Polyglucosan body density in the aged mouse hippocampus is controlled by a novel modifier locus on chromosome 1.

Aging can be associated with the accumulation of hypobranched glycogen molecules (polyglucosan bodies, PGBs), particularly in astrocytes of the hippocampus. While PGBs have a detrimental effect on cognition in diseases such as adult polyglucosan body disease and Lafora disease, the underlying mechanism and clinical relevance of age-related PGB accumulation remains unknown. Here, we have investigated the genetic basis and functional impact of age-related PGB accumulation in 32 fully sequenced BXD-type strains of mice which exhibit a 400-fold variation in PGB burden in 16-18 month old females. We mapped a major locus controlling PGB density in the hippocampus to chromosome 1 at 72-75 Mb (linkage of 4.9 -logP), which we defined as the Pgb1 locus. To identify potentially causal gene variants within Pgb1, we generated extensive hippocampal transcriptome datasets and identified two strong candidate genes for which mRNA correlates with PGB density-Smarcal1 and Usp37. In addition, both Smarcal1 and Usp37 contain non-synonymous allele variations likely to impact protein function. A phenome-wide association analysis highlighted a trans-regulatory effect of the Pgb1 locus on expression of Hp1bp3, a gene known to play a role in age-related changes in learning and memory. To investigate the potential impact of PGBs on cognition, we performed conditioned fear memory testing on strains displaying varying degrees of PGB burden, and a phenome-wide association scan of ~12,000 traits. Importantly, we did not find any evidence suggesting a negative impact of PGB burden on cognitive capacity. Taken together, we have identified a major modifier locus controlling PGB burden in the hippocampus and shed light on the genetic architecture and clinical relevance of this strikingly heterogeneous hippocampal phenotype.

Evaluation of learning and exposure in the undergraduate interventional radiology curriculum (ELIXIR).

AIM: To gauge current final year medical students' exposure to interventional radiology (IR)and assess their perceptions of IR as a prospective career option. MATERIALS AND METHODS: An online questionnaire comprising of questions that gauge final-year medical students' understanding of and exposure to IR based on the recommendations set out by the British Society of Interventional Radiology (BSIR), was sent out to final-year students across 34 UK medical schools. RESULTS: Five hundred and ten responses were collected from 33 out of 34 eligible medical schools. Sixty-four per cent of respondents rated their own IR knowledge as inadequate. On average, only 50% of all subtopics proposed in the BSIR undergraduate curriculum was covered during medical school and 32.7% of respondents were not exposed to any fundamental IR principles and techniques recommended by the BSIR during medical school. Regarding careers, 2.7% of respondents reported a definite interest in pursuing a career in IR. Most respondents (89.8%) felt that there was insufficient undergraduate teaching on IR and that they lacked information to consider pursuing a career in IR (87.5%). CONCLUSION: Insufficient exposure and teaching on IR throughout medical schools have led to a lack of awareness and consideration of IR as a future career choice amongst UK medical students. The re-evaluation of IR teaching in the medical school curricula is needed. In the long-term, such recommendations could provide the much-needed solution to the workforce shortages seen in IR.

Contamination of the central medical air supply with water leading to mass ventilator failure.

Here, we present a case of mass ventilator failure due to contaminated medical air. Multiple ventilators failed routine tests, including almost all of the ventilators in our intensive care unit. A faulty air compressor had led to water contamination of our centre's supply of medical air. Water entered the pipeline supply of air and, hence the ventilators and anaesthetic machines. The disruption of the machines' proportional mixer valve resulted in unreliable delivery of fresh gas flow. This malfunction was discovered during routine pre-use checks, and backup ventilators were available to replace the faulty ventilators. A shortage of equipment was averted due to a serendipitous availability of ventilator stockpiles prepared for the COVID-19 pandemic. Ventilator shortages are commonly described in mass casualty and pandemic scenarios. While there are multiple strategies described in literature to augment and maximise equipment available for mechanical ventilation, stockpiling equipment remains an expensive but necessary component of disaster contingency planning.

