Rule-based modelling provides an extendable framework for comparing candidate mechanisms underpinning clathrin polymerisation

Abstract Polymerisation of clathrin is a key process that underlies clathrin-mediated endocytosis. Clathrin-coated vesicles are responsible for cell internalization of external substances required for normal homeostasis and life –sustaining activity. There are several hypotheses describing formation of closed clathrin structures. According to one of the proposed mechanisms cage formation may start from a flat lattice buildup on the cellular membrane, which is later transformed into a curved structure. Creation of the curved surface requires rearrangement of the lattice, induced by additional molecular mechanisms. Different potential mechanisms require a modeling framework that can be easily modified to compare between them. We created an extendable rule-based model that describes polymerisation of clathrin molecules and various scenarios of cage formation. Using Global Sensitivity Analysis (GSA) we obtained parameter sets describing clathrin pentagon closure and the emergence/production and closure of large-size clathrin cages/vesicles. We were able to demonstrate that the model can reproduce budding of the clathrin cage from an initial flat array

Health Resource Utilisation and Disparities: an Ecological Study of Admission Patterns Across Ethnicity in England Between 2017 and 2020.

BACKGROUND AND AIM: The COVID-19 pandemic highlighted adverse outcomes in Asian, Black, and ethnic minority groups. More research is required to explore underlying ethnic health inequalities. In this study, we aim to examine pre-COVID ethnic inequalities more generally through healthcare utilisation to contextualise underlying inequalities that were present before the pandemic. DESIGN: This was an ecological study exploring all admissions to NHS hospitals in England from 2017 to 2020. METHODS: The primary outcomes were admission rates within ethnic groups. Secondary outcomes included age-specific and age-standardised admission rates. Sub-analysis of admission rates across an index of multiple deprivation (IMD) deciles was also performed to contextualise the impact of socioeconomic differences amongst ethnic categories. Results were presented as a relative ratio (RR) with 95% confidence intervals. RESULTS: Age-standardised admission rates were higher in Asian (RR 1.40 [1.38-1.41] in 2019) and Black (RR 1.37 [1.37-1.38]) and lower in Mixed groups (RR 0.91 [0.90-0.91]) relative to White. There was significant missingness or misassignment of ethnicity in NHS admissions: with 11.7% of admissions having an unknown/not-stated ethnicity assignment and 'other' ethnicity being significantly over-represented. Admission rates did not mirror the degree of deprivation across all ethnic categories. CONCLUSIONS: This study shows Black and Asian ethnic groups have higher admission rates compared to White across all age groups and when standardised for age. There is evidence of incomplete and misidentification of ethnicity assignment in NHS admission records, which may introduce bias to work on these datasets. Differences in admission rates across individual ethnic categories cannot solely be explained by socioeconomic status. Further work is needed to identify ethnicity-specific factors of these inequalities to allow targeted interventions at the local level

Long-term disease interactions amongst surgical patients: a population cohort study.

BACKGROUND: The average age of the surgical population continues to increase, as does prevalence of long-term diseases. However, outcomes amongst multi-morbid surgical patients are not well described. METHODS: We included adults undergoing non-obstetric surgical procedures in the English National Health Service between January 2010 and December 2015. Patients could be included multiple times in sequential 90-day procedure spells. Multi-morbidity was defined as presence of two or more long-term diseases identified using a modified Charlson comorbidity index. The primary outcome was 90-day postoperative death. Secondary outcomes included emergency hospital readmission within 90 days. We calculated age- and sex-adjusted odds ratios (OR) with 95% confidence intervals (CI) using logistic regression. We compared the outcomes associated with different disease combinations. RESULTS: We identified 20 193 659 procedure spells among 13 062 715 individuals aged 57 (standard deviation 19) yr. Multi-morbidity was present among 2 577 049 (12.8%) spells with 195 965 deaths (7.6%), compared with 17 616 610 (88.2%) spells without multi-morbidity with 163 529 deaths (0.9%). Multi-morbidity was present in 1 902 859/16 946 808 (11.2%) elective spells, with 57 663 deaths (2.7%, OR 4.9 [95% CI: 4.9-4.9]), and 674 190/3 246 851 (20.7%) non-elective spells, with 138 302 deaths (20.5%, OR 3.0 [95% CI: 3.0-3.1]). Emergency readmission followed 547 399 (22.0%) spells with multi-morbidity compared with 1 255 526 (7.2%) without. Multi-morbid patients accounted for 57 663/114 783 (50.2%) deaths after elective spells, and 138 302/244 711 (56.5%) after non-elective spells. The rate of death varied five-fold from lowest to highest risk disease pairs. CONCLUSION: One in eight patients undergoing surgery have multi-morbidity, accounting for more than half of all postoperative deaths. Disease interactions amongst multi-morbid patients is an important determinant of patient outcome

The lifetime risk of surgery in England: a nationwide observational cohort study.

