Characterization of central manifestations in patients with Niemann-Pick disease type C.

PURPOSE: Niemann-Pick disease type C (NPC) is a rare lysosomal storage disease characterized by progressive neurodegeneration and neuropsychiatric symptoms. This study investigated pathophysiological mechanisms underlying motor deficits, particularly speech production, and cognitive impairment. METHODS: We prospectively phenotyped 8 adults with NPC and age-sex-matched healthy controls using a comprehensive assessment battery, encompassing clinical presentation, plasma biomarkers, hand-motor skills, speech production, cognitive tasks, and (micro-)structural and functional central nervous system properties through magnetic resonance imaging. RESULTS: Patients with NPC demonstrated deficits in fine-motor skills, speech production timing and coordination, and cognitive performance. Magnetic resonance imaging revealed reduced cortical thickness and volume in cerebellar subdivisions (lobule VI and crus I), cortical (frontal, temporal, and cingulate gyri) and subcortical (thalamus and basal ganglia) regions, and increased choroid plexus volumes in NPC. White matter fractional anisotropy was reduced in specific pathways (intracerebellar input and Purkinje tracts), whereas diffusion tensor imaging graph theory analysis identified altered structural connectivity. Patients with NPC exhibited altered activity in sensorimotor and cognitive processing hubs during resting-state and speech production. Canonical component analysis highlighted the role of cerebellar-cerebral circuitry in NPC and its integration with behavioral performance and disease severity. CONCLUSION: This deep phenotyping approach offers a comprehensive systems neuroscience understanding of NPC motor and cognitive impairments, identifying potential central nervous system biomarkers.

Cachexia index for prognostication in surgical patients with locally advanced oesophageal or gastric cancer: multicentre cohort study.

BACKGROUND: Features of cancer cachexia adversely influence patient outcomes, yet few currently inform clinical decision-making. This study assessed the value of the cachexia index (CXI), a novel prognostic marker, in patients for whom neoadjuvant chemotherapy and surgery for oesophagogastric cancer is planned. METHODS: Consecutive patients newly diagnosed with locally advanced (T3-4 or at least N1) oesophagogastric cancer between 1 January 2010 and 31 December 2015 were identified through the West of Scotland and South-East Scotland Cancer Networks. CXI was calculated as (L3 skeletal muscle index) × (serum albumin)/(neutrophil lymphocyte ratio). Sex-stratified cut-off values were determined based on the area under the curve (AUC), and patients were divided into groups with low or normal CXI. Primary outcomes were disease progression during neoadjuvant chemotherapy and overall survival (at least 5 years of follow-up). RESULTS: Overall, 385 patients (72% men, median age 66 years) were treated with neoadjuvant chemotherapy for oesophageal (274) or gastric (111) cancer across the study interval. Although patients with a low CXI (men: CXI below 52 (AUC 0.707); women: CXI below 41 (AUC 0.759)) were older with more co-morbidity, disease characteristics were comparable to those in patients with a normal CXI. Rates of disease progression during neoadjuvant chemotherapy, leading to inoperability, were higher in patients with a low CXI (28 versus 12%; adjusted OR 3.07, 95% c.i. 1.67 to 5.64; P < 0.001). Low CXI was associated with worsened postoperative mortality (P = 0.019) and decreased overall survival (median 14.9 versus 56.9 months; adjusted HR 1.85, 1.42 to 2.42; P < 0.001). CONCLUSION: CXI is associated with disease progression, worse postoperative mortality, and overall survival, and could improve prognostication and decision-making in patients with locally advanced oesophagogastric cancer.

Non-invasive assessment of stimulation-specific changes in cerebral glucose metabolism with functional PET.

