Management and patient outcomes following admission with acute cholecystitis in Ireland: A national registry-based study.

INTRODUCTION: Acute cholecystitis is a common general surgical emergency, accounting for 3-10 % of all patients attending with acute abdominal pain. International guidelines suggest that emergency cholecystectomy is the treatment of choice for uncomplicated acute cholecystitis where feasible. There is a paucity of published data on the uptake of emergency cholecystectomy in Ireland. AIM: The aim of this study was to evaluate the management of acute cholecystitis in Ireland and to establish the rate of emergency cholecystectomy performed. METHODS: All patients with acute cholecystitis presenting to public hospitals in Ireland between January 2017 and July 2023 were identified using the National Quality Assurance and Improvement System (NQAIS). Data were collected on patient demographics, co-morbidities, length of stay, operative intervention, endoscopic intervention, critical care admissions, in-patient mortality, and readmissions. Propensity score matched analysis and logistic regression were performed to account for selection bias in comparing patients managed with cholecystectomy and those managed conservatively. RESULTS: 20,886 admission episodes were identified involving 17,958 patients. 3585 (20 %) patients underwent emergency cholecystectomy in total. 3436 (96 %) of these were performed laparoscopically, with 140 (4 %) requiring conversion to an open procedure, and common bile duct injuries occurring in 4 (0.1 %) of patients. In comparison to patients treated conservatively, patients who underwent cholecystectomy were younger (median 50 v 60 years, p < 0.001) and more likely to be female (64 % v 55 % p < 0.001). Following propensity score matched analysis, those who had an emergency cholecystectomy had reduced length of stay (LOS) (median 5 days (IQR 3-8) v 6 days (interquartile range (IQR) 3-10), p < 0.001) and fewer readmissions to hospital (282 (8 %) v 492 (14 %), p < 0.001). On logistic regression, age >65 (OR 1.526), CCI >3 (OR 2.281) and non-operative management (OR 1.136) were significant risk factors for adverse outcome. CONCLUSION: Uptake of emergency cholecystectomy in Ireland remains low, and is carried out on a younger, fitter cohort of patients. In those patients, however, it is associated with improved outcomes for cholecystitis compared to conservative management, including shorter LOS and reduced readmission rates for matched cohorts.

Use of real-time electronic extremity dosimeters for monitoring and optimisation of radiopharmacy technique.

Radiopharmacy staff members are subject to extremity radiation doses, particularly to the fingertips. Dosemeters, such as, thermoluminescent detectors (TLDs) are currently used for monitoring fingertip doses. This study aimed to use real-time dosemeters to monitor radiopharmacy extremity doses to identify specific procedural steps associated with higher fingertip doses and, subsequently, reduce dose through promotion of optimised radiation protection practises. Five radiopharmacy operators were monitored using an ED3 active extremity dosemeter with a detector attached to each tip of the index fingers. Dose rate and accumulated dose data were matched to the handled radioactivity data, of99mTc-labelled radiopharmaceuticals only, with the dose per activity (µSv MBq-1) calculated for each step. Once baseline dose data was established, an educational session identified technique adjustments toward improved radiation protection. A subsequent monitored session was undertaken with the dose data compared to quantify changes in operator doses. Radiopharmacy steps which significantly contributed to extremity doses were identified. The average accumulated dose per activity across all procedural steps for the99mTc-labelled radiopharmaceuticals for all operators before the educational session was 0.042 ± 0.045µSv MBq-1and 0.042 ± 0.041µSv MBq-1(n= 89) for non-dominant and dominant index fingertips, respectively, and 0.030 ± 0.044µSv MBq-1and 0.031 ± 0.032µSv MBq-1(n= 97), respectively, afterwards. Overall, there was an average 40.7% reduction in the total extremity dose received after the educational session. Real-time electronic extremity dosemeters for monitoring radiopharmacy extremity dose presented as a useful tool for incorporation into radiation protection education and training, towards optimised radiopharmacy technique.

Preclinical Assessment of the Abuse Potential of Purified Botanical Cannabidiol: Self-Administration, Drug Discrimination, and Physical Dependence.

