Fiber Mediated Receptor Masking in Non-Infected Bystander Cells Restricts Adenovirus Cell Killing Effect but Promotes Adenovirus Host Co-Existence

The basic concept of conditionally replicating adenoviruses (CRAD) as oncolytic agents is that progenies generated from each round of infection will disperse, infect and kill new cancer cells. However, CRAD has only inhibited, but not eradicated tumor growth in xenograft tumor therapy, and CRAD therapy has had only marginal clinical benefit to cancer patients. Here, we found that CRAD propagation and cancer cell survival co-existed for long periods of time when infection was initiated at low multiplicity of infection (MOI), and cancer cell killing was inefficient and slow compared to the assumed cell killing effect upon infection at high MOI. Excessive production of fiber molecules from initial CRAD infection of only 1 to 2% cancer cells and their release prior to the viral particle itself caused a tropism-specific receptor masking in both infected and non-infected bystander cells. Consequently, the non-infected bystander cells were inefficiently bound and infected by CRAD progenies. Further, fiber overproduction with concomitant restriction of adenovirus spread was observed in xenograft cancer therapy models. Besides the CAR-binding Ad4, Ad5, and Ad37, infection with CD46-binding Ad35 and Ad11 also caused receptor masking. Fiber overproduction and its resulting receptor masking thus play a key role in limiting CRAD functionality, but potentially promote adenovirus and host cell co-existence. These findings also give important clues for understanding mechanisms underlying the natural infection course of various adenoviruses

Global economic burden of unmet surgical need for appendicitis

Background: There is a substantial gap in provision of adequate surgical care in many low-and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods: Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results: Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion: For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Global variation in anastomosis and end colostomy formation following left-sided colorectal resection

Background End colostomy rates following colorectal resection vary across institutions in high-income settings, being influenced by patient, disease, surgeon and system factors. This study aimed to assess global variation in end colostomy rates after left-sided colorectal resection. Methods This study comprised an analysis of GlobalSurg-1 and -2 international, prospective, observational cohort studies (2014, 2016), including consecutive adult patients undergoing elective or emergency left-sided colorectal resection within discrete 2-week windows. Countries were grouped into high-, middle- and low-income tertiles according to the United Nations Human Development Index (HDI). Factors associated with colostomy formation versus primary anastomosis were explored using a multilevel, multivariable logistic regression model. Results In total, 1635 patients from 242 hospitals in 57 countries undergoing left-sided colorectal resection were included: 113 (6·9 per cent) from low-HDI, 254 (15·5 per cent) from middle-HDI and 1268 (77·6 per cent) from high-HDI countries. There was a higher proportion of patients with perforated disease (57·5, 40·9 and 35·4 per cent; P < 0·001) and subsequent use of end colostomy (52·2, 24·8 and 18·9 per cent; P < 0·001) in low- compared with middle- and high-HDI settings. The association with colostomy use in low-HDI settings persisted (odds ratio (OR) 3·20, 95 per cent c.i. 1·35 to 7·57; P = 0·008) after risk adjustment for malignant disease (OR 2·34, 1·65 to 3·32; P < 0·001), emergency surgery (OR 4·08, 2·73 to 6·10; P < 0·001), time to operation at least 48 h (OR 1·99, 1·28 to 3·09; P = 0·002) and disease perforation (OR 4·00, 2·81 to 5·69; P < 0·001). Conclusion Global differences existed in the proportion of patients receiving end stomas after left-sided colorectal resection based on income, which went beyond case mix alone

Introduced marine macroalgae and habitat modifiers : their ecological role and significant attributes