PURPOSE: Functional positron emission tomography (fPET) with [18F]FDG allows quantification of stimulation-induced changes in glucose metabolism independent of neurovascular coupling. However, the gold standard for quantification requires invasive arterial blood sampling, limiting its widespread use. Here, we introduce a novel fPET method without the need for an input function. METHODS: We validated the approach using two datasets (DS). For DS1, 52 volunteers (23.2 ± 3.3 years, 24 females) performed Tetris® during a [18F]FDG fPET scan (bolus + constant infusion). For DS2, 18 participants (24.2 ± 4.3 years, 8 females) performed an eyes-open/finger tapping task (constant infusion). Task-specific changes in metabolism were assessed with the general linear model (GLM) and cerebral metabolic rate of glucose (CMRGlu) was quantified with the Patlak plot as reference. We then estimated simplified outcome parameters, including GLM beta values and percent signal change (%SC), and compared them, region and whole-brain-wise. RESULTS: We observed higher agreement with the reference for DS1 than DS2. Both DS resulted in strong correlations between regional task-specific beta estimates and CMRGlu (r = 0.763…0.912). %SC of beta values exhibited strong agreement with %SC of CMRGlu (r = 0.909…0.999). Average activation maps showed a high spatial similarity between CMRGlu and beta estimates (Dice = 0.870…0.979) as well as %SC (Dice = 0.932…0.997), respectively. CONCLUSION: The non-invasive method reliably estimates task-specific changes in glucose metabolism without blood sampling. This streamlines fPET, albeit with the trade-off of being unable to quantify baseline metabolism. The simplification enhances its applicability in research and clinical settings.

Prodromal Parkinson's disease and the catecholaldehyde hypothesis: Insight from olfactory bulb organotypic cultures.

Parkinson's disease (PD) is a progressive, neurodegenerative disorder with an increasing incidence, unknown etiology, and is currently incurable. Advances in understanding the pathological mechanisms at a molecular level have been slow, with little attention focused on the early prodromal phase of the disease. Consequently, the development of early-acting disease-modifying therapies has been hindered. The olfactory bulb (OB), the brain region responsible for initial processing of olfactory information, is particularly affected early in PD at both functional and molecular levels but there is little information on how the cells in this region are affected by disease. Organotypic and primary OB cultures were developed and characterized. These platforms were then used to assess the effects of 3,4-dihydroxyphenylacetylaldehyde (DOPAL), a metabolite of dopamine present in increased levels in post-mortem PD tissue and which is thought to contribute to PD pathogenesis. Our findings showed that DOPAL exposure can recapitulate many aspects of PD pathology. Oxidative stress, depolarization of mitochondrial membranes, and neurodegeneration were all induced by DOPAL addition, as were measured transcriptomic changes consistent with those reported in PD clinical studies. These olfactory models of prodromal disease lend credence to the catecholaldehyde hypothesis of PD and provide insight into the mechanisms by which the OB may be involved in disease progression.

The prognostic impact of pre-treatment cachexia in resectional surgery for oesophagogastric cancer: a meta-analysis and meta-regression.

BACKGROUND: Cancer cachexia is not purely an end-stage phenomenon and can influence the outcomes of patients with potentially curable disease. This review examines the effect of pre-treatment cachexia on overall survival, in patients undergoing surgical resection of oesophagogastric cancer. METHODS: A systematic literature search of MEDLINE, EMBASE and Cochrane Library databases was conducted, from January 2000 to May 2022, to identify studies reporting the influence of cachexia on patients undergoing an oesophagogastric resection for cancer with curative intent. Meta-analyses of the primary (overall survival) and secondary (disease-free survival and postoperative mortality) outcomes were performed using random-effects modelling. Meta-regression was used to examine disease stage as a potential confounder. RESULTS: Ten non-randomized studies, comprising 7186 patients, were eligible for inclusion. The prevalence of pre-treatment cachexia was 35 per cent (95 per cent c.i.: 24-47 per cent). Pooled adjusted hazard ratios showed that cachexia was adversely associated with overall survival (HR 1.46, 95 per cent c.i.: 1.31-1.60, P < 0.001). Meta-analysis of proportions identified decreased overall survival at 1-, 3- and 5-years in cachectic cohorts. Pre-treatment cachexia was not a predictor of disease-free survival and further data are required to establish its influence on postoperative mortality. The proportion of patients with stage III/IV disease was a significant moderator of between-study heterogeneity. Cachexia may have a greater influence on overall survival in studies where more patients have a locally advanced malignancy. CONCLUSION: Pre-treatment cachexia adversely influences overall survival following resection of an oesophagogastric malignancy.

ABCB1 variants and sex affect serotonin transporter occupancy in the brain.

