scientific and regulatory, and to examine the challenges and opportunities in this field. These aspects were considered from the quality, and non-clinical and clinical perspectives, including current imaging techniques, with a focus on AMI and CHF. The scope of this overview is to present the European regulatory viewpoint on cell-based therapies for cardiac repair in the context of scientific observations.

Chronic nicotine administration does not alter cognitive or mood associated behavioural parameters.

Nicotine, the major specific alkaloid in tobacco smoke, exhibits widespread pharmacological effects and may contribute to deterioration in behaviour. The present study thus examined the effects of its chronic administration on some cognitive and mood associated behaviours. Adult rats weighing between 150 and 200g were randomly divided into 4 groups each of 5 females and 5 males. Three groups were administered graded doses of nicotine at 0.25, 2 and 4mg/kg body weight via subcutaneous injections. One group served as control and received normal saline (vehicle for nicotine). Behavioural tests were performed using the Y-maze, elevated-plus maze (EPM) and tail suspension tests (TST) at various time points. Nicotine produced no significant effect in spontaneous alternation on Y-maze, nor on six parameters scored on EPM (open arm entries, time spent in open arms, time per open arm entries, open/closed arm quotient, closed arm entries, and total arm entries), and also no significant effect on immobility time in TST. This lack of effects was observed to be independent of sex and dose administered. The study shows that nicotine does not produce long-term changes in some cognitive and mood associated behaviours, thus suggesting it could be well tolerated even following chronic administration.

Challenges with advanced therapy medicinal products and how to meet them.

Advanced therapy medicinal products (ATMPs), which include gene therapy medicinal products, somatic cell therapy medicinal products and tissue-engineered products, are at the cutting edge of innovation and offer a major hope for various diseases for which there are limited or no therapeutic options. They have therefore been subject to considerable interest and debate. Following the European regulation on ATMPs, a consolidated regulatory framework for these innovative medicines has recently been established. Central to this framework is the Committee for Advanced Therapies (CAT) at the European Medicines Agency (EMA), comprising a multidisciplinary scientific expert committee, representing all EU member states and European Free Trade Association countries, as well as patient and medical associations. In this article, the CAT discusses some of the typical issues raised by developers of ATMPs, and highlights the opportunities for such companies and research groups to approach the EMA and the CAT as a regulatory advisor during development.