Ultrasound-guided day-case wide-bore percutaneous mucin aspiration in advanced pseudomyxoma peritonei.

AIM: To evaluate percutaneous ultrasound-guided day-case mucin aspiration in advanced pseudomyxoma peritonei (PMP) using a wide-bore drain with regards to its safety and efficacy. MATERIALS AND METHODS: All patients who underwent percutaneous mucin aspiration for PMP between 2019-2021 at a single national peritoneal tumour service were included in this study. Under local anaesthesia, a suction-enabled 28-32 F catheter was used for drainage following wire-guided track dilatation. The volume drained and difference in abdominal girth pre- and post-procedure were measured. Patients graded difficulty in breathing and abdominal discomfort pre- and post-procedure. Histology reports were reviewed. RESULTS: Sixteen patients received 56 percutaneous mucin aspirations between 2019-2021. The aetiology was a low-grade appendiceal mucinous neoplasm (LAMN) in 50% of patients. The mean amount of mucin drained was 7,320 ± 3,000ml (range 300-13,500 ml). The mean reduction in abdominal girth post-procedure was 12.2 ± 5 cm (range 0-27 cm). Only grade 1 complications were observed. CONCLUSION: Percutaneous ultrasound-guided day-case aspiration of mucin for advanced and recurrent PMP using a wide-bore drain is a safe and effective procedure. It may be used in the palliative setting or as a bridge to surgery in the very symptomatic patient or if there is a reversible contraindication to surgery.

An Optimised Monophasic Faecal Extraction Method for LC-MS Analysis and Its Application in Gastrointestinal Disease.

Liquid chromatography coupled with mass spectrometry (LC-MS) metabolomic approaches are widely used to investigate underlying pathogenesis of gastrointestinal disease and mechanism of action of treatments. However, there is an unmet requirement to assess faecal metabolite extraction methods for large-scale metabolomics studies. Current methods often rely on biphasic extractions using harmful halogenated solvents, making automation and large-scale studies challenging. The present study reports an optimised monophasic faecal extraction protocol that is suitable for untargeted and targeted LC-MS analyses. The impact of several experimental parameters, including sample weight, extraction solvent, cellular disruption method, and sample-to-solvent ratio, were investigated. It is suggested that a 50 mg freeze-dried faecal sample should be used in a methanol extraction (1:20) using bead beating as the means of cell disruption. This is revealed by a significant increase in number of metabolites detected, improved signal intensity, and wide metabolic coverage given by each of the above extraction parameters. Finally, we addressed the applicability of the method on faecal samples from patients with Crohn's disease (CD) and coeliac disease (CoD), two distinct chronic gastrointestinal diseases involving metabolic perturbations. Untargeted and targeted metabolomic analysis demonstrated the ability of the developed method to detect and stratify metabolites extracted from patient groups and healthy controls (HC), highlighting characteristic changes in the faecal metabolome according to disease. The method developed is, therefore, suitable for the analysis of patients with gastrointestinal disease and can be used to detect and distinguish differences in the metabolomes of CD, CoD, and HC.

Evaluating the Effectiveness of Digital Content Marketing Under Mixed Reality Training Platform on the Online Purchase Intention.

The purpose of this research is to investigate the effectiveness of Digital Content Marketing (DCM) on a Mixed Reality (MR) training platform environment with the consideration of online purchase intention (OPI) through social media. E-commerce today encounters several common issues that cause customers to have reservations to purchase online. With the absence of physical contact points, customers often perceive more risks when making purchase decisions. Furthermore, online retailers often find it hard to engage customers and develop long-term relationships. In this research, a Structural Equation Model (SEM) is proposed to examine the efficacy of DCM from both immediate and long-term OPI. The results examine whether adopting DCM on an MR training platform environment through social media brings positive results in OPI. Empirical research was carried out through online questionnaires collected in 2021 and 2022. A total of 374 questionnaires were qualified for data analysis in this study, conducted with IBM SPSS and AMOS. The results imply that DCM is critical to stimulating both immediate and long-term OPI. The immediate OPI is positively affected by increasing perceived value through MR in DCM. Regarding the long-term OPI, increased customer engagement with DCM under MR environment can cultivate brand trust and significantly affect the long-term OPI.