Strategies to personalize psychopharmacological treatment promise to improve efficacy and tolerability. We measured serotonin transporter occupancy immediately after infusion of the widely prescribed P-glycoprotein substrate citalopram and assessed to what extent variants of the ABCB1 gene affect drug target engagement in the brain in vivo. A total of 79 participants (39 female) including 31 patients with major depression and 48 healthy volunteers underwent two PET/MRI scans with the tracer [11C]DASB and placebo-controlled infusion of citalopram (8 mg) in a cross-over design. We tested the effect of six ABCB1 single nucleotide polymorphisms and found lower SERT occupancy in ABCB1 rs2235015 minor allele carriers (n = 26, MAF = 0.18) compared to major allele homozygotes (t73 = 2.73, pFWE < 0.05) as well as in men compared to women (t73 = 3.33, pFWE < 0.05). These effects were robust to correction for citalopram plasma concentration, age and diagnosis. From occupancy we derived the ratio of occupied to unoccupied SERT, because in theory this measure is equal to the product of drug affinity and concentration at target sites. A model combining genotype with basic clinical variables, predicted that, at the same dosage, occupied to unoccupied SERT ratio was -14.48 ± 5.38% lower in rs2235015 minor allele carriers, +19.10 ± 6.95% higher in women, -4.83 ± 2.70% lower per 10 kg bodyweight, and -2.68 ± 3.07% lower per 10 years of age. Our results support the exploration of clinical algorithms with adjustment of initial citalopram dosing and highlight the potential of imaging-genetics for precision pharmacotherapy in psychiatry.

White matter association tracts underlying language and theory of mind: An investigation of 809 brains from the Human Connectome Project.

Language and theory of mind (ToM) are the cognitive capacities that allow for the successful interpretation and expression of meaning. While functional MRI investigations are able to consistently localize language and ToM to specific cortical regions, diffusion MRI investigations point to an inconsistent and sometimes overlapping set of white matter tracts associated with these two cognitive domains. To further examine the white matter tracts that may underlie these domains, we use a two-tensor tractography method to investigate the white matter microstructure of 809 participants from the Human Connectome Project. 20 association white matter tracts (10 in each hemisphere) are uniquely identified by leveraging a neuroanatomist-curated automated white matter tract atlas. The fractional anisotropy (FA), mean diffusivity (MD), and number of streamlines (NoS) are measured for each white matter tract. Performance on neuropsychological assessments of semantic memory (NIH Toolbox Picture Vocabulary Test, TPVT) and emotion perception (Penn Emotion Recognition Test, PERT) are used to measure critical subcomponents of the language and ToM networks, respectively. Regression models are constructed to examine how structural measurements of left and right white matter tracts influence performance across these two assessments. We find that semantic memory performance is influenced by the number of streamlines of the left superior longitudinal fasciculus III (SLF-III), and emotion perception performance is influenced by the number of streamlines of the right SLF-III. Additionally, we find that performance on both semantic memory & emotion perception is influenced by the FA of the left arcuate fasciculus (AF). The results point to multiple, overlapping white matter tracts that underlie the cognitive domains of language and ToM. Results are discussed in terms of hemispheric dominance and concordance with prior investigations.

Establishing electroporation thresholds for targeted cell specific cardiac ablation in a 2D culture model.

BACKGROUND: Irreversible electroporation has emerged as a new modality to overcome issues associated with other energy sources for cardiac ablation. Strong evidence on the optimal, effective, and selective voltage threshold is lacking for both in vitro and preclinical in vivo studies. The aim of this study is to examine the optimal threshold for selective cell ablation on cardiac associated cell types. METHODS: Conventional monophasic and biphasic pulses of different field strength were delivered in a monolayer culture system of cardiomyocytes, neurons, and adipocytes. The dynamics of cell death mechanisms were examined at different time points. RESULTS: Neurons exhibit higher susceptibility to electroporation and cell death at higher field strength of 1250 V/cm in comparison to cardiomyocytes. Cardiac adipocytes showed lower susceptibility to electroporation in comparison to other cell types. A significant proportion of cardiomyocytes recovered after 24 h postelectroporation, while neuronal cell death remained consistent but with a significant delayed cell death at a higher voltage threshold. Caspase 3/7 activity was observed in both cardiomyocytes and neurons, with a higher level of activity in cardiomyocytes in response to electroporation. Biphasic and monophasic pulses showed no significant difference in both cell types, and significantly lower cell death in neurons when inter pulse interval was reduced. CONCLUSIONS: This study presents important findings on the differences in the susceptibility of neurons and cardiomyocytes to irreversible electroporation. Cell type alone yielded selective and different dynamics in terms of the evolution and signaling mechanism of cell death in response to electroporation.