BACKGROUND: The average number of times a person will have surgery in their lifetime, and the amount of surgical healthcare resources they use, is unknown. Lifetime risk is a measure of the risk of an average person having a specific event within their lifetime. We report the lifetime risk of surgery and the change observed during the first year of the COVID-19 pandemic. METHODS: We conducted a population cohort study using hospital episode statistics to identify all patients undergoing surgery between January 1, 2016, and December 31, 2020, in England. We calculated age- and sex-specific incidence rates of surgery and combined these with routinely available population and mortality data from the Office for National Statistics. We computed the probability of requiring surgery stratified by 5-yr epochs (age 0-4 to ≥90 yr). Our primary analysis calculated lifetime risk for all surgery using the life table method. We assessed the impact of the COVID-19 pandemic, comparing a pre-pandemic and a pandemic period. RESULTS: Between 2016 and 2020, 23 427 531 patients underwent surgery, of which 11 937 062 were first surgeries. The average denominator population for England was 55.9 million. The lifetime risk of first surgery was 60.2% (95% confidence interval 55.1-65.4%) for women and 59.1% (95% confidence interval 54.2-64.1%) for men. The COVID-19 pandemic decreased the lifetime risk of first surgery by 32.3% for women and by 31.7% for men. This estimated lifetime risk should only be applied to the English population. CONCLUSIONS: This population epidemiological analysis suggests that approximately 60% of people in England will undergo surgery in their lifetime

A statistical analysis proposal: Emergency hospital admissions associated with Non-Communicable Diseases 1998-2019: An Ecological Study

A statistical analysis proposal to use aggregated hospital admission data from 1998-2019 to investigate the relationship between non-communicable disease groups and associated emergency admissions to hospital

Long-term mortality following complications after elective surgery: a secondary analysis of pooled data from two prospective cohort studies.

BACKGROUND: Complications after surgery affect survival and quality of life. We aimed to confirm the relationship between postoperative complications and death within 1 yr after surgery. METHODS: We conducted a secondary analysis of pooled data from two prospective cohort studies of patients undergoing surgery in five high-income countries between 2012 and 2014. Exposure was any complication within 30 days after surgery. Primary outcome was death within 1 yr after surgery, ascertained by direct follow-up or linkage to national registers. We adjusted for clinically important covariates using a mixed-effect multivariable Cox proportional hazards regression model. We conducted a planned subgroup analysis by type of complication. Data are presented as mean with standard deviation (sd), n (%), and adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs). RESULTS: The pooled cohort included 10 132 patients. After excluding 399 (3.9%) patients with missing data or incomplete follow-up, 9733 patients were analysed. The mean age was 59 [sd 16.8] yr, and 5362 (55.1%) were female. Of 9733 patients, 1841 (18.9%) had complications within 30 days after surgery, and 319 (3.3%) died within 1 yr after surgery. Of 1841 patients with complications, 138 (7.5%) died within 1 yr after surgery compared with 181 (2.3%) of 7892 patients without complications (aHR 1.94 [95% CI: 1.53-2.46]). Respiratory failure was associated with the highest risk of death, resulting in six deaths amongst 28 patients (21.4%). CONCLUSIONS: Postoperative complications are associated with increased mortality at 1 yr. Further research is needed to identify patients at risk of complications and to reduce mortality

The main actors involved in parasitization of Heliothis virescens larva

At the moment of parasitization by another insect, the host Heliothis larva is able to defend itself by the activation of humoral and cellular defenses characterized by unusual reactions of hemocytes in response to external stimuli. Here, we have combined light and electron microscopy, staining reactions, and immunocytochemical characterization to analyze the activation and deactivation of one of the most important immune responses involved in invertebrates defense, i.e., melanin production and deposition. The insect host/parasitoid system is a good model to study these events. The activated granulocytes of the host insect are a major repository of amyloid fibrils forming a lattice in the cell. Subsequently, the exocytosed amyloid lattice constitutes the template for melanin deposition in the hemocel. Furthermore, cross-talk between immune and neuroendocrine systems mediated by hormones, cytokines, and neuromodulators with the activation of stress-sensoring circuits to produce and release molecules such as adrenocorticotropin hormone, alpha melanocyte-stimulating hormone, and neutral endopeptidase occurs. Thus, parasitization promotes massive morphological and physiological modifications in the host insect hemocytes and mimics general stress conditions in which phenomena such as amyloid fibril formation, melanin polymerization, pro-inflammatory cytokine production, and activation of the adrenocorticotropin hormone system occur. These events observed in invertebrates are also reported in the literature for vertebrates, suggesting that this network of mechanisms and responses is maintained throughout evolution

A narrative review on the similarities and dissimilarities between myalgic encephalomyelitis/chronic fatigue syndrome (me/cfs) and sickness behavior

It is of importance whether myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a variant of sickness behavior. The latter is induced by acute infections/injury being principally mediated through proinflammatory cytokines. Sickness is a beneficial behavioral response that serves to enhance recovery, conserves energy and plays a role in the resolution of inflammation. There are behavioral/symptomatic similarities (for example, fatigue, malaise, hyperalgesia) and dissimilarities (gastrointestinal symptoms, anorexia and weight loss) between sickness and ME/CFS. While sickness is an adaptive response induced by proinflammatory cytokines, ME/CFS is a chronic, disabling disorder, where the pathophysiology is related to activation of immunoinflammatory and oxidative pathways and autoimmune responses. While sickness behavior is a state of energy conservation, which plays a role in combating pathogens, ME/CFS is a chronic disease underpinned by a state of energy depletion. While sickness is an acute response to infection/injury, the trigger factors in ME/CFS are less well defined and encompass acute and chronic infections, as well as inflammatory or autoimmune diseases. It is concluded that sickness behavior and ME/CFS are two different conditions