PRAME immunostain expression in sebaceous lesions, cutaneous carcinomas and adnexal structures.

The use of immunostain for PRAME antigen is well established for cutaneous melanolocytic lesions. However, its staining in other cutaneous structures and lesions is under reported. This study assessed PRAME staining in a large cohort of normal skin tissue, sebaceous lesions, and cutaneous carcinomas to better delineate patterns of PRAME immunoreactivity. PRAME immunostaining was performed on sections of sebaceous lesions and tissue microarrays of basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs). Normal cutaneous adnexal structures were assessed on the sections of sebaceous lesions. For sebaceous lesions and non-lesional sebaceous glands, PRAME immunostaining was assessed for mature, germinative and sebocytes independently. A total of 193 sebaceous lesions, 64 BCCs and 35 SCCs were stained for PRAME immunostain. Staining pattern was predominantly cytoplasmic in normal apocrine glands, germinative sebocytes of sebaceous glands, and hair germs (p<0.001). Lesional sebocytes did not show different staining compared to normal sebaceous glands (p>0.05). Rare nuclear staining was observed in the normal epidermis (0.6%) and junctional melanocytes (4.1%). BCC, SCC and sebaceous carcinoma all showed low levels of PRAME immunoreactivity with variable proportions of cases demonstrating nuclear staining (BCC 59.4%, SCC 37.1%, sebaceous carcinoma 5.3%). PRAME immunostaining is positive in germinative sebocytes, various cutaneous structures and carcinomas. Nuclear staining, identical to melanoma, was observed in normal epidermis, junctional melanocytes, BCCs, SCCs, and sebaceous carcinomas. The pattern of PRAME staining in the skin must be recognised to avoid pitfalls in interpretating PRAME immunostain.

Sarcopenia in Distal Radius Fractures: A Scoping Review.

BACKGROUND: Sarcopenia is an emerging disease that adversely impacts outcomes of older adults across the spectrum of fragility fractures. Few studies have examined sarcopenia in upstream fragility fractures such as the distal radius. Understanding the state of current evidence is essential in defining a research agenda in this critical area of sentinel distal radius fractures and sarcopenia. OBJECTIVES: The aim of this scoping review was to summarize existing literature on sarcopenia in distal radius fracture in older adults, and to identify research areas and gaps to guide future studies. METHODS: We utilized the 5-stage framework of Arksey and O'Malley. We searched studies from 2010 to 2020 relating to «Sarcopenia¼ and «Distal radius fractures¼ in major databases. Two reviewers independently screened articles for inclusion and conducted full text reviews of shortlisted articles. We extracted data on research areas, key findings, and study limitations. RESULTS: Thirteen studies met the inclusion and exclusion criteria. They covered the areas of epidemiology (N=9), risk factors (N=4), basic science (N=2), outcomes (N=1), and diagnostic modalities (N=1). There were no studies on screening/case finding, prognostic scoring, intervention, or health economics. Identified limitations included the lack of clear definition and diagnostic criteria for sarcopenia, and lack of, or inappropriate, control group. Majority of studies were retrospective or cross-sectional in study design. CONCLUSIONS: This scoping review on sarcopenia in distal radius fractures highlighted gaps in research areas and in the rigor of studies conducted, and the need for more prospective cohort and interventional studies. Building upon current consensus criteria, we propose setting a research agenda along the timeline of sarcopenia management, from screening through to intervention and follow-up, which will inform future research in this early disease cohort of fragility fractures.

Global parental leave in surgical careers: differences according to gender, geographical regions and surgical career stages.

