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Low EBV, youth, and first-time donor status are major risk factors for IRs and DRs. Women are more likely than men to report DRs. Delayed and off-site reactions lead to potentially preventable morbidity. Understanding the physiologic basis of DRs may lead to the development of appropriate interventions to reduce their likelihood.

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This paper identifies deficiencies in some current practices of causation and risk evaluation by toxicologists and formulates an evidence-based solution. The practice of toxicology focuses on adverse health events caused by physical or chemical agents. Some relations between agents and events are identified risks, meaning unwanted events known to occur at some frequency. However, other relations that are only possibilities – not known to occur (and may never be realized) – also are sometimes called risks and are even expressed quantitatively. The seemingly slight differences in connotation among various uses of the word ‘risk’ conceal deeply philosophic differences in the epistemology of harm. We label as ‘nomological possibilities’ (not as risks) all predictions of harm that are known not to be physically or logically impossible. Some of these nomological possibilities are known to be causal. We term them ‘epistemic’. Epistemic possibilities are risks. The remaining nomological possibilities are called ‘uncertainties’. Distinguishing risks (epistemic relationships) from among all nomological possibilities requires knowledge of causation. Causality becomes knowable when scientific experiments demonstrate, in a strong, consistent (repeatable), specific, dose-dependent, coherent, temporal and predictive manner that a change in a stimulus determines an asymmetric, directional change in the effect. Many believe that a similar set of characteristics, popularly called the ‘Hill Criteria’, make it possible, if knowledge is robust, to infer causation from only observational (nonexperimental) studies, where allocation of test subjects or items is not under the control of the investigator. Until the 1980s, medical decisions about diagnosis, prevention, treatment or harm were often made authoritatively. Rather than employing a rigorous evaluation of causal relationships and applying these criteria to the published knowledge, the field of medicine was dominated by authority-based opinions, expressed by experts (or consensus groups of experts) relying on their education, training, experience, wisdom, prestige, intuition, skill and improvisation. In response, evidence-based medicine (EBM) was developed, to make a conscientious, explicit and judicious use of current best evidence in deciding about the care of individual patients. Now globally embraced, EBM employs a structured, ‘transparent’ protocol for carrying out a deliberate, objective, unbiased and systematic review of the evidence about a formally framed question. Not only in medicine, but now in dentistry, engineering and other fields that have adapted the methods of EBM, it is the quality of the evidence and the rigor of the analysis through evidence-based logic (EBL), rather than the professional standing of the reviewer, that leads to evidence-based conclusions about what is known. Recent studies have disclosed that toxicologists (individually or in expert groups), not unlike their medical counterparts prior to EBM, show distressing variations in their biases with regard to data selection, data interpretation and data evaluation when performing reviews for causation analyses. Moreover, toxicologists often fail to acknowledge explicitly (particularly in regulatory and policymaking arenas) when shortcomings in the evidence necessitate reliance upon authority-based opinions, rather than evidence-based conclusions (Guzelian PS, Guzelian CP. Authority-based explanation. Science 2004; 303: 1468-69). Accordingly, for answering questions about general and specific causation, we have constructed a framework for evidence-based toxicology (EBT), derived from the accepted principles of EBM and expressed succinctly as three stages, comprising 12 total steps. These are: 1) collecting and evaluating the relevant data (Source, Exposure, Dose, Diagnosis); 2) collecting and evaluating the relevant knowledge (Frame the question, Assemble the relevant (delimited) literature, Assess and critique the literature); and 3) Joining data with knowledge to arrive at a conclusion (General causation – answer to the framed question, Dose-response, Timing, Alternative cause, Coherence). The second of these stages (which amounts to an analysis of general causation), is addressed by an EBM-styled approach (adapted for the infrequent availability of human experimental studies in environmental toxicology). This involves assembling literature (through documented algorithms for database queries), excluding irrelevancies by use of delimiters as filters, and ranking and rating the remaining articles for strength of study design and for quality of execution gauged by application of either a ready-made quality assessment instrument or a custom designed checklist or scale. The results of this systematic review (including a structured review of relevant animal and in vitro studies) are then themselves systematically used to determine which causation criteria are fulfilled. Toxicology is maturing from a derivative science largely devoted to routinized performance and interpretation of safety tests, to a discipline deeply enmeshed in the remarkable advances in biochemistry and molecular biology to better understanding the nature and mechanism of adverse effects caused by chemicals. It is time for toxicologists, like scientists in other fields, to formalize a method for differentiating settled toxicological knowledge of risk from mere nomological possibility, and for communicating their conclusions to other scientists and the public. It is time for EBT.

The total synthesis of [Ψ[C(=S)NH]Tpg4]vancomycin aglycon (8) and its unique AgOAc-promoted single-step conversion to [Ψ[C(=NH)NH]Tpg4]vancomycin aglycon (7), conducted on a fully deprotected substrate, are disclosed. The synthetic approach not only permits access to 7, but it also allows late stage access to related residue 4 derivatives, alternative access to [Ψ[CH2NH]Tpg4]vancomycin aglycon (6) from a common late stage intermediate, and provides authentic residue 4 thioamide and amidine derivatives of the vancomycin aglycon that will facilitate ongoing efforts on their semisynthetic preparation. In addition to early stage residue 4 thioamide introduction, allowing differentiation of one of seven amide bonds central to the vancomycin core structure, the approach relied on two aromatic nucleophilic substitution reactions for formation of the 16-membered diaryl ethers in the CD/DE ring systems, an effective macrolactamization for closure of the 12-membered biaryl AB ring system, and the defined order of CD, AB, and DE ring closures. This order of ring closures follows their increasing ease of thermal atropisomer equilibration, permitting the recycling of any newly generated unnatural atropisomer under progressively milder thermal conditions where the atropoisomer stereochemistry already set is not impacted. Full details of the evaluation of 7 and 8 along with several related key synthetic compounds containing the core residue 4 amidine and thioamide modifications are reported. The binding affinity of compounds containing the residue 4 amidine with the model d-Ala-d-Ala ligand 2 was found to be only 2–3 times less than the vancomycin aglycon (5) and this binding affinity is maintained with the model d-Ala-d-Lac ligand 4, representing a nearly 600-fold increase in affinity relative to the vancomycin aglycon. Importantly, the amidines display effective dual, balanced binding affinity for both ligands (Ka 2/4 = 0.9–1.05) and they exhibit potent antimicrobial activity against VanA resistant bacteria (E. faecalis, VanA VRE) at a level accurately reflecting these binding characteristics (MIC = 0.3–0.6 µg/mL), charting a rational approach forward in the development of antibiotics for the treatment of vancomycin-resistant bacterial infections. In sharp contrast, 8 and related residue 4 thioamides failed to bind either 2 or 4 to any appreciable extent, do not exhibit antimicrobial activity, and serve to further underscore the remarkable behavior of the residue 4 amidines.

The interventions to reduce vasovagal reactions in whole blood donors were effective. Future efforts to reduce reactions in blood donors can build on the strengths and avoid the weaknesses identified while conducting and analyzing the data from this study.

The glycopeptide antibiotics are the most important class of drugs used in the treatment of resistant bacterial infections including those caused by methicillin-resistant Staphylococcus aureus (MRSA). After more than 50 years of clinical use, the emergence of glycopeptide resistant Gram-positive pathogens such as vancomycin-resistant enterococci (VRE) and vancomycin-resistant Staphylococcus aureus (VRSA) presents a serious global challenge to public health at a time few new antibiotics are being developed. This has led to renewed interest in the search for additional effective treatments including the development of new derivatives of the glycopeptