Implementation of a ‘standard’ LIMS

This article is an extract of a presentation given at the LIMS conference in the Hague June 4, 1997 [S.M. Fransen et al., Presentation given at the conference LIMS 97, June 4 1997 in the Hague.]. It describes the project steps for the LIMS project in the Danish company Novo Nordisk, with focus on vendor evaluation, validation and implementation of a ‘Standard’ LIMS software. The main project steps are described and experiences gained are discussed.     

Laparoscopic total and partial nephrectomy-the new standard?

Laparoscopic radical nephrectomy has been shown in long-term follow-up to provide shorter patient hospitalization and effective cancer control with no significant difference in survival compared with open radical nephrectomy. The major technical issue for success of laparoscopic partial nephrectomy is hemostatic control, and several techniques have been developed to improve control. Laparoscopic partial nephrectomy continues to evolve along two therapeutic technical avenues: hilar clamping with ischemia versus no hilar clamping. The benefits of laparoscopy for the kidney have clearly been demonstrated in terms of less pain, decreased convalescence, and decreased narcotic requirements. With short-term outcomes demonstrating laparoscopic partial nephrectomy as an efficacious procedure, the role of laparoscopic partial nephrectomy should continue to increase.     

Is meta-analysis the platinum standard of evidence?

An astonishing volume and diversity of evidence is available for many hypotheses in the biomedical and social sciences. Some of this evidence—usually from randomized controlled trials (RCTs)—is amalgamated by meta-analysis. Despite the ongoing debate regarding whether or not RCTs are the ‘gold-standard’ of evidence, it is usually meta-analysis which is considered the best source of evidence: meta-analysis is thought by many to be the platinum standard of evidence. However, I argue that meta-analysis falls far short of that standard. Different meta-analyses of the same evidence can reach contradictory conclusions. Meta-analysis fails to provide objective grounds for intersubjective assessments of hypotheses because numerous decisions must be made when performing a meta-analysis which allow wide latitude for subjective idiosyncrasies to influence its outcome. I end by suggesting that an older tradition of evidence in medicine—the plurality of reasoning strategies appealed to by the epidemiologist Sir Bradford Hill—is a superior strategy for assessing a large volume and diversity of evidence.     

A standard model of Alzheimer’s disease?

ABSTRACT

The recent Research Framework proposed by the US National Institute on Aging and the Alzheimer’s Association (NIA-AA) recommends that Alzheimer’s disease be defined by its specific biology rather than by non-specific neurodegenerative and syndromal features. By affirming markers of abnormal Aβ and tau proteins as the essential pathobiological signature of Alzheimer’s disease, the Framework tacitly reinforces the amyloid (Aβ) cascade as the leading theory of Alzheimer pathogenesis. In light of recent evidence that the cascade is driven by the misfolding and templated aggregation of Aβ and tau, we believe that an empirically grounded Standard Model of Alzheimer’s pathogenesis is within reach. A Standard Model can clarify and consolidate existing information, contextualize risk factors and the complex disease phenotype, identify testable hypotheses for future research, and pave the most direct path to effective prevention and treatment.     

Elacestrant in metastatic breast cancer: Is the “standard of care” meeting standard requirements?

The EMERALD trial was an open label phase 3 trial evaluating elacestrant, the first oral selective estrogen receptor degrader (SERD), as compared to “standard of care”, in ER+/HER2- (hormone receptor positive, no HER2 overexpression) advanced or metastatic breast cancer.The EMERALD trial restricted the “standard of care” control arm to limited options that may have led to a substandard control arm. We describe how the EMERALD trial protocol allowed different clinically inappropriate scenarios in the control arm, according to prior therapy. The main relevant question remains the potential advantage of elacestrant over fulvestrant in fulvestrant-naive patients.Analyzing outcomes in subgroups according to prior and per-protocol therapy would help analyzing trial results. However, these subgroup results may be non-significant, and another randomized trial will be needed. Trials should be designed to answer directly clinical questions that are relevant.     

The standard of neutrality: still flapping in the breeze?

Neutrality plays an important role as a null model in evolutionary biology. Recent theoretical advances suggest that neutrality is not a unitary concept, and we identify three distinct forms of neutrality. Eu‐neutrality means that types do not differ in any measurable way and is thus the idealized form of neutrality. However, individuals or species that do differ in important ways can behave neutrally under some circumstances, both broadening and complicating the applicability of the concept of neutrality. Our second two types of neutrality address two quite different forms of context‐dependent neutrality. Circum‐neutrality means that two character states have the same direct effect on fitness but do not evolve neutrally because of differences in their circumstances. Iso‐neutrality means that two types are equivalent in some population or ecological contexts but not in others, producing an isocline. Confounding of these different definitions has created significant confusion about which models are truly neutral, why some models behave neutrally even when there are large differences in reproductive outputs, and what these different views of neutrality mean to practicing biologists. These complications call into question the acceptance of neutral models as null models and suggest that a better approach is to compare the predictions of models that differ in sources of stochasticity and degree of selection.     