Cannabidiol (CBD) is a constituent of the cannabis plant with a diverse array of pharmacological activities as well as potential therapeutic uses. An oral formulation of CBD (Epidiolex in the US; Epidyolex in Europe) is approved for treating seizures associated with rare and severe forms of epilepsy. These studies, which supported the approval of the medication, investigated abuse-related effects of CBD in rats and nonhuman primates (NHPs) using drug self-administration, drug discrimination, and physical dependence procedures and characterized its pharmacokinetics. In NHPs (n = 5) that self-administered midazolam (0.01 or 0.032 mg/kg/infusion), CBD (0.1-3.2 mg/kg/infusion) failed to maintain responding above vehicle levels. CBD maintained very modest levels of self-administration in rats (n = 7-8) that self-administered heroin (0.015 mg/kg/infusion) and did not increase drug-lever responding, up to a dose of 150 mg/kg (by mouth), in rats (n = 6) trained to discriminate 0.5 mg/kg (i.p.) midazolam. In juvenile (5-6 weeks old) and adult (10-11 weeks old) male and female rats, discontinuation of chronic treatment (twice daily for 20 days) with an oral formulation of CBD (20 or 100 mg/kg, by mouth) did not reliably produce signs of withdrawal. Pharmacokinetic studies confirmed that the dosing regimens used in these studies resulted in therapeutically relevant plasma levels. Taken together, the lack of reliable self-administration, the failure to increase drug-lever responding in rats trained to discriminate midazolam, and the absence of withdrawal signs upon discontinuation of chronic treatment indicate that CBD has very low abuse potential and is unlikely to produce physical dependence. SIGNIFICANCE STATEMENT: Legalization of cannabis across the United States and elsewhere has led to intense investigation into the safety and therapeutic potential of cannabis and its constituent materials, including cannabidiol (CBD). Results of these preclinical abuse potential studies on CBD indicate no rewarding properties, physical dependence potential, or similarity to a benzodiazepine. Together with data from in vitro pharmacology and human abuse potential studies, the abuse potential of Epidiolex in humans is likely to be negligible.

The effect of magnesium administration on erythrocyte transketolase activity in alcoholic patients treated with thiamine.

BACKGROUND AND AIMS: Chronic alcoholic patients are at increased risk of developing deficiencies of thiamine and magnesium. Thiamine is an essential co-factor for a number of enzymes involved in carbohydrate metabolism and requires optimal levels of magnesium for biological function. However, whilst thiamine supplementation is well established for the treatment of alcoholic patients, the importance of magnesium is often overlooked. We describe the effect of concurrent thiamine and magnesium administration on the activity of the thiamine-dependent enzyme erythrocyte transketolase in a cohort of chronic alcoholic patients. METHODS: Baseline erythrocyte transketolase activities were measured on blood samples collected from 36 chronic alcoholic patients presenting acutely to the Accident and Emergency department. Patients received either intravenous Pabrinex (thiamine) supplemented with magnesium sulphate (n = 18) or Pabrinex only (n = 18). Post-treatment bloods were collected for re-assessment of erythrocyte transketolase activity. The change in transketolase activities (pre-vs. post-treatment) between the two patient groups were compared by Mann-Whitney U test. RESULTS: The increase in transketolase activity following treatment in the cohort receiving Pabrinex supplemented with magnesium sulphate was significantly greater (p = 0.018) than that produced in the cohort receiving Pabrinex alone. CONCLUSION: In the acute management of a sample of chronic alcoholic patients, those receiving magnesium sulphate with Pabrinex have higher increases in erythrocyte transketolase activity compared with those receiving Pabrinex alone. We conclude that concurrent magnesium administration with Pabrinex may be required for enabling full efficacy of Pabrinex treatment, as demonstrated by its positive effect on erythrocyte transketolase activity.

Aberrant right posterior sectoral duct injury necessitating liver resection.

Aberrant insertion of the right posterior sectoral duct is a particularly hazardous variation of biliary anatomy which makes it prone to injury during laparoscopic cholecystectomy. Such injuries are challenging to manage, as multiple therapeutic options are available with no clear consensus in the literature for an optimal approach. Options include conservative management, intraoperative ligation of the injured duct, Roux-en-Y reconstruction and segmental liver resection. Most cases in the literature advocate for nonoperative management or hepaticojejunostomy. We present an unusual case of aberrant right posterior sectoral duct injury in which neither of these approaches was viable, necessitating a bi-segmental liver resection.

