Determining Cognitive Workload Using Physiological Measurements: Pupillometry and Heart-Rate Variability.

The adoption of Industry 4.0 technologies in manufacturing systems has accelerated in recent years, with a shift towards understanding operators' well-being and resilience within the context of creating a human-centric manufacturing environment. In addition to measuring physical workload, monitoring operators' cognitive workload is becoming a key element in maintaining a healthy and high-performing working environment in future digitalized manufacturing systems. The current approaches to the measurement of cognitive workload may be inadequate when human operators are faced with a series of new digitalized technologies, where their impact on operators' mental workload and performance needs to be better understood. Therefore, a new method for measuring and determining the cognitive workload is required. Here, we propose a new method for determining cognitive-workload indices in a human-centric environment. The approach provides a method to define and verify the relationships between the factors of task complexity, cognitive workload, operators' level of expertise, and indirectly, the operator performance level in a highly digitalized manufacturing environment. Our strategy is tested in a series of experiments where operators perform assembly tasks on a Wankel Engine block. The physiological signals from heart-rate variability and pupillometry bio-markers of 17 operators were captured and analysed using eye-tracking and electrocardiogram sensors. The experimental results demonstrate statistically significant differences in both cardiac and pupillometry-based cognitive load indices across the four task complexity levels (rest, low, medium, and high). Notably, these developed indices also provide better indications of cognitive load responding to changes in complexity compared to other measures. Additionally, while experts appear to exhibit lower cognitive loads across all complexity levels, further analysis is required to confirm statistically significant differences. In conclusion, the results from both measurement sensors are found to be compatible and in support of the proposed new approach. Our strategy should be useful for designing and optimizing workplace environments based on the cognitive load experienced by operators.

Unsedated Transnasal Endoscopy: A Safe, Well-Tolerated and Accurate Alternative to Standard Diagnostic Peroral Endoscopy.

Diagnostic unsedated transnasal endoscopy (uTNE) has been proven to be a safe and well-tolerated procedure. Although its utilization in the United Kingdom (UK) is increasing, it is currently available in only a few centers. Through consideration of recent studies, we aimed to perform an updated review of the technological advances in uTNE, consider their impact on diagnostic accuracy, and to determine the role of uTNE in the COVID-19 era. Current literature has shown that the diagnostic accuracy of uTNE for identification of esophageal pathology is equivalent to conventional esophagogastroduodenoscopy (cEGD). Concerns regarding suction and biopsy size have been addressed by the introduction of TNE scopes with working channels of 2.4 mm. Advances in imaging have improved detection of early gastric cancers. The procedure is associated with less cardiac stress and reduced aerosol production; when combined with no need for sedation and improved rates of patient turnover, uTNE is an efficient and safe alternative to cEGD in the COVID-19 era. We conclude that advances in technology have improved the diagnostic accuracy of uTNE to the point where it could be considered the first line diagnostic endoscopic investigation in the majority of patients. It could also play a central role in the recovery of diagnostic endoscopic services during the COVID-19 pandemic.

In utero Zika virus exposure and neurodevelopment at 24 months in toddlers normocephalic at birth: a cohort study.

