Tocilizumab use during Covid-19 should alert an orthopaedic surgeon for the surgical management of arthroplasty patients: A narrative review

The crisis of Covid-19 has shaken the world healthcare systems. The intensive care resources to manage the medical conditions associated with Covid-19 are consistently found to be inadequate with exploration and implementation of newer treatment avenues for an early recovery. Presently, the use of Tocilizumab (TCZ) in severe to critical affection of Covid-19 is being practiced as an off-label therapy. A narrative review of present knowledge regarding TCZ pharmacology, indications of its use, and potential side effects with clinical implications for an orthopedic surgeon is presented. The article discusses the clinicopathological factors required to be monitored during the perioperative management of an orthopedic patient who may have received TCZ for Covid-19 related illness. The implications of its usage should alert the orthopaedic surgeons for future management of their arthritic surgical patients. The commonly associated side effects and complications in the post-operative phase following an arthroplasty or any orthopaedic surgery are an area of concern and considerable uncertainty. In the post-Covid-19 recovery phase, when surgeons need to plan a surgical intervention then a thorough evaluation of their Covid-19 medical management history may be warranted. Practical guidelines for the management of arthritic surgical patients have been postulated. With an unregulated increased usage of TCZ during Covid-19 management, an orthopaedic surgeon should worry and needs to be aware of the possible consequences in the perioperative period for the post-surgery management. Future research to gain more insights will confirm the implied concerns.

Management of concomitant coronary artery disease and aortic valve stenosis in the era of transcatheter aortic valve treatment

Severe calcific aortic stenosis (AS) and coronary artery disease (CAD) have common risk factors and are frequently encountered in the same patient in clinical practice. CAD has been reported in ≥ 50% of AS patients undergoing both surgical treatment and transcatheter aortic valve implantation (TAVI). In the last two decades, TAVI has been established as a less invasive alternative to surgery. Recently, more and more young and low surgical risk patients undergo TAVI. Despite the high prevalence of CAD in patients treated with TAVI, the management strategy of concomitant CAD in these patients remains an area of considerable uncertainty. This review provides an updated overview of the current knowledge about this topic and offers points for reflection about the best approach to use.

Alternative Futures for the Digital Transformation: A Macro-Level Schumpeterian Perspective

This paper develops and deploys a theoretical framework for assessing the prospects of a cluster of technologies driving what is often called the digital transformation. There is considerable uncertainty regarding this transformation’s future trajectory, and to understand and bound that uncertainty, we build on Schumpeter’s macro-level theory of economy-wide, technological revolutions and on the work of several scholars who have extended that theory. In this perspective, such revolutions’ trajectories are shaped primarily by the interaction of changes within and between three spheres—technology, organization, and public policy. We enrich this account by identifying the critical problems and the collective choices among competing solutions to those problems that together shape the trajectory of each revolution. We argue that the digital transformation represents a new phase in the wider arc of the information and communication technology revolution—a phase promising much wider deployment—and that the trajectory of this deployment depends on collective choices to be made in the organization and public policy spheres. Combining in a 2 × 2 matrix the two main alternative solutions on offer in each of these two spheres, we identify four scenarios for the future trajectory of the digital transformation: digital authoritarianism, digital oligarchy, digital localism, and digital democracy. We discuss how these scenarios can help us trace and understand the future trajectory of the digital transformation.

Intrinsic Strand-Incision Activity of Human UNG: Implications for Nick Generation in Immunoglobulin Gene Diversification

Uracil arises in cellular DNA by cytosine (C) deamination and erroneous replicative incorporation of deoxyuridine monophosphate opposite adenine. The former generates C → thymine transition mutations if uracil is not removed by uracil-DNA glycosylase (UDG) and replaced by C by the base excision repair (BER) pathway. The primary human UDG is hUNG. During immunoglobulin gene diversification in activated B cells, targeted cytosine deamination by activation-induced cytidine deaminase followed by uracil excision by hUNG is important for class switch recombination (CSR) and somatic hypermutation by providing the substrate for DNA double-strand breaks and mutagenesis, respectively. However, considerable uncertainty remains regarding the mechanisms leading to DNA incision following uracil excision: based on the general BER scheme, apurinic/apyrimidinic (AP) endonuclease (APE1 and/or APE2) is believed to generate the strand break by incising the AP site generated by hUNG. We report here that hUNG may incise the DNA backbone subsequent to uracil excision resulting in a 3´-α,β-unsaturated aldehyde designated uracil-DNA incision product (UIP), and a 5´-phosphate. The formation of UIP accords with an elimination (E2) reaction where deprotonation of C2´ occurs via the formation of a C1´ enolate intermediate. UIP is removed from the 3´-end by hAPE1. This shows that the first two steps in uracil BER can be performed by hUNG, which might explain the significant residual CSR activity in cells deficient in APE1 and APE2.