Replaying the game: hypnagogic images in normals and amnesics.

Participants playing the computer game Tetris reported intrusive, stereotypical, visual images of the game at sleep onset. Three amnesic patients with extensive bilateral medial temporal lobe damage produced similar hypnagogic reports despite being unable to recall playing the game, suggesting that such imagery may arise without important contribution from the declarative memory system. In addition, control participants reported images from previously played versions of the game, demonstrating that remote memories can influence the images from recent waking experience.

Achievable outcomes in the management of proximal cholangiocarcinoma: an update prepared using "evidence-based practice" techniques.

BACKGROUND: The purpose of this study is to evaluate recently reported outcomes for treatment options for proximal cholangiocarcinoma (CCA). MATERIALS AND METHODS: Standard evidence based practice techniques were used to formulate a question, search, appraise and evaluate the retrieved literature. Our question was "In patients with CCA, how do stenting alone, stenting in addition to brachytherapy (BT) or photodynamic therapy (PDT), resection and orthotopic liver transplantation with neoadjuvant chemoradiation (OLT) compare for long-term survival? RESULTS: Level 1b survival data was available for stenting alone (179 days), BT and metal stenting (388 days) and PDT with plastic stenting (493 days) and no survival difference was evident with metal vs. plastic stenting or unilateral vs. bilateral stenting. Five year survival data (level 3) was available for OLT (80%), formally curative trisegmentectomy with or without portal vein resection (72% and 52%) and hepatectomy (18%-23%). CONCLUSION: All patients with proximal CCA should be reviewed by a multidisciplinary team to determine appropriate treatment. For unresectable CCA, patients should be assessed for OLT with neoadjuvant chemoradiation, while those who are unsuitable would appear to have the longest survival with PDT. Extended resection in operable candidates may improve survival over right or left hepatectomy but increased perioperative mortality is a consideration.

Alanine in HI: a silent mutation cries out!

It is a widely held paradigm in molecular biology that a change in the third base of a codon is silent in terms of expression. In this investigation, results are presented that challenge that paradigm, at least in terms of one polymorphism in KCNJ11, which is one of five genes that have been implicated in the disorder Hyperinsulinism of Infancy. In two cohorts of Australian patients, an uneven distribution of KCNJ11 SNP's was observed. A silent polymorphism at codon 190 was over-represented in the patients who responded well to medical treatment and under-represented in those that required radical surgical intervention. In an attempt to investigate this polymorphism, it was expressed in vitro and western blot analysis showed that there were virtually no bands from the homozygous variant samples, while strong bands were seen in normal controls. The human genome is highly redundant in terms of tRNA species for each amino acids but enigmatically under-represents a number of specific codons. The polymorphism in question occurs within one such codon. We propose that the presence of a base change at the third position of codon that is not represented by a corresponding anti-codon within the human nuclear tRNA leads to a decreased rate of expression of the protein.

Pseudogenes and the electron transport chain.

With the advent of easy access to the human genome sequence, molecular biology techniques to target respirome-specific genes have begun to be exploited in the study of human disorders and in particular human cancers. In some recent publications it would appear that some investigators have inappropriately targeted pseudogenes rather than functional genes. The high transcription level and generally small size of many of the genes in the respirome make them prone to duplications in the form of processed pseudogenes within the human genome. Such genes can be challenging to analyse using standard molecular genetics approaches. In this presentation, we offer an analysis of pseudogenes that have been identified to have significant homology with some elements of the respirome. Other sequence elements such as Alu repeats, which present similar research obstacles, are also discussed.

Analysis of SDHD and MMP12 in an affected solar keratosis and control cohort.