Pseudo-homology of protein standard structures formed by two consecutive β-strands

Protein standard structures formed by two consecutive β-strands connected by short loops are considered in this paper. A stereochemical analysis of each standard structure has been performed to determine the necessary conditions which must be fulfilled in the amino acid sequence encoding the standard structure. It is shown that amino acid sequences coding for the same standard structure in ditterent proteins have practically the same order of hydrophobic, hydrophilic and glycine residues. The results of the stereochemical analysis are confirmed by a large number of examples from known protein structures.     

A question of conflict: Three‐item and standard parsimony compared

A simple example of conflicting data, relevant to comparison between standard and three‐item parsimony analysis, is two characters (nodes, trees) differently relating four taxa: (AB)CD and A(BCD). This conflict is differently resolved by standard and three‐item analysis, which with fractional weighting yields the unique result (AB)(CD). There is reason to consider this result as the more accurate resolution of these conflicting data.     

Cecal ligation and puncture: the gold standard model for polymicrobial sepsis?

Sepsis is a serious medical condition characterized by dysregulated systemic inflammatory responses followed by immunosuppression. To study the pathophysiology of sepsis, diverse animal models have been developed. Polymicrobial sepsis induced by cecal ligation and puncture (CLP) is the most frequently used model because it closely resembles the progression and characteristics of human sepsis. Here we summarize the role of several immune components in the pathogenesis of sepsis induced by CLP. However, several therapies proposed on the basis of promising results obtained by CLP could not be translated to the clinic. This demonstrates that experimental sepsis models do not completely mimic human sepsis. We propose several strategies to narrow the gap between experimental sepsis models and clinical sepsis, including targeting factors that contribute to the immunosuppressive phase of sepsis, and reproducing the heterogeneity of human patients.     

Diagnostics for herpes simplex virus: is PCR the new gold standard?

Herpes simplex virus (HSV) is one of the most common, yet frequently overlooked, sexually transmitted infections. Since the type of HSV infection affects prognosis and subsequent counseling, type-specific testing to distinguish HSV-1 from HSV-2 is recommended. Although PCR has been the diagnostic standard for HSV infections of the central nervous system, until now viral culture has been the test of choice for HSV genital infection. However, HSV PCR, with its consistently and substantially higher rate of HSV detection, will likely replace viral culture as the gold standard for the diagnosis of genital herpes in people with active mucocutaneous lesions, regardless of anatomic location or viral type. Alternatively, type-specific serologic tests based on glycoprotein G should be the test of choice to establish the diagnosis of HSV infection when no active lesion is present. Given the difficulty in making the clinical diagnosis of HSV, the growing worldwide prevalence of genital herpes and the availability of effective antiviral therapy, there is an increased demand for rapid, accurate laboratory diagnosis of patients with HSV.     

The biological standard of living in Suriname,c. 1870–1975

The physical stature of Surinamese soldiers is estimated to have increased by more than 3 cm between 1870 and 1909. In the subsequent four decades, the increase in adult male and female height amounted to 0.3–0.5 cm and 0.9–1.0 cm per decade, respectively. This increase in height continued and accelerated during the second half of the twentieth century. Height increase among African and Hindustani Surinamese males and females was similar. Height differences between African and Hindustani Surinamese were therefore fairly constant over time, at 4–5 cm. Other indicators of nutritional and health status, such as infant mortality, showed continuous improvement, whereas per capita calorie and protein availability improved in the twentieth century.     

Models of human genetic disease: how biased are the standard formulae?

Standard theory provides a simple prediction for the frequency of a recessive lethal allele conferring heterozygous protection against an infectious disease (the best-known example being sickle cell protection against malaria). This relationship allows historic disease mortality rates to be estimated. There are, however, hidden biases in this approach. Reproductively active human females in archaic societies normally produce children at intervals of around 4 years. If death of the fetus or young infant (less than around 3 years of age) occurs, then the mother re-enters oestrus and produces another child. This 'reproductive compensation' reduces selection against the agent causing early mortality (the recessive allele or infective agent) and biases our estimates of historic mortality rates. The magnitude of these biases is investigated. Re-conception also constitutes a demographic selective pressure acting alongside natural selection: lethal genetic diseases (or tightly linked loci) will be selected to become ever more virulent, killing at ever decreasing ages, to allow the mother to re-enter oestrus and re-conceive a (hopefully unaffected) sibling; this effect also invalidates statistical tests using the number of alleles to distinguish overdominance from drift as explanations for high allele frequency. The same bias affects calculations of mutation/selection balance: for any given mutation rate, syndromes which kill early in life will reach much higher frequencies than those killing at later ages. An intriguing consequence is that lethal recessive disorders in humans will increase in frequency by up to 45% as a consequence of the recent demographic transition to planned family size.     