BACKGROUND: In utero exposure to Zika virus (ZIKV) is known to be associated with birth defects. The impact of in utero ZIKV exposure on neurodevelopmental outcomes in early childhood remains unclear. The objective of this study was to determine the impact of in utero ZIKV exposure on neurodevelopment at 24 months of age among toddlers who were born normocephalic to women who were pregnant during the 2016 ZIKV outbreak in French territories in the Americas. METHODS: We conducted a population-based mother-child cohort study of women whose pregnancies overlapped with the 2016 ZIKV epidemic in Guadeloupe, Martinique, and French Guiana. Infants were included in this analysis if maternal ZIKV infection during pregnancy could be determined, the newborn had a gestational age ≥ 35 weeks, there were no abnormal transfontanelle cerebral ultrasound findings after delivery or no abnormal ultrasound findings on the last ultrasound performed during the third trimester of the mother's pregnancy, there was an absence of microcephaly at birth, and the parent completed the 24-month neurodevelopment assessment of the infant at 24 months (± 1 month) of age. ZIKV exposure of the toddler was determined by evidence of maternal ZIKV infection during pregnancy. Neurodevelopment assessments included the Ages and Stages Questionnaire (ASQ) for five dimensions of general development-communication, gross motor, fine motor, problem solving, and personal-social skills; the Modified Checklist for Autism on Toddlers (M-CHAT) for behavior; and the French MacArthur Inventory Scales (IFDC) for French language acquisition. RESULTS: Between June 2018 and August 2019, 156 toddlers with and 79 toddlers without in utero ZIKV exposure completed neurodevelopment assessments. Twenty-four (15.4%) ZIKV-exposed toddlers and 20 (25.3%) ZIKV-unexposed toddlers had an ASQ result below the reference - 2SD cut-off (P = 0.10) for at least one of the five ASQ dimensions. CONCLUSION: In one of the largest population-based cohorts of in utero ZIKV-exposed, normocephalic newborns to date, there were minimal differences apparent in neurodevelopment outcomes at 24 months of age compared to ZIKV-unexposed toddlers at 24 months of age. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02810210 . Registered 20 June 2016.

Analysis of colectomy rates for ulcerative colitis in pre- and postbiological eras in Lothian, Scotland.

AIM: Biological treatment is effective in maintaining remission in ulcerative colitis (UC), although the effect on colectomy rates remains unclear. In the UK the use of antitumour necrosis factor and anti-α4ß7 treatments for maintenance therapy in UC was restricted until 2015. The aim of this study was to describe the impact that this change in the prescribing of biologicals had on colectomy rates for UC. METHOD: All patients (adult and paediatric) with a diagnosis of UC who received maintenance biological treatment and/or underwent a colectomy in Lothian, Scotland between 2005 and 2018 were identified. Linear and segmental regression analyses were used to identify the annual percentage change (APC) and temporal trends (statistical joinpoints) in biological prescription and colectomy rates. RESULTS: Rates of initiation of maintenance biological therapy increased from 0.05 per 100 UC patients in 2005 to 1.26 in 2018 (p < 0.001). Colectomy rates per 100 UC patients fell from 1.47 colectomies in 2005 to 0.44 in 2018 (p < 0.001). The APC for colectomy decreased by 4.1% per year between 2005 and 2014 and by 18.9% between 2014 and 2018. Temporal trend analysis (2005-2018) identified a significant joinpoint in colectomy rates in 2014 (p = 0.019). CONCLUSION: The use of maintenance biological therapy increased sharply following the change in guidance. This has been paralleled by a significant reduction in the rates of colectomy over the same time period.

Prognostic factors associated with unhealed perineal wounds post-proctectomy for perianal Crohn's disease: a two-centre study.

AIM: The aim of this work was to determine the factors associated with poor wound healing in patients with perianal Crohn's disease (pCD) who had undergone proctectomy in the era of biologic therapies. METHOD: Case record review was performed on 103 patients with pCD who underwent proctectomy at St Mark's Hospital, Harrow and the Western General Hospital, Edinburgh between 2005 and 2017. Healing rates at 6 and 12 months post-proctectomy were considered; univariate analysis was performed. RESULTS: Sixty out of 103 patients (58.3%) had failure of wound healing at 6 months and 41/103 (39.8%) at 12 months. In total, 63.1% (65/103) patients received biologic therapies prior to proctectomy; however, exposure to biologics was not a significant factor in predicting failure of wound healing at 12 months (infliximab p = 0.255; adalimumab p = 0.889; vedolizumab p = 0.153). Male gender was the only variable associated with poor wound healing at 12 months on univariate analysis (p = 0.017). A lower pre-operative C-reactive protein was associated with early wound healing at 6 months compared with at 12 months (p = 0.041) on univariate analysis. Other parameters not associated with rates of wound healing included smoking status, corticosteroid exposure, thiopurine exposure, number of previous biologics, perianal sepsis on MRI within the last 12 months, duration of CD prior to proctectomy and pre-operative albumin. CONCLUSION: More than a third of patients had unhealed wounds 12 months after proctectomy. We report that unhealed wounds are more common in male patients. Importantly, our results also suggest that exposure to biologics does not affect rates of wound healing.