The incidence of Squamous Cell Carcinoma (SCG) is growing in certain populations to the extent that it is now the most common skin lesion in young men and women in high ultraviolet exposure regions such as Queensland. In terms of incidence up to 40% of the Australian population over 40 years of age is thought to possess the precancerous Solar Keratosis (SK) lesion and with a small, but significant, chance of progression into SCC, understanding the genetic events that play a role in this process is essential. The major aims of this study were to analyse whole blood derived samples for DNA aberrations in genes associated with tumour development and cellular maintenance, with the ultimate aim of identifying genes associated with non-melanoma skin cancer development. More specifically the first aim of this project was to analyse the SDHD and MMP12 genes via Dual-Labelled Probe Real-Time PCR for copy number aberrations in an affected Solar Keratosis and control cohort. It was found that 12 samples had identifiable copy-number aberrations in either the SDHD or MMP12 gene (this means that a genetic section of either of these two genes is aberrantly amplified or deleted), with five of the samples exhibiting aberrations in both genes. The significance of this study is the contribution to the knowledge of the genetic pathways that are malformed in the progression and development of the pre-cancerous skin lesion Solar Keratosis.

The role of ATP sensitive channels in insulin secretion and the implications in persistent hyperinsulinemic hypoglycaemia of infancy (PHHI).

Persistent Hyperinsulinemic Hypoglycaemia of Infancy (PHHI) is a metabolic syndrome of unregulated insulin secretion. It is a heterogenous disease with causes linked to mutations of the ATP sensitive potassium channels of the beta cell, as well as to metabolism in the beta cell. 5 candidate genes--ABCC8, KCNJ11, GCK, GLUD1 and SCHAD have been implicated in the disease so far, however the aetiology of the disease remains unknown in up to 50% of all patients. We genotyped 43 subjects with PHHI (20 surgically treated and 23 medically treated) for disease associated mutations in the candidate genes. Mutations on ABCC8 were identified in 16 of the 20 (80%) of the surgically treated patients. One putative mutation was identified in the medically treated cohort. The polymorphism E23K on KCNJ11 that is associated with NIDDM was differentially distributed in the 2 cohorts. We discuss the mutations identified, emphasise the importance of the K-ATP channel in physiological processes and discuss the possibility that the disease is caused by mutations in other genes associated with insulin release, glucose metabolism in the beta cell or beta cell apoptosis and survival. We propose that these processes must be explored in order to further our understanding of PHHI.

PTEN and NDUFB8 aberrations in cervical cancer tissue.

Cervical cancer is one of the world's major health issues. Despite many studies in this field, the carcinogenetic events of malignant conversion in cervical tumours have not been significantly characterised. The first aim of this project was to investigate the mutation status of the tumour suppressor gene- Phosphatase and Tension Homolog (PTEN)--in cervical cancer tissue. The second aim of this study was the analysis in the same cervical cancer tissue for aberrations in the mitochondrial electron transport chain subunit gene NDUFB8, which is localised to the same chromosomal contig as PTEN. The third aim was the evaluation of the potential therapeutic anti-cancer drug 2,4-Thiazolidinediones (TZDs) and its affect in regulating the PTEN protein in a cervical cancer cell line (HeLa). To approach the aims, paraffin-embedded cancerous cervical tissue and non-cancerous cervical tissue were obtained. DNA recovered from those tissues was then used to investigate the putative genomic changes regarding the NDUFB8 gene utilising SYBR Green I Real-Time PCR. The PTEN gene was studied via Dual-Labelled probe Real-Time PCR. To investigate the protein expression change of the PTEN protein, HeLa cells were firstly treated with different concentrations of 2,4-Thiazolidinediones and the level of PTEN protein expression was then observed utilising standard protein assays. Results indicated that there were putative copy-number changes between the cancerous cervical tissue and non-cancerous cervical tissue, with regard to the PTEN locus. This implies a potential gain of the PTEN gene in cancerous cervical tissue. With regards to normal cervical tissue versus cancerous cervical tissue no significant melting temperature differences were observed with the SYBR Green I Real-Time PCR in respect to the NDUFB8 gene. A putative up-regulation of PTEN protein was observed in TZD treated HeLa cells.

MELD score as a prognostic model for listing acute liver failure patients for liver transplantation.