Biosimilars 2.0: Guiding principles for a global “patients first” standard

In the European Union, biosimilar products have been approved since 2006 under an abbreviated pathway that leverages their similarity to an existing “reference” biological product. The products approved to date are based on recombinant versions of endogenous proteins with well-understood structures and pharmacology, but complicated safety and immunogenicity profiles. The period during the 2000s that included the first reviews, approvals, sale and use of biosimilars is referred to herein as “Biosimilars 1.0.” Over the next several years, a new and advanced tranche of biosimilars will be developed for complex reference products, including medicines used in the treatment of cancer and autoimmune diseases. A global market for biosimilars is developing and this may well foreshadow the beginning of the second era of product development. This Biosimilars 2.0 period will likely be characterized by the development of complex products, global harmonization of standards and the increasing demand for long-term monitoring of pharmaceuticals. The products developed in this period should exhibit high levels of fidelity to the reference products and should be rigorously evaluated in analytical, non-clinical and clinical comparisons. Additionally, Biosimilars 2.0 manufacturers should strive for transparency in their labels and take proactive strides to be accountable to providers and patients for the quality of their products. An important opportunity now exists for the healthcare community, industry and regulators to work in partnership, to outline the appropriate standards for these products and to facilitate increased access while meeting patients'' needs.Key words: biotechnology, biosimilars, generic drugs, monoclonal antibodies, pharmacodynamics, pharmacokinetics     

Does decomposition of standard materials differ among grassland patches maintained by livestock?

Grazing can modify vegetation structure and species composition through selective consumption, modifying plant litter quality and hence decomposability. In most grasslands, moderate stocking rates maintain a mosaic of high‐quality patches, preferentially used by herbivores (‘grazing lawns’), and low‐quality tall patches, which are avoided. In grazing lawns decomposition rates can be accelerated because of the higher litter quality of its component species and, besides, through the indirect effect of increased nutrient availability in soil. We aimed at testing this indirect effect using standard materials, comparing their decomposition in grazing lawns, open and closed tall tussock grasslands. We selected 10 patches of each type and sampled floristic composition, soil variables and cattle dung deposition. Standard materials were filter paper and Poa stuckertii litter. We prepared litterbags of 0.3 mm (thin mesh) and 1 mm mesh size (coarse mesh). Samples were incubated for 65 days in two ways: above‐ground (thin and coarse mesh) and below‐ground (only thin mesh), aiming at analysing the conditions for decomposition for surface litter and buried litter or dead roots, respectively. Physical and chemical soil variables did not differ among patch types, despite the differences in species composition. Closed tussock grasslands showed the lowest dung deposition, confirming the less intense use of these patches. Soil nitrogen availability (N‐NO₃^‐ and N‐NH₄⁺) was not significantly different among patch types. Each standard material followed a different decomposition pattern across patch types. For above‐ground incubated samples, Poa litter decomposed significantly faster in lawns, and slower in open tussock grasslands. Filter paper decomposed significantly faster in closed tussock grasslands than in the other two patch types. Decomposition of below‐ground incubated samples did not significantly differ among patch types, in line with results for soil variables. Above‐ground differences in decomposition may be associated with differences in microclimatic conditions resulting from differences in vegetation structure.     

Modification of the GeneScan 2500™ fluorescent dye standard for accurate product sizing

This article describes a procedure for modification of the commercially prepared GeneScan 2500™ size standard for allelotyping with large DNA fragments such as variable number tandem repeats (VNTRs). Here a procedure was used to adapt commercially available size standards for the sizing of the interleukin-6 (IL6) 3′VNTR, which has allele sizes ranging from 600 to 900 base pairs. The procedure involves inclusion of products from the target PCR reaction as additional size standards for use with the size standard and is therefore applicable to the sizing of any product with any commercial size standard. Initially alleles were sized by fluorescent cycle sequencing to give a true estimate of their size (base pairs). Subsequently, the major alleles were labeled with a pig-tailed ROX-dye-labeled primer and inserted into the standard range. Finally alleles were resized following PCR with an un pig tailed HEX labeled primer and the modified standard. Once the size standard is modified, stocks can be stored indefinitely and replenished by re-PCR of selected alleles using the ROX-labeled primer. Modification of this approach can be applied to the sizing of any product where it is thought that commercially available size standards are performing suboptimally. Modification of size standards in this way does not affect performance in size regions other than those for which the extra products are included.