SARS-CoV-2 infection in schools in a northern French city: a retrospective serological cohort study in an area of high transmission, France, January to April 2020.

BackgroundChildren's role in SARS-CoV-2 epidemiology remains unclear. We investigated an initially unnoticed SARS-CoV-2 outbreak linked to schools in northern France, beginning as early as mid-January 2020.AimsThis retrospective observational study documents the extent of SARS-CoV-2 transmission, linked to an affected high school (n = 664 participants) and primary schools (n = 1,340 study participants), in the context of unsuspected SARS-CoV-2 circulation and limited control measures.MethodsBetween 30 March and 30 April 2020, all school staff, as well as pupils and their parents and relatives were invited for SARS-CoV-2 antibody testing and to complete a questionnaire covering symptom history since 13 January 2020.ResultsIn the high school, infection attack rates were 38.1% (91/239), 43.4% (23/53), and 59.3% (16/27), in pupils, teachers, and non-teaching staff respectively vs 10.1% (23/228) and 12.0% (14/117) in the pupils' parents and relatives (p < 0.001). Among the six primary schools, three children attending separate schools at the outbreak start, while symptomatic, might have introduced SARS-CoV-2 there, but symptomatic secondary cases related to them could not be definitely identified. In the primary schools overall, antibody prevalence in pupils sharing classes with symptomatic cases was higher than in pupils from other classes: 15/65 (23.1%) vs 30/445 (6.7%) (p < 0.001). Among 46 SARS-CoV-2 seropositive pupils < 12 years old, 20 were asymptomatic. Whether past HKU1 and OC43 seasonal coronavirus infection protected against SARS-CoV-2 infection in 6-11 year olds could not be inferred.ConclusionsViral circulation can occur in high and primary schools so keeping them open requires consideration of appropriate control measures and enhanced surveillance.

Occupational therapy intervention for cancer patients following hospital discharge: How and when should we intervene? A systematic review.

INTRODUCTION: Advances in cancer treatment over the last decade have led to increased survival rates. As a result, survivors are living longer with and beyond cancer, often with greater levels of morbidity. Occupational therapists, with their focus on remedial and compensatory strategies to improve function and participation, are well suited to assess and intervene with this population. Despite this, little research exists to demonstrate the efficacy of interventions and value of the occupational therapy role. This systematic review aimed to review how and when occupational therapists provide services for adult patients with cancer and identify where they add the most value. METHODS: A systematic search was conducted of six electronic databases. Eligible studies reported on occupational therapy interventions targeting management of cancer symptoms, rehabilitation or environmental modifications for adult cancer patients discharged from acute hospital services. Data extraction and quality assessment were undertaken by two reviewers. Narrative synthesis summarised the attributes and treatment outcomes of each intervention. RESULTS: Nine articles were included from a total of 309 articles retrieved. Eight different interventions were reported for people with cancer (n = 531). Small sample sizes and methodological quality precluded any formal analysis; however, intervention components that showed positive results were person-centred, individualised and included regular monitoring and flexibility in care, with input from multidisciplinary health professionals. Therapists also need to reflect upon the optimal duration of interventions and selection of outcome measures that specifically match intervention components. CONCLUSION: Despite inconclusive support of any particular type of intervention, this systematic review identified several successful intervention components for occupational therapists working with people with or beyond cancer. Overall, findings suggest that monitored tailored programmes compensating for fluctuations in a patient's condition have efficacy to improve patient outcomes and should be considered when delivering intervention with patients post hospital discharge.