It More than Adds Up: Interaction of Antibiotic Mixing and Temperature

Use of antibiotics for the treatment and prevention of bacterial infections in humans, agri- and aquaculture as well as livestock rearing leads to antibiotic pollution of fresh water and these antibiotics have an impact on free-living bacteria. While we know which antibiotics are most common in natural environments such as rivers and streams, there is considerable uncertainty regarding antibiotics’ interactions with one another and the effect of abiotic factors such as temperature. Here, we used an experimental approach to explore the effects of antibiotic identity, concentration, mixing and water temperature on the growth of Pseudomonas fluorescens, a common, ubiquitous bacterium. We exposed P. fluorescens to the four antibiotics most commonly found in surface waters (ciprofloxacin, ofloxacin, sulfamethoxazole and sulfapyridine) and investigated antibiotic interactions for single and mixed treatments at different, field-realistic temperatures. We observed an overall dependence of antibiotic potency on temperature, as temperature increased efficacy of ciprofloxacin and ofloxacin with their EC50 lowered by >75% with a 10 °C temperature increase. Further, we show that mixtures of ciprofloxacin and ofloxacin, despite both belonging to the fluoroquinolone class, exhibit low-temperature-dependent synergistic effects in inhibiting bacterial growth. These findings highlight the context dependency of antibiotic efficacy. They further suggest antibiotic-specific off-target effects that only affect the bacteria once they enter a certain temperature range. This has important implications as freshwater systems already contain multi-drug antibiotic cocktails and are changing temperature due to environmental warming. These factors will interact and affect aquatic food webs, and hence this creates an urgent need to adapt and improve laboratory testing conditions to closer reflect natural environments.

How might climate change affect river flows across West Africa?

West Africa and its semi-arid Sahelian region are one of the world’s most vulnerable regions to climate change with a history of extreme climate variability. There is still considerable uncertainty as to how projected climate change will affect precipitation at local and regional scales and the consequent impact on river flows and water resources across West Africa. Here, we aim to address this uncertainty by configuring a regional-scale hydrological model to West Africa. The model (hydrological modelling framework for West Africa—HMF-WA) simulates spatially consistent river flows on a 0.1° × 0.1° grid (approximately 10 km × 10 km) continuously across the whole domain and includes estimates of anthropogenic water use, wetland inundation, and local hydrological features such as endorheic regions. Regional-scale hydrological simulations driven by observed weather data are assessed against observed flows before undertaking an analysis of the impact of projected future climate scenarios from the CMIP5 on river flows up to the end of the twenty-first century. The results indicate that projected future changes in river flows are highly spatially variable across West Africa, particularly across the Sahelian region where the predicted changes are more pronounced. The study shows that median peak flows are projected to decrease by 23% in the west (e.g. Senegal) and increase by 80% in the eastern region (e.g. Chad) by the 2050s. The projected reductions in river flows in western Sahel lead to future droughts and water shortages more likely, while in the eastern Sahel, projected increases lead to future frequent floods.

Economies of Scale and Sustainability in Local Government: A Complex Issue

Local governments may seek efficient public service delivery through scaling up production, and the quest for the optimal local government size has attracted extensive attention of scholars and policy makers. Indeed, if scale matters for local government efficiency, increasing size may be a key factor in achieving more value for money for citizens. As such, getting scale right may contribute significantly to achieving the Sustainable Development Goals (SDGs) as set out in the 2030 Agenda. Nonetheless, there is considerable uncertainty with regard to how scale shapes the average cost of local government service delivery. These uncertainties may have contributed to policy makers and public organizations disregarding the often inconclusive and sometimes contradictory empirical evidence in stimulating and allowing mergers and consolidation in many Western countries. This Special Issue is concerned with economies of scale in local government. Interesting issues to be addressed relate to the existence of general and service specific economies of scale and the implications of both for local government policy regarding various types of scaling (amalgamation, cooperation, and outsourcing). Based on a brief literature review, we inventory a number of issues which warrant further research. One of the conclusions is that the relationship between scale and sustainability is a complex issue with many aspects. Examples include the relation between economies of scale and outsourcing and cooperation, issues concerned with multi-level aspects of scale, and the trade-off that may exist between achieving economies of scale and cost efficiency (e.g., transition cost of mergers). Another conclusion is that no such thing as “one size fits all” exists. Different perspectives may play a role and should be born in mind when suggesting solutions and providing recommendations to achieve sustainable goals.