Understanding Cancer Cachexia and Its Implications in Upper Gastrointestinal Cancers.

OPINION STATEMENT: Considerable advances in the investigation and management of oesophagogastric cancer have occurred over the last few decades. While the historically dismal prognosis associated with these diseases has improved, outcomes remain very poor. Cancer cachexia is an often neglected, yet critical, factor for this patient group. There is a persuasive argument that a lack of assessment and treatment of cachexia has limited progress in oesophagogastric cancer care. In the curative setting, the stage of the host (based on factors such as body composition, function, and inflammatory status), alongside tumour stage, has the potential to influence treatment efficacy. Phenotypical features of cachexia may decrease the survival benefit of (peri-operative) chemoradiotherapy, immunotherapy, or surgical resection in patients with potentially curative malignancy. Most patients with oesophagogastric cancer unfortunately present with disease which is not amenable, or is unlikely to respond, to these treatments. In the palliative setting, host factors can similarly impair results from systemic anti-cancer therapies, cause adverse symptoms, and reduce quality of life. To optimise treatment pathways and enhance patient outcomes, we must utilise this information during clinical decision-making. As our understanding of the genesis of cancer cachexia improves and more therapeutic options, ranging from basic (e.g. exercise and nutrition) to targeted (e.g. anti-IL1 α and anti-GDF-15), become available, there can be grounds for optimism. Cachexia can change from a hitherto neglected condition to an integral part of the oesophagogastric cancer treatment pathway.

Temporal Trends in the Investigation, Management and Outcomes of Acute Appendicitis over 15 Years in the North of England: A Retrospective Cohort Study.

BACKGROUND: Acute appendicitis is a common surgical emergency with an estimated lifetime prevalence of 8.6% for males and 6.7% for females. Despite the frequency of presentation, considerable variation in clinical practice exists. Our study aimed to explore temporal trends in the investigation, treatment and outcomes for patients with appendicitis between 2002 and 2016. METHODS: Data collected included all patients aged ≥16 years across the NHS trusts in Northern England between 01/01/2002 and 31/12/2016 diagnosed with appendicitis. Patient demographics, co-morbidity and management strategies were included. Outcomes of interest were length of stay and inpatient mortality. RESULTS: Over a 15 years period, 22,137 patients were admitted with acute appendicitis. A consistent male preponderance (n = 11,952, 54%) was observed, and median age increased over time (2002-2006: 36.4 vs. 2012-2016: 39.5, p < 0.001). Comorbidity of patients also increased (p < 0.001) in recent years. Computed tomography (CT) use increased from 0.8 to 21.9% (p < 0.001) over the study period. Following CT scanning, there was a longer time to theatre (1.22 vs. 0.70 days, p < 0.001), and patients were more frequently managed non-operatively (23.8% vs. 5.7%, p < 0.001). The utilisation of laparoscopic approaches significantly increased from 4.1 to 70.4% (p < 0.001). Laparoscopic patients had a shorter median length of stay (2.97 days) when compared with open surgery (4.44 days) or non-operative (6.19 days) patients. The 30-day mortality rate was 0.33% overall and decreased with time (p = 0.004). CONCLUSIONS: CT and laparoscopic surgery are increasingly utilised in the management of appendicitis. Along with other advances in clinical practice, they have led to reduced lengths of stay and mortality.

Design of a Planner-Based Intervention to Facilitate Diet Behaviour Change in Type 2 Diabetes.