Intrafamily Transmission of Monkeypox Virus, Central African Republic, 2018.

Monkeypox is a rare viral zoonotic disease; primary infections are reported from remote forest areas of Central and West Africa. We report an investigation of a monkeypox outbreak in Lobaye, southwest Central African Republic, in October 2018.

A Review of Asymptomatic and Subclinical Middle East Respiratory Syndrome Coronavirus Infections.

The epidemiology of Middle East respiratory syndrome coronavirus (MERS-CoV) since 2012 has been largely characterized by recurrent zoonotic spillover from dromedary camels followed by limited human-to-human transmission, predominantly in health-care settings. The full extent of infection of MERS-CoV is not clear, nor is the extent and/or role of asymptomatic infections in transmission. We conducted a review of molecular and serological investigations through PubMed and EMBASE from September 2012 to November 15, 2018, to measure subclinical or asymptomatic MERS-CoV infection within and outside of health-care settings. We performed retrospective analysis of laboratory-confirmed MERS-CoV infections reported to the World Health Organization to November 27, 2018, to summarize what is known about asymptomatic infections identified through national surveillance systems. We identified 23 studies reporting evidence of MERS-CoV infection outside of health-care settings, mainly of camel workers, with seroprevalence ranges of 0%-67% depending on the study location. We identified 20 studies in health-care settings of health-care worker (HCW) and family contacts, of which 11 documented molecular evidence of MERS-CoV infection among asymptomatic contacts. Since 2012, 298 laboratory-confirmed cases were reported as asymptomatic to the World Health Organization, 164 of whom were HCWs. The potential to transmit MERS-CoV to others has been demonstrated in viral-shedding studies of asymptomatic MERS infections. Our results highlight the possibility for onward transmission of MERS-CoV from asymptomatic individuals. Screening of HCW contacts of patients with confirmed MERS-CoV is currently recommended, but systematic screening of non-HCW contacts outside of health-care facilities should be encouraged.

Increased mucosal CD4+ T cell activation in rhesus macaques following vaccination with an adenoviral vector.

UNLABELLED: The possibility that vaccination with adenovirus (AdV) vectors increased mucosal T cell activation remains a central hypothesis to explain the potential enhancement of HIV acquisition within the Step trial. Modeling this within rhesus macaques is complicated because human adenoviruses, including human adenovirus type 5 (HAdV-5), are not endogenous to macaques. Here, we tested whether vaccination with a rhesus macaque-derived adenoviral vector (simian adenovirus 7 [SAdV-7]) enhances mucosal T cell activation within rhesus macaques. Following intramuscular SAdV-7 vaccination, we observed a pronounced increase in SAdV-7-specific CD4(+) T cell responses in peripheral blood and, more dramatically, in rectal mucosa tissue. Vaccination also induced a significant increase in the frequency of activated memory CD4(+) T cells in SAdV-7- and HAdV-5-vaccinated animals in the rectal mucosa but not in peripheral blood. These fluctuations within the rectal mucosa were also associated with a pronounced decrease in the relative frequency of naive resting CD4(+) T cells. Together, these results indicate that peripheral vaccination with an AdV vector can increase the activation of mucosal CD4(+) T cells, potentially providing an experimental model to further evaluate the role of host-vector interactions in increased HIV acquisition after AdV vector vaccination. IMPORTANCE: The possibility that vaccination with a human adenovirus 5 vector increased mucosal T cell activation remains a central hypothesis to explain the potential enhancement of human immunodeficiency virus (HIV) acquisition within the Step trial. In this study, we tested whether vaccination with a rhesus macaque-derived adenoviral vector in rhesus macaques enhances mucosal CD4(+) T cell activation, the main cell target of simian immunodeficiency virus (SIV)/HIV. The results showed that vaccination with an adenoviral vector indeed increases activation of mucosal CD4(+) T cells and potentially increases susceptibility to SIV infection.