BACKGROUND: There is a lack of information regarding the provision of parental leave for surgical careers. This survey study aims to evaluate the experience of maternity/paternity leave and views on work-life balance globally. METHODS: A 55-item online survey in 24 languages was distributed via social media as per CHERRIES guideline from February to March 2020. It explored parental leave entitlements, attitude towards leave taking, financial impact, time spent with children and compatibility of parenthood with surgical career. RESULTS: Of the 1393 (male : female, 514 : 829) respondents from 65 countries, there were 479 medical students, 349 surgical trainees and 513 consultants. Consultants had less than the recommended duration of maternity leave (43.8 versus 29.1 per cent), no paid maternity (8.3 versus 3.2 per cent) or paternity leave (19.3 versus 11.0 per cent) compared with trainees. Females were less likely to have children than males (36.8 versus 45.6 per cent, P = 0.010) and were more often told surgery is incompatible with parenthood (80.2 versus 59.5 per cent, P < 0.001). Males spent less than 20 per cent of their salary on childcare and fewer than 30 hours/week with their children. More than half (59.2 per cent) of medical students did not believe a surgical career allowed work-life balance. CONCLUSION: Surgeons across the globe had inadequate parental leave. Significant gender disparity was seen in multiple aspects.

Ocular leptospirosis in four patients: A diagnostic dilemma.

Leptospirosis is a zoonotic disease that is caused by the pathogenic spirochetes of the genus Leptospira. The infection occurs worldwide and is particularly more common in the tropics. However, it is becoming a neglected reemerging global health disease due to rapid urbanisation. This disease has a wide range of clinical manifestations from flu-like illness to pneumonia, acute kidney injury, etc. But many uncommon clinical findings are being reported as well. In this paper, we report four patients who presented initially with uveitic features who turned out serologically positive for Leptospira after extensive investigations.

The 2021 WHO Classification of Tumors of the Central Nervous System: a summary.

The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, is the sixth version of the international standard for the classification of brain and spinal cord tumors. Building on the 2016 updated fourth edition and the work of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy, the 2021 fifth edition introduces major changes that advance the role of molecular diagnostics in CNS tumor classification. At the same time, it remains wedded to other established approaches to tumor diagnosis such as histology and immunohistochemistry. In doing so, the fifth edition establishes some different approaches to both CNS tumor nomenclature and grading and it emphasizes the importance of integrated diagnoses and layered reports. New tumor types and subtypes are introduced, some based on novel diagnostic technologies such as DNA methylome profiling. The present review summarizes the major general changes in the 2021 fifth edition classification and the specific changes in each taxonomic category. It is hoped that this summary provides an overview to facilitate more in-depth exploration of the entire fifth edition of the WHO Classification of Tumors of the Central Nervous System.

25S rDNA genotyping and multi-locus sequence typing of Candida albicans of pathogenic and commensal origins in the Klang Valley, Malaysia.

Candida albicans is an important opportunistic fungal pathogen capable of causing fatal systemic infections in humans. Presently in Malaysia, there is little information available on the genetic diversity of this organism and trends in behavioural characteristics. In this project, three genotyping methods: 25S rDNA genotyping, Alternative Lengthening of Telomerase (ALT) sequence typing and Multi-Locus Sequence Typing (MLST) were applied to study the genetic diversity of strains from infected hospital in-patients and asymptomatic individuals in the community. The results showed that, with the 25S rDNA genotyping, as in other parts of the world, the most common genotype was type A which accounted for approximately 70% of the 111 isolates tested. Further typing with the ALT sequence showed type 3 to be the most common in the isolates tested. MLST analysis revealed many possibly novel sequence types, as well as a statistically significant association between pathogenicity and a group of closely related isolates, most of which were from hospital samples. Further work on genotypes associated with enhanced virulence will help to clarify the value of genotyping for clinical and epidemiological investigations.

cIMPACT-NOW update 6: new entity and diagnostic principle recommendations of the cIMPACT-Utrecht meeting on future CNS tumor classification and grading.

