Evidence-based care: 2. Setting guidelines: how should we manage this problem?

There are four steps in determining how to manage a clinical problem. The first is to formulate questions that are answerable; the second is to locate and synthesize the evidence needed to answer the questions; the third is to estimate the expected benefits, harms and costs of each option based on the evidence; and the fourth is to judge the relative value of the expected outcomes to conclude whether the benefits are worth the harms and costs. It is impractical to repeat these steps for every clinical decision. Therefore, implicitly or explicitly, physicians rely on guidelines, "rules" that simplify decision making about complex problems. If the methods used to develop a guideline are not explicit it is difficult or impossible to know how much confidence to place in it. Therefore, for common and important clinical problems, physicians should rely on guidelines that are systematically developed using explicit methods.     

Characterization of large intact protein ions by mass spectrometry: What directions should we follow?

Theoretically, the gas-phase interrogation of whole proteoforms via mass spectrometry, known as top-down proteomics, bypasses the protein inference problem that afflicts peptide-centric proteomic approaches. Despite this obvious advantage, the application of top-down proteomics remains rare, mainly due to limited throughput and difficulty of analyzing proteins >30 kDa. Here we will discuss some of the problems encountered during the characterization of large proteoforms, and guided by a combination of theoretical background and experimental evidence we will describe some innovative data acquisition strategies and novel mass spectrometry technologies that can at least partially overcome such limitations.     

Sudden cardiac death: what should we tell the family?

The sudden unexpected death of a child or a young person can have enormous implications for the surviving family members in addition to the immediate shock, sadness and sense of loss. The sudden loss of a sibling without any prior medical history may confront the family members with the question whether the sudden death was caused by a genetic condition and the fear that other family members may suffer the same fate.     

When should we save the most endangered species?

At the heart of our efforts to protect threatened species, there is a controversial debate about whether to give priority to cost-effective actions or whether focusing solely on the most endangered species will ultimately lead to preservation of the greatest number of species. By framing this debate within a decision-analytic framework, we show that allocating resources solely to the most endangered species will typically not minimise the number of extinctions in the long-term, as this does not account for the risk of less endangered species going extinct in the future. It is only favoured when our planning timeframe is short or we have a long-term view and we are optimistic about future conditions. Conservation funding tends to be short-term in nature, which biases allocations to more endangered species. Our work highlights the need to consider resource allocation for biodiversity over the long-term; 'preventive conservation', rather than just short-term fire-fighting.     

Arctic parasitology: why should we care?

The significant impact on human and animal health from parasitic infections in tropical regions is well known, but parasites of medical and veterinary importance are also found in the Arctic. Subsistence hunting and inadequate food inspection can expose people of the Arctic to foodborne parasites. Parasitic infections can influence the health of wildlife populations and thereby food security. The low ecological diversity that characterizes the Arctic imparts vulnerability. In addition, parasitic invasions and altered transmission of endemic parasites are evident and anticipated to continue under current climate changes, manifesting as pathogen range expansion, host switching, and/or disease emergence or reduction. However, Arctic ecosystems can provide useful models for understanding climate-induced shifts in host-parasite ecology in other regions.     

The genome in space and time: Does form always follow function?

Recent systematic studies using newly developed genomic approaches have revealed common mechanisms and principles that underpin the spatial organization of eukaryotic genomes and allow them to respond and adapt to diverse functional demands. Genomes harbor, interpret, and propagate genetic and epigenetic information, and the three-dimensional (3D) organization of genomes in the nucleus should be intrinsically linked to their biological functions. However, our understanding of the mechanisms underlying both the topological organization of genomes and the various nuclear processes is still largely incomplete. In this essay, we focus on the functional relevance as well as the biophysical properties of common organizational themes in genomes (e.g. looping, clustering, compartmentalization, and dynamics), and examine the interconnection between genome structure and function from this angle. Present evidence supports the idea that, in general, genome architecture reflects and influences genome function, and is relatively stable. However, the answer as to whether genome architecture is a hallmark of cell identity remains elusive.     

ATG proteins: Are we always looking at autophagy?

Autophagy is an intracellular degradation pathway that is regulated by the autophagy-related (ATG) proteins. For a long time it has been thought that ATG proteins were exclusively required for autophagy, but recent experimental evidence has revealed that these proteins are part of other cellular pathways, individually or as a functional group. To estimate the extent of these so-called unconventional functions of the ATG proteins, we decided to perform an unbiased siRNA screen targeting the entire ATG proteome and used viral replication as the readout. Our results have uncovered that a surprisingly high number of ATG proteins (36%) have a positive or negative role in promoting virus replication outside their classical role in autophagy. With the increasing knowledge about ATG protein unconventional functions and our investigation results, the interpretations about the possible involvement of autophagy in cellular or organismal functions that solely rely on the depletion of a single ATG protein, should be considered cautiously.     

Xenografts: are the risks so great that we should not proceed?

Animal organs could save patients needing transplants, but further research is necessary to resolve remaining problems with organ rejection. Furthermore, xenotransplantation risks transmitting animal pathogens to patients and to the general population. It would be unethical to proceed with clinical trials before principles and procedures for dealing with this risk are in place.     

Human fungal pathogens: Why should we learn?

Human fungal pathogens that cause invasive infections are hidden killers, taking lives of one and a half million people every year. However, research progress in this field has not been rapid enough to effectively prevent or treat life-threatening fungal diseases. To update recent research progress and promote more active research in the field of human fungal pathogens, eleven review articles concerning the virulence mechanisms and host interactions of four major human fungal pathogens–Candida albicans, Cryptococcus neoformans, Aspergillus fumigatus, and Histoplasma capsulatum–are presented in this special issue.