Contribution of TRPC3 to store-operated calcium entry and inflammatory transductions in primary nociceptors.

BACKGROUND: Prolonged intracellular calcium elevation contributes to sensitization of nociceptors and chronic pain in inflammatory conditions. The underlying molecular mechanisms remain unknown but store-operated calcium entry (SOCE) components participate in calcium homeostasis, potentially playing a significant role in chronic pain pathologies. Most G protein-coupled receptors activated by inflammatory mediators trigger calcium-dependent signaling pathways and stimulate SOCE in primary afferents. The aim of the present study was to investigate the role of TRPC3, a calcium-permeable non-selective cation channel coupled to phospholipase C and highly expressed in DRG, as a link between activation of pro-inflammatory metabotropic receptors and SOCE in nociceptive pathways. RESULTS: Using in situ hybridization, we determined that TRPC3 and TRPC1 constitute the major TRPC subunits expressed in adult rat DRG. TRPC3 was found localized exclusively in small and medium diameter sensory neurons. Heterologous overexpression of TRPC3 channel subunits in cultured primary DRG neurons evoked a significant increase of Gd3+-sensitive SOCE following thapsigargin-induced calcium store depletion. Conversely, using the same calcium add-back protocol, knockdown of endogenous TRPC3 with shRNA-mediated interference or pharmacological inhibition with the selective TRPC3 antagonist Pyr10 induced a substantial decrease of SOCE, indicating a significant role of TRPC3 in SOCE in DRG nociceptors. Activation of P2Y2 purinoceptors or PAR2 protease receptors triggered a strong increase in intracellular calcium in conditions of TRPC3 overexpression. Additionally, knockdown of native TRPC3 or its selective pharmacological blockade suppressed UTP- or PAR2 agonist-evoked calcium responses as well as sensitization of DRG neurons. These data show a robust link between activation of pro-inflammatory receptors and calcium homeostasis through TRPC3-containing channels operating both in receptor- and store-operated mode. CONCLUSIONS: Our findings highlight a major contribution of TRPC3 to neuronal calcium homeostasis in somatosensory pathways based on the unique ability of these cation channels to engage in both SOCE and receptor-operated calcium influx. This is the first evidence for TRPC3 as a SOCE component in DRG neurons. The flexible role of TRPC3 in calcium signaling as well as its functional coupling to pro-inflammatory metabotropic receptors involved in peripheral sensitization makes it a potential target for therapeutic strategies in chronic pain conditions.

Comparison of clinical outcomes over time of inpatients with healthcare-associated or community-acquired coronavirus disease 2019 (COVID-19): A multicenter, prospective cohort study.

OBJECTIVE: To compare clinical outcomes over time of inpatients with healthcare-associated coronavirus disease 2019 (HA-COVID-19) versus community-acquired COVID-19 (CA-COVID-19). DESIGN: We conducted a multicenter, prospective observational cohort study of inpatients with COVID-19. SETTING: The study was conducted across 16 acute-care hospitals in Switzerland. PARTICIPANTS AND METHODS: We compared HA-COVID-19 cases, defined as patients with a positive severe acute respiratory coronavirus virus 2 (SARS-CoV-2) test > 5 days after hospital admission, with hospitalized CA-COVID-19 cases, defined as those who tested positive within 5 days of admission. The composite primary outcome was patient transfer to an intensive care unit (ICU) or an intermediate care unit (IMCU) and/or all-cause in-hospital mortality. We used cause-specific Cox regression and Fine-Gray regression to model the time to the composite clinical outcome, adjusting for confounders and accounting for the competing event of discharge from hospital. We compared our results to those from a conventional approach using an adjusted logistic regression model where time-varying effects and competitive risk were ignored. RESULTS: Between February 19, 2020, and December 31, 2020, we included 1,337 HA-COVID-19 cases and 9,068 CA-COVID-19 cases. HA-COVID-19 patients were significantly older: median, 80 (interquartile range [IQR], 71-87) versus median 70 (IQR, 57-80) (P < .001). A greater proportion of HA-COVID-19 patients had a Charlson comorbidity index ≥ 5 (79% vs 55%; P < .001) than did CA-COVID-19 patients. In time-varying analyses, between day 0 and 8, HA-COVID-19 cases had a decreased risk of death or ICU or IMCU transfer compared to CA-COVID-19 cases (cause-specific hazard ratio [csHR], 0.43; 95% confidence interval [CI], 0.33-0.56). In contrast, from day 8 to 30, HA-COVID-19 cases had an increased risk of death or ICU or IMCU transfer (csHR, 1.49; 95% CI, 1.20-1.85), with no significant effect on the rate of discharge (csHR, 0.83; 95% CI, 0.61-1.14). In the conventional logistic regression model, HA-COVID-19 was protective against transfer to an ICU or IMCU and/or all-cause in-hospital mortality (adjusted odds ratio [aOR], 0.79, 95% CI, 0.67-0.93). CONCLUSIONS: The risk of adverse clinical outcomes for HA-COVID-19 cases increased substantially over time in hospital and exceeded that for CA-COVID-19. Using approaches that do not account for time-varying effects or competing events may not fully capture the true risk of HA-COVID-19 compared to CA-COVID-19.