OBJECTIVES: The King's College Hospital (KCH) criteria are widely used for listing patients with acute liver failure (ALF) for liver transplantation (LT). Recent reports have suggested that the Model for End-Stage Liver Disease (MELD) score may be useful in assessing prognosis in ALF (nonparacetamol). This study compares prognostic accuracy of the two systems in patients with paracetamol (POD)-induced ALF treated in this unit. METHODS: Seventy-two patients (average age 38 years; F:M ratio 2:1) admitted from 1994 to 2005 with POD-related ALF were studied. Clinical and biochemical parameters were recorded. The effect of applying a MELD score of greater than 30 as listing criteria for LT was calculated and compared with the KCH criteria. Outcomes were defined as LT, death, or full recovery. RESULTS: Thirty-one patients (43%) recovered with medical therapy, 29 (40%) patients died, and 12 (17%) underwent LT. Sixty five percent of patients had a MELD > 30 and therefore could potentially be listed on admission; however, using KCH criteria only 24% patients were listed immediately. Sensitivity and negative predictive value of MELD was higher then KCH; however, we found KCH to have much higher specificity and positive predictive value. CONCLUSION: MELD has higher sensitivity and negative predictive value for POD-induced ALF than the KCH criteria. However, the high false-positive rate associated with MELD limits its clinical utility. The high negative predictive value of MELD score may allow it to be used in conjunction with KCH criteria to avoid unneeded LT in patients who will likely recover spontaneously.

Daily morphine administration increases impulsivity in rats responding under a 5-choice serial reaction time task.

BACKGROUND AND PURPOSE: Repeated administration of a µ opioid receptor agonist can enhance some forms of impulsivity, such as delay discounting. However, it is unclear whether repeated administration alters motor impulsivity. EXPERIMENTAL APPROACH: We examined the effects of acute administration of morphine and amphetamine prior to and during daily morphine administration in rats responding under a five-choice serial reaction time task. Rats (n = 5) were trained to detect a brief flash of light presented randomly in one of five response holes; responding in the target hole delivered food, whereas responding in the wrong hole or responding prior to illumination of the target stimulus (premature response) initiated a timeout. Premature responding served as an index of motor impulsivity. KEY RESULTS: Administered acutely, morphine (0.1-10 mg·kg(-1) , i.p.) increased omissions and modestly, although not significantly, premature responding without affecting response accuracy; amphetamine (0.1-1.78 mg·kg(-1) , i.p.) increased premature responding without changing omissions or response accuracy. After 3 weeks of 10 mg·kg(-1) ·day(-1) morphine, tolerance developed to its effects on omissions whereas premature responding increased approximately fourfold, compared with baseline. Effects of amphetamine were not significantly affected by daily morphine administration. CONCLUSIONS AND IMPLICATIONS: These data suggest that repeated administration of morphine increased effects of morphine on motor impulsivity, although tolerance developed to other effects, such as omissions. To the extent that impulsivity is a risk factor for drug abuse, repeated administration of µ opioid receptor agonists, for recreational or therapeutic purposes, might increase impulsivity and thus the risk for drug abuse.

Iatrogenic common bile duct injuries: Increasing complexity in the laparoscopic era: A prospective cohort study.

PURPOSE: Iatrogenic bile duct injury (BDI) is the most significant associated complication to laparoscopic cholecystectomy (LC). Little is known about the evolution of the pattern of BDI in the era of laparoscopy. The aim of the study is to assess the pattern of post-LC BDIs managed in a tertiary referral centre. METHODS: Post-LC BDI referred over two decades were studied. Demographic data, type of BDI (classified using the Strasberg System), clinical symptoms, diagnostic investigations, timing of referral, post-referral management and morbidity were analysed. The pattern of injury, associated vascular injuries rate and their management were compared over two time periods (1992-2004,2005-2014). RESULTS: 78 BDIs were referred. During the second time period Strasberg A injuries decreased from 14% to 0 and Strasberg E1increased from 4% to 23%, the rate of associated vascular injury was six time higher (3.6% versus 22.7%), more patients had an attempted repair at the index hospital (16% versus 35%) sand fewer patients could be managed without surgical intervention at the referral hospital (28% versus 4%). CONCLUSION: Complexity of referred BDIs and rate of associated vascular injuries have increased over time. These findings led to more patients managed requiring surgical intervention at the referral hospital.

Partial PFO Closure for Persistent Hypoxemia in a Patient with Ebstein Anomaly.