Invasive, non-indigenous species (NIS) have become an increasing problem worldwide, with impacts on the diversity and ecosystem functioning of native communities. Marine invasive NIS also have a negative economical impact through increased abundance of toxic species, fouling of man-made underwater structures, and reduced recreational values of beaches. Only a small proportion of the NIS becomes invasive (i.e., having a negative ecological and/or economical impact), but once a species has been established much effort and resources are needed to remove it. In the present thesis I discuss possible factors determining the success of macroalgal introductions and their impacts. A species of special concern in this thesis is the non-indigenous marine red alga Gracilaria vermiculophylla (Ohmi) Papenfuss, seen for the first time in the archipelago of Göteborg, Sweden, in the summer of 2003. Firstly, I highlight some positive and negative impacts caused by NIS as habitat modifiers. Secondly, I describe, by quantitative ranking, whether there are any common patterns of species traits increasing the likelihood of macroalgal NIS, introduced into a new area, becoming established and spread. In general, introduced and invasive species were ranked more hazardous than the native and non-invasive species introduced in Europe. Applying the quantitative species traits ranking on G. vermiculophylla rendered it among the most invasive red algae in Europe. Thirdly, I show the ability of G. vermiculophylla to withstand an emerged situation of more than five months, e.g. simulating transportation in a dredger or among fishing nets. The results indicate that G. vermiculophylla can easily survive long transportation in darkness such as in a ballast tank, and without being submerged in water. It also survived salinities down to 2 in a laboratory experiment, indicating that this species can survive in the innermost parts of the Baltic Sea (the Bothnian Bay). With the help of an event tree I illustrate the potential impact an establishment of G. vermiculophylla could have in the Baltic Sea. Fourthly, I show the distribution pattern within 150 km of the Swedish west coast in two years time for G. vermiculophylla. Furthermore, I describe the community associated with this species collected from Sweden, Denmark and the United States. In total, nearly 100 different taxa in twelve phyla were found associated with G. vermiculophylla. Finally, the impact of G. vermiculophylla on the native eelgrass, Zostera marina, was assessed using a modelling approach. The model output showed a negative effect on Z. marina already at low densities of G. vermiculophylla. This thesis contributes to a wider understanding of macroalgal introductions in general and of the ecology and ecophysiology of the invasive red alga G. vermiculophylla in particular. Such knowledge is important for management and stresses the importance of monitoring the Swedish coastline for early detection of NIS

A benefit analysis of screening for invasive species - base-rate uncertainty and the value of information

1.. Implementation of the full spectra of screening tools to prevent the introduction of invasive species results in a need to evaluate the cost-efficiency of gathering the information needed to screen for these species. 2. We show how the Bayesian value of information approach can be used to derive the benefit of a screening model based on species traits, which in combination with the base rate of invasiveness, i.e. the proportion of invasive species among those introduced and established, predicts species-specific invasiveness. 3. A pre-posterior Bayesian analysis demonstrated that the benefit of the screening model of invasiveness depends on both the accuracy in predictions and the uncertainty in the base rate of invasiveness. However, even though increasing model accuracy always generates higher model benefit, acknowledging or neglecting the uncertainty in the base rate of invasiveness does not. This means that uncertainty in the base rate is important to consider in the cost-benefit analysis of the screening model. 4. As an example, we derived the benefit of basing decisions on a screening model trained for a data set on species traits of invasive and non-invasive marine macroalgae introduced into Europe. The benefit ranged from 0.6% to 19% of the loss of introducing an invasive species, where the actual value can be estimated if we know the monetary values of impacts from introducing invasive and not introducing non-invasive species. 5. Cost-benefit analyses of screening models for invasive species is one means to reach efficient management of the risks of non-indigenous species. Value of information is a useful tool for benefit analysis of predictive models with respect to decision-making, which goes beyond the investigations of model accuracy. Here, we use value of information analysis to evaluate which sources of uncertainty that is most worth while to reduce and how to set the cost of gathering further species-specific information which will improve the accuracy of a screening

Gracilaria vermiculophylla (Ohmi) Papenfuss, 1967 (Rhodophyta, Gracilariaceae) in northern Europe, with emphasis on Danish conditions, and what to expect in the future

Gracilaria vermiculophylla, a red macroalga from the West Pacific, was discovered in western Germany (the Wadden Sea) in 2002 and has since also been observed in Sweden (from about 70 km south to about 80 km north of Göteborg), Denmark (Wadden Sea, Horsens Fjord, Limfjorden, Vejle Fjord, Holckenhavn Fjord, Øster Hurup Harbor) and eastern Germany (Kiel Bay). Today, less than 5 years following its first observation in the Wadden Sea the invader is common in many invaded regions, often being amongst the most abundant macroalgal species. G. vermiculophylla is successful in shallow protected soft-bottom estuaries and bays, typically in association with ubiquitous native invertebrates (lugworms, tube-building worms, mussels, cockles, snails). The invertebrates provide substratum for holdfast attachment and thalli incorporation, most likely increasing the stability of local G. vermiculophylla populations. We hypothesize that this substratum provision is highly important for its general invasion success. We also confirm that G. vermiculophylla can maintain growth at all salinities experienced along Danish coastlines (8.5-34 psu). In addition, laboratory experiments indicate that the ubiquitous grazer Littorina littorea has the potential to control G. vermiculophylla growth under specific environmental conditions, but also that L. littorea may facilitate small-scale dispersal within invaded locations, because grazing increases thalli fragmentation rates. Given its widespread distribution, rapid range expansion, and known ecological traits, G. vermiculophylla is clearly a permanent resident of northern European waters