Controlling the hospital aquatic reservoir of multidrug-resistant organisms: a cross-sectional study followed by a nested randomized trial of sink decontamination.

OBJECTIVES: The hospital water environment is an important reservoir of multidrug-resistant organisms (MDROs) and presents a risk for patient safety. We assessed the effectiveness of thermal and chemical interventions on sinks contaminated with MDRO in the hospital setting. METHODS: We conducted a cross-sectional assessment of MDRO contamination of sinks and toilets in 26 clinical wards of a tertiary care hospital. MDRO-contaminated sink traps were then replaced and randomized (1:1:1) to receive chemical (sodium hypochlorite), thermal disinfection (steam), or no intervention. Interventions were repeated weekly for 4 weeks. Sinks were resampled 7 days after the last intervention. The primary outcome was the proportion of decontaminated sinks. MDROs of interest were extended spectrum beta-lactamase (ESBL) producing and carbapenemase-producing Enterobacterales, and non-fermentative Gram-negative bacilli. RESULTS: In the cross-sectional assessment, at least one MDRO was identified in 258 (36%) of the 748 samples and in 91 (47%) of the 192 water sources. In total, 57 (42%) of the 137 sinks and 34 (62%) of the 55 toilets were contaminated with 137 different MDROs. The most common MDRO were ESBL Enterobacterales (69%, 95/137), followed by Verona Integron-Borne Metallo-ß-Lactamase (VIM) carbapenemase producing Pseudomonas aeruginosa (9%, 12/137) and Citrobacter spp. (6%, 5/137). In the nested randomized trial, five of the 16 sinks (31%) in the chemical disinfection group were decontaminated, compared with 8 of 18 (44%) in the control group (OR 0.58; 95% CI, 0.14-2.32) and 9 of 17 (53%) in the thermal disinfection group (OR 1.40; 95% CI, 0.37-5.32). DISCUSSION: Our study failed to demonstrate an added benefit of repeated chemical or thermal disinfection, beyond changing sink traps, in the MDRO decontamination of sinks. Routine chlorine-based disinfection of sinks may need to be reconsidered.

Validation of the ACE [Albumin, CRP, and Endoscopy] Index in Acute Colitis: Analysis of the CONSTRUCT dataset.