Diet behaviour is influenced by the interplay of the physical and social environment as well as macro-level and individual factors. In this study, we focus on diet behaviour at an individual level and describe the design of a behaviour change artefact to support diet behaviour change in persons with type 2 diabetes. This artefact was designed using a human-centred design methodology and the Behaviour Change Wheel framework. The designed artefact sought to support diet behaviour change through the addition of healthy foods and the reduction or removal of unhealthy foods over a 12-week period. These targeted behaviours were supported by the enabling behaviours of water consumption and mindfulness practice. The artefact created was a behaviour change planner in calendar format, that incorporated behaviour change techniques and which focused on changing diet behaviour gradually over the 12-week period. The behaviour change planner forms part of a behaviour change intervention which also includes a preparatory workbook exercise and one-to-one action planning sessions and can be customised for each participant.

NRXN1α+/- is associated with increased excitability in ASD iPSC-derived neurons.

BACKGROUND: NRXN1 deletions are identified as one of major rare risk factors for autism spectrum disorder (ASD) and other neurodevelopmental disorders. ASD has 30% co-morbidity with epilepsy, and the latter is associated with excessive neuronal firing. NRXN1 encodes hundreds of presynaptic neuro-adhesion proteins categorized as NRXN1α/ß/γ. Previous studies on cultured cells show that the short NRXN1ß primarily exerts excitation effect, whereas the long NRXN1α which is more commonly deleted in patients involves in both excitation and inhibition. However, patient-derived models are essential for understanding functional consequences of NRXN1α deletions in human neurons. We recently derived induced pluripotent stem cells (iPSCs) from five controls and three ASD patients carrying NRXN1α+/- and showed increased calcium transients in patient neurons. METHODS: In this study we investigated the electrophysiological properties of iPSC-derived cortical neurons in control and ASD patients carrying NRXN1α+/- using patch clamping. Whole genome RNA sequencing was carried out to further understand the potential underlying molecular mechanism. RESULTS: NRXN1α+/- cortical neurons were shown to display larger sodium currents, higher AP amplitude and accelerated depolarization time. RNASeq analyses revealed transcriptomic changes with significant upregulation glutamatergic synapse and ion channels/transporter activity including voltage-gated potassium channels (GRIN1, GRIN3B, SLC17A6, CACNG3, CACNA1A, SHANK1), which are likely to couple with the increased excitability in NRXN1α+/- cortical neurons. CONCLUSIONS: Together with recent evidence of increased calcium transients, our results showed that human NRXN1α+/- isoform deletions altered neuronal excitability and non-synaptic function, and NRXN1α+/- patient iPSCs may be used as an ASD model for therapeutic development with calcium transients and excitability as readouts.

Allergen labelling: Current practice and improvement from a communication perspective.

BACKGROUND: Allergen information on product labels is crucial in food allergy management, though inadequacy in current labelling practices is one of the major causes for accidental reactions upon consuming prepacked food products. OBJECTIVE: This study analyses current status of communicating allergen information on food labels and provides practical recommendations for improving the label format based on communication theory. METHODS: Product labels (N 288) of seven food categories from private label products and brands were obtained at three retailers in the Netherlands. Information regarding the 14 EU-regulated allergens was evaluated by the frequency of emphasizing allergens in the ingredient list, use of precautionary allergen labelling (PAL), icons and an allergen information section. Effectiveness of communication was assessed evaluating readability and findability of information on allergens using principles of Gestalt and Cognitive Load theories. RESULTS: As requested by EU regulation 1169/2011, emphasizing allergens in the ingredient list was almost 100%, all other presentations of information on allergens on labels was highly diverse. A separate allergen information section was present on most private label products. This section could, but not necessarily did, repeat allergens from the ingredient list and/or give a PAL. Brands often provided a PAL at the end of the ingredient list. Part of the products displayed an icon at different locations of the label. Label background, a lack of cohesion and variation in location of topics hamper the identification of relevant information on allergens by (allergic) consumers. Recommendations include a standardized order for mandatory and voluntary topics on the label and a separate allergen information section. CONCLUSION AND CLINICAL RELEVANCE: Overall, consumers encounter a wide and inconsistent range in ways of presentation of allergen information on labels. Standardization according to basic design principles can improve usability and support safe food purchases for allergic consumers.

Poor understanding of allergen labelling by allergic and non-allergic consumers.