Ebstein anomaly is characterized by deformities of the anterior leaflet of the tricuspid valve and atrialization of the right ventricle. Patients with severe tricuspid regurgitation are recommended to have tricuspid valve surgery with concomitant atrial septal defect closure. A 73-year-old female with Ebstein anomaly presented with severe hypoxemia. Transthoracic echocardiography revealed severe tricuspid regurgitation and a patent foramen ovale with right-to-left shunting. Complete percutaneous patent foramen ovale closure led to acute decompensation; however, partial closure led to hemodynamic stability and improved oxygenation. In conclusion, similar patients with "patent foramen ovale dependency" from longstanding shunts may benefit from partial patent foramen ovale closure.

Segmental duodenal resection: indications, surgical techniques and postoperative outcomes.

INTRODUCTION: Segmental duodenal resections (DR) have been increasingly performed for the treatment of primary duodenal tumours. The aim of the study is to review the indications for, clinical and operative details, and outcomes of patients undergoing elective DR. MATERIAL AND METHODS: We retrospectively reviewed all patients who underwent elective segmental DR for the treatment of primary duodenal tumours, at a single institution between January 2007 and December 2013. Demographic data, clinical presentation, preoperative investigations, operative details, postoperative complications/mortality and histopathological results were recorded. RESULTS: In the study period, 11 duodenal resections were performed (7 male, median age 61 years). Thirty-six percent of the patients presented with anaemia. Surgical resection included two or more segments in seven patients. The most frequently resected part of the duodenum was segment 3 (n = 7). Median operative time was 191 min and blood loss was 675 ml. End-to-end and end-to-side anastomoses were performed in equal numbers. The pathology of resected specimens included adenocarcinoma (n = 4), gastrointestinal stromal tumour (GIST) (n = 1), adenoma (n = 5) and lymphoma (n = 1). Median hospital stay was 14 days. Overall, 30-day morbidity rate was 82% (78% Clavien 2 or less). CONCLUSIONS: Segmental duodenal resection is a safe and effective surgical technique for the resection of primary duodenal tumours.

Molecular cytogenetic analysis of basal cell carcinoma DNA using comparative genomic hybridization.

In an attempt to define genomic copy number changes associated with the development of basal cell carcinoma, we investigated 15 sporadic tumors by comparative genomic hybridization. With the incorporation of tissue microdissection and degenerate oligonucleotide primed-polymerase chain reaction we were able to isolate, and then universally amplify, DNA from the tumor type. This combined approach allows the investigation of chromosomal imbalances within a histologically distinct region of tissue. Using comparative genomic hybridization we have observed novel and recurrent chromosomal gains at 6p (47%), 6q (20%), 9p (20%), 7 (13%), and X (13%). In addition comparative genomic hybridization revealed regional loss on 9q in 33% of tested tumors encompassing 9q22.3 to which the putative tumor suppressor gene, Patched, has been mapped. The deletion of Patched has been indicated in the development of hereditary and sporadic basal cell carcinomas. The identification of these recurrent genetic aberrations suggests that basal cell carcinomas may not be as genetically stable as previously thought. Further investigation of these regions may lead to the identification of other genes responsible for basal cell carcinoma formation.

Cybrids in Alzheimer's disease: a cellular model of the disease?

The mitochondrial electron transport chain enzyme cytochrome c oxidase (COX) is defective in patients with sporadic Alzheimer's disease (AD). This defect arises from the mutation of mitochondrial DNA (mtDNA). To develop a tissue culture system that would express this genetically derived bioenergetic lesion and permit characterization of its functional consequences, we depleted Ntera2/D1 (NT2) teratocarcinoma cells of endogenous mtDNA and repopulated them with platelet mtDNA from AD patients. Cytochrome c oxidase activity was depressed in the resulting AD cytoplasmic hybrids (cybrids) compared with cybrids prepared with mtDNA from non-AD controls. Reactive oxygen species (ROS) production and free radical scavenging enzyme activities were significantly elevated in AD cybrids. A COX defect in NT2 AD cybrid lines indicates that AD patients possess mtDNA COX gene mutations that are sufficient for determining this biochemical lesion. Expression of unique functional characteristics (increased ROS production and free radical scavenging enzyme activities) relevant to neurodegeneration demonstrates the utility of these cells in defining AD pathophysiology at a cellular level. This in vitro tissue culture model of AD may prove useful in drug screening.