BACKGROUND AND AIMS: In 2020 we reported the ACE Index in acute colitis which used biochemical and endoscopic parameters to predict steroid non-response on admission in patients with acute ulcerative colitis [UC]. We aimed to validate the ACE Index in an independent cohort. METHODS: The validation cohort comprised patients screened as eligible for inclusion in the CONSTRUCT study, a prospective, randomized, placebo-controlled trial which compared the effectiveness of treatment with infliximab vs ciclosporin in patients admitted with acute UC. The CONSTRUCT cohort database was reviewed at The Edinburgh IBD Unit and the same biochemical and endoscopic variables and cut-off values as those in the derivation cohort were applied to the validation cohort. RESULTS: In total, 800 patients were identified; 62.5% [55/88] of patients with a maximum ACE Index of 3 did not respond to intravenous [IV] steroids (positive predictive value [PPV] 62.5%, negative predictive value [NPV] 79.8%). Furthermore, 79.8% [158/198] of patients with an ACE Index of 0 responded to IV steroids [PPV 79.8%, NPV 62.5%]. Receiver operator characteristic [ROC] curve analysis produced an area under the curve [AUC] of 0.663 [p < 0.001]. CONCLUSIONS: We have now reported and externally validated the ACE Index in acute colitis in a combined cohort of over 1000 patients from across the UK. The ACE Index may be used in conjunction with clinical judgement to help identify patients admitted with active UC who are at high risk of not responding to IV steroids. Further studies are required to improve objectivity and accuracy of assessment.

Tailoring follow-up endoscopy in patients with severe oesophagitis.

Objective: We aimed to investigate the clinical utility of follow-up oesophagogastroduodenoscopy (OGD2) in patients with severe oesophagitis (Los Angeles grades C or D) through evaluating the yield of Barrett's oesophagus (BO), cancer, dysplasia and strictures. Second, we aimed to determine if the Clinical Frailty Scale (CFS) may be used to identify patients to undergo OGD2s. Design/method: Patients in NHS Lothian with an index OGD (OGD1) diagnosis of severe oesophagitis between 1 January 2014 and 31 December 2015 were identified. Univariate analysis identified factors associated with grade. Patients were stratified by frailty and a diagnosis of stricture, cancer, dysplasia and BO. Results: In total 964 patients were diagnosed with severe oesophagitis, 61.7% grade C and 38.3% grade D. The diagnostic yield of new pathology at OGD2 was 13.2% (n=51), new strictures (2.3%), dysplasia (0.5%), cancer (0.3%) and BO (10.1%). A total of 140 patients had clinical frailty (CFS score ≥5), 88.6% of which were deceased at review (median of 76 months). In total 16.4% of frail patients underwent OGD2s and five new pathologies were diagnosed, none of which were significantly associated with grade. Among non-frail patients at OGD2, BO was the only pathology more common (p=0.010) in patients with grade D. Rates of cancer, dysplasia and strictures did not vary significantly between grades. Conclusion: Our data demonstrate that OGD2s in patients with severe oesophagitis may be tailored according to clinical frailty and only be offered to non-frail patients. In non-frail patients OGD2s have similar pick-up rates of sinister pathology in both grades of severe oesophagitis.

Differential expression and pharmacology of native P2X receptors in rat and primate sensory neurons.

Evidence suggesting the involvement of P2X2 and P2X3 in chronic pain has been obtained mostly from rodent models. Here we show that rodents may be poor predictors of P2X3 pharmacology in human. We demonstrate that monkey and human dorsal root ganglion (DRG) neurons do not express appreciable levels of P2X2 subunit, contrary to rat sensory neurons. Additionally, we report functional P2X3 activity in monkey DRG neurons and confirm the absence of functional P2X2/3 receptors. Interestingly, native P2X3 receptors in rat and monkey DRGs show similar agonist potency, but different antagonist potencies for TNP-ATP [2-O-(2,4,6-trinitrophenyl)-ATP] and RO51. This unexpected difference in antagonist potency was confirmed by comparing rat and human P2X3 receptors in HEK293 cells. Mutagenesis studies reveal that two extracellular residues, A197 and T202, are synergistically responsible for the potency drop in primate P2X3 receptors. These results uncover species-specific P2X3 pharmacology and identify key mechanisms impacting the translatability of potential analgesics targeting P2X3 receptors.