cIMPACT-NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was established to evaluate and make practical recommendations on recent advances in the field of CNS tumor classification, particularly in light of the rapid progress in molecular insights into these neoplasms. For Round 2 of its deliberations, cIMPACT-NOW Working Committee 3 was reconstituted and convened in Utrecht, The Netherlands, for a meeting designed to review putative new CNS tumor types in advance of any future World Health Organization meeting on CNS tumor classification. In preparatory activities for the meeting and at the actual meeting, a list of possible entities was assembled and each type and subtype debated. Working Committee 3 recommended that a substantial number of newly recognized types and subtypes should be considered for inclusion in future CNS tumor classifications. In addition, the group endorsed a number of principles-relating to classification categories, approaches to classification, nomenclature, and grading-that the group hopes will also inform the future classification of CNS neoplasms.

C-reactive protein level as a predictor of difficult emergency laparoscopic cholecystectomy.

Background: Studies focused on C-reactive protein (CRP) as a marker of difficult laparoscopic cholecystectomy are limited to small case series. The aim of this study was to evaluate the association between preoperative CRP concentration and difficulty of laparoscopic cholecystectomy in patients admitted with a biliary emergency presentation. Methods: Patients with an emergency admission for biliary disease treated between 2012 and 2017 with a documented preoperative CRP level were analysed. Elective patients and those with other concurrent causes of increased CRP concentration were excluded. The intraoperative difficulty grade was based on the Nassar scale. Statistical analysis was conducted to determine the association of preoperative CRP level with difficulty grading, adjusted for the interval to surgery. Results: A total of 804 emergency patients were included. The mean preoperative peak CRP level was 64·7 mg/l for operative difficulty grade I, 69·6 mg/l for grade II, 98·2 mg/l for grade III, 217·5 mg/l for grade IV and 193·1 mg/l for grade V, indicating a significant association between CRP concentration and Nassar grade (P < 0·001). Receiver operating characteristic (ROC) curve analysis showed an area under the curve of 0·78 (95 per cent c.i. 0·75 to 0·82), differentiating patients with grade I-III from those with grade IV-V operative difficulty. ROC curve analysis found a cut-off CRP value of 90 mg/l, with 71·5 per cent sensitivity and 70·5 per cent specificity in predicting operative difficulty of grade IV or V. Logistic regression analysis found preoperative peak CRP level to be predictive of Nassar grade I-III versus grade IV-V operative difficulty, also when adjusted for timing of surgery (odds ratio 5·90, 95 per cent c.i. 2·80 to 12·50). Conclusion: Raised preoperative CRP levels are associated with greater operative difficulty based on Nassar scale grading.

Detecting Graft-Derived Cell-Free DNA Through Amplification Refractory Mutation System Polymerase Chain Reaction in Living-Donor Liver Transplantation: Report of 2 Cases.

Graft-derived cell-free DNA (Gcf-DNA) is a non-invasive biomarker to monitor graft function. There are different methods to quantify Gcf-DNA, such as the classical Y-chromosome method and the latest digital droplet polymerase chain reaction method. In this study, we reported 2 patients genetically diagnosed with propionic acidemia (PA) went through living-donor liver transplantation (LDLT), and monitoring the change of Gcf-DNA examined by the amplification refractory mutation system polymerase chain reaction (ARMS-PCR) method. Two patients went through the operation successfully, and a 5 mL whole blood specimen was collected at 6 specific time points (day 0, day 1, day 7, day 14, day 30, day 60). The comparison of Gcf-DNA and the routine liver function showed that they have similar change-tendency curves, with the curves reaching the top at day 1 because of ischemia-reperfusion injury and generally declining from day 7-day 60 along with recovery of the patient. Applying the ARMS-PCR method to detect Gcf-DNA can be done without knowing the donor information and is not limited by donor-recipient-sex-mismatch condition. In conclusion, Gcf-DNA is a promising biomarker that can monitor graft function in LDLT, and we will apply it in more samples and observe it long term to validate its efficiency in the future.