Phylogenetic analysis of the Neotropical Albitarsis Complex based on mitogenome data

Background Some of the most important malaria vectors in South America belong to the Albitarsis Complex (Culicidae; Anophelinae; Anopheles). Understanding the origin, nature, and geographical distribution of species diversity in this important complex has important implications for vector incrimination, control, and management, and for modelling future responses to climate change, deforestation, and human population expansion. This study attempts to further explore species diversity and evolutionary history in the Albitarsis Complex by undertaking a characterization and phylogenetic analysis of the mitogenome of all 10 putative taxa in the Albitarsis Complex. Methods Mitogenome assembly and annotation allowed for feature comparison among Albitarsis Complex and Anopheles species. Selection analysis was conducted across all 13 protein-coding genes. Maximum likelihood and Bayesian inference methods were used to construct gene and species trees, respectively. Bayesian methods were also used to jointly estimate species delimitation and species trees. Results Gene composition and order were conserved across species within the complex. Unique signatures of positive selection were detected in two species—Anopheles janconnae and An. albitarsis G—which may have played a role in the recent and rapid diversification of the complex. The COI gene phylogeny does not fully recover the mitogenome phylogeny, and a multispecies coalescent-based phylogeny shows that considerable uncertainty exists through much of the mitogenome species tree. The origin of divergence in the complex dates to the Pliocene/Pleistocene boundary, and divergence within the distinct northern South American clade is estimated at approximately 1 million years ago. Neither the phylogenetic trees nor the delimitation approach rejected the 10-species hypothesis, although the analyses could not exclude the possibility that four putative species with scant a priori support (An. albitarsis G, An. albitarsis H, An. albitarsis I, and An. albitarsis J), represent population-level, rather than species-level, splits. Conclusion The lack of resolution in much of the species tree and the limitations of the delimitation analysis warrant future studies on the complex using genome-wide data and the inclusion of additional specimens, particularly from two putative species, An. albitarsis I and An. albitarsis J. Graphical Abstract

Skill Acquisition and Data Sales

We develop a data-sales model to study the implications of alternative data for financial markets. Investors acquire skills to process the purchased raw data, and developing such skills is costly and involves considerable uncertainty. The data vendor controls the size of the data sample to influence the precision of the information investors can extract from the purchased data. Price informativeness is hump-shaped in skill-acquisition costs although the cost of capital and return volatility are U-shaped in skill-acquisition costs. Similar patterns can arise for skill mean and volatility. Our analysis suggests that the funds and data industries foster each other. This paper was accepted by Agostino Capponi, finance.

P.136 Evaluating outcome prediction models in endovascular treatment for acute ischemic stroke using baseline, treatment and post-treatment variables

Background: Predicting outcomes after endovascular treatment (EVT) for acute ischemic stroke with baseline variables remains a challenge. We assessed the performance of stroke outcome prediction models for EVT in acute ischemic stroke in an iterative fashion using baseline, treatment-related and post-treatment variables. Methods: Data from the ESCAPE-NA1 trial were used to build 4 outcome prediction models using multi-variable logistic regression: Model 1 included baseline variables only that are available prior to treatment decision-making, model 2 included additional treatment-related variables, model 3 additional early post-treatment variables, and model 4 additional late post-treatment variables. The primary outcome was 90-day modified Rankin Scale score 0-2. Model performance was compared using the area under the curve (AUC). Results: Among 1,105 patients, good outcome was achieved by 666 (60.3%). When using baseline variables only (model 1), the AUC was 0.74 (95%CI:0.71-0.77); this iteratively improved when treatment and post-treatment variables were added to the models (model 2: AUC 0.77,95%CI: 0.74-0.80, model 3: AUC 0.80,95%CI:0.77-0.83, model 4: AUC 0.82, 95%CI:0.79-0.85). Conclusions: Predicting EVT outcomes using baseline variables alone is inaccurate in one in four patients, and may be inappropriate for patient selection. Even the most comprehensive models with treatment-related and post-treatment factors involve considerable uncertainty.