BACKGROUND: Understanding consumers' interpretation of allergy information is crucial for effective food safety policies. We evaluated consumer understanding of allergy information on foods in controlled, experimental studies. METHOD: Using 18 packaged foods, we evaluated consumer understanding of information about allergens in two experiments: First, a comparison of foods with no stated allergen versus allergen as a stated ingredient versus a precautionary allergen label (PAL); second, a comparison of three common variants of PAL. In each experiment, consumers with and without self-reported food allergy were asked to estimate the risk of allergic reaction and to rate the comprehensibility of the allergen information. In the second experiment, consumers were also asked which form of PAL they preferred. RESULTS: Risk of reaction was assessed as high and low for foods with the allergen stated as ingredient, or without any mention of allergen. However, risk assessment for PAL varied and was judged as higher by non-allergic than allergic participants (82% vs. 58%, p < .001). Understanding of risk associated with PAL also varied by health literacy (p < .001). Both allergic and non-allergic consumers judged all forms of allergy information to be unclear, especially products with no allergy information for non-allergic consumers. Products with a 'Produced in a Factory' PAL were perceived as less risky than 'May contain' or 'Traces of' PALs (p < .001), less than 40% of participants judged PAL information to be comprehensible, and participants preferred 'May contain' over the other PALs. CONCLUSION: Both allergic and non-allergic consumers find allergen information difficult to interpret on packaged foods and misunderstand PAL, incorrectly distinguishing different risk levels for different PAL wording. Clearer allergy information guidelines are called for, and the use of only one PAL wording is recommended.

Measurement of the Charge-Averaged Elastic Lepton-Proton Scattering Cross Section by the OLYMPUS Experiment.

We report the first measurement of the average of the electron-proton and positron-proton elastic scattering cross sections. This lepton charge-averaged cross section is insensitive to the leading effects of hard two-photon exchange, giving more robust access to the proton's electromagnetic form factors. The cross section was extracted from data taken by the OLYMPUS experiment at DESY, in which alternating stored electron and positron beams were scattered from a windowless gaseous hydrogen target. Elastic scattering events were identified from the coincident detection of the scattered lepton and recoil proton in a large-acceptance toroidal spectrometer. The luminosity was determined from the rates of Møller, Bhabha, and elastic scattering in forward electromagnetic calorimeters. The data provide some selectivity between existing form factor global fits and will provide valuable constraints to future fits.

The impact of surgical subspecialization on patient outcomes following emergency colorectal resections in the north of England: a retrospective cohort study.

AIM: Emergency colorectal surgery is associated with significant morbidity and mortality. Most general surgeons have a subspecialty, which forms the focus of their elective work, allowing development of specialist skill sets. The aim of this study was to assess the impact of consultant subspecialization on patient outcomes following emergency colorectal resections. METHODS: Data were requested for all emergency admissions under a general surgeon between 1 January 2002 and 31 December 2016 within the north of England. These were acquired from individual Trusts following Caldicott approval. Data included demographics, diagnoses and any procedures undertaken. Patients were assigned to cohorts based on the subspecialist interest of the consultant they were under the care of. The primary outcome of interest was 30-day postoperative mortality. Categorical data were compared with the chi-squared test, and continuous data with the t test or ANOVA. A logistic regression model determined factors associated with 30-day in-hospital mortality. RESULTS: Overall, 7648 emergency colorectal resections were performed with a 30-day postoperative mortality of 13.8%. This was significantly lower if the responsible consultant was a colorectal surgeon compared with other general surgery subspecialties (11.8% vs. 15.2%, P < 0.001). This was significant on univariate analysis (OR 0.75, P < 0.001); however, following multivariable adjustment, this was not statistically significant (P = 0.380). The colorectal specialists had a higher laparoscopy rate than their colleagues-9.8% versus 6.8% (P < 0.001). Stoma rates were also lower (46.9% vs. 51.0%, P = 0.001) and anastomosis rates higher (55.9% vs. 49.3%, P < 0.001) amongst colorectal surgeons. CONCLUSION: These findings add to the growing body of evidence that patient outcomes may be improved by involving subspecialists in colorectal emergencies.

In Vitro Model to Investigate Communication between Dorsal Root Ganglion and Spinal Cord Glia.

Chronic discogenic back pain is associated with increased inflammatory cytokine levels that can influence the proximal peripheral nervous system, namely the dorsal root ganglion (DRG). However, transition to chronic pain is widely thought to involve glial activation in the spinal cord. In this study, an in vitro model was used to evaluate the communication between DRG and spinal cord glia. Primary neonatal rat DRG cells were treated with/without inflammatory cytokines (TNF-α, IL-1ß, and IL-6). The conditioned media were collected at two time points (12 and 24 h) and applied to spinal cord mixed glial culture (MGC) for 24 h. Adult bovine DRG and spinal cord cell cultures were also tested, as an alternative large animal model, and results were compared with the neonatal rat findings. Compared with untreated DRG-conditioned medium, the second cytokine-treated DRG-conditioned medium (following medium change, thus containing solely DRG-derived molecules) elevated CD11b expression and calcium signal in neonatal rat microglia and enhanced Iba1 expression in adult bovine microglia. Cytokine treatment induced a DRG-mediated microgliosis. The described in vitro model allows the use of cells from large species and may represent an alternative to animal pain models (3R principles).

Decision analysis of minimally invasive management options for cholecysto-choledocholithiasis.

BACKGROUND: The management of cholecysto-choledocholithiasis is controversial with the risks and benefits of one versus two-stage approaches debated. This study aims to perform decision analysis of minimally invasive laparo-endoscopic approaches. METHODS: An advanced decision tree was constructed to compare pre, intra and post-operative ERCP and laparoscopic common bile duct exploration in terms of primary ductal clearance and significant complications for patients intended to undergo laparoscopic cholecystectomy. Transition probabilities were calculated from randomised controlled trials following a comprehensive literature search. Model uncertainties were extensively tested through deterministic and probabilistic Monte Carlo sensitivity analysis. Utility outcomes were 1 and 0.5 for successful primary clearance without and with complications, respectively, and 0 for failure of primary clearance of the duct. RESULTS: Twenty-one studies (n = 2697) were included in the analysis. At base case analysis, a laparo-endoscopic rendezvous approach had the highest utility output (0.90; no complication probability: 0.87/complication probability 0.06). Laparoscopic common bile duct exploration was ranked second with a utility output 0.87 (no complication probability: 0.82/complication probability 0.10). Pre-operative ERCP utility score was 0.84 (no complication probability: 0.78/ complication probability 0.11) and post-operative ERCP utility score was 0.78 (no complication probability: 0.71/complication probability 0.13). Monte Carlo analysis showed that laparo-endoscopic rendezvous and laparoscopic common bile duct exploration had an equal mean utility output of 0.57 (standard deviation 0.36; variance 0.13; 95% confidence interval 0.00-0.99 versus standard deviation 0.34; variance 0.12; 95% confidence interval 0.01-0.98). Laparo-endoscopic rendezvous had a superior treatment selection frequency of 39.93% followed by laparoscopic bile duct exploration (36.11%), pre-operative ERCP (20.67%) and post-operative ERCP (2.99%). CONCLUSION: One-stage approach to the management of cholecysto-choledocholithiasis is superior to two-stage, in terms of primary clearance of the duct and risk of operative morbidity. Laparo-endoscopic rendezvous approach could offer marginal additional benefit but more high-quality randomised controlled trials are needed.

The prospects of sitting 'end of year' open book exams in the light of COVID-19: A medical student's perspective.

Medical schools in the UK have been forced to dramatically restructure teaching and assessment amidst the Coronavirus (COVID-19) pandemic. As part of this, some have opted to assess progression through open book examinations (OBE). I aim to share my thoughts as an unsettled 4th year medical student about to embark on my first set of clinical exams conducted in this format. The difficulties associated with preparing for examinations under such unique and challenging circumstances cannot be underestimated. Working from home, during social distancing, surrounds students with the extra family stresses that we are all facing during this pandemic. This combined with a new, unfamiliar examination format will inevitably lead to students feeling daunted. While some would argue that an OBE may reward good problem solvers, students still require a strong foundation of knowledge. The luxury of reference will not be afforded in all clinical settings thus leading to concerns regarding students skimming over essential learning points. Furthermore, we cannot ignore the increased opportunity for academic misconduct resulting from an open book assessment format. Why are medical schools placing undue stress on students who could instead focus their attention on living compassionately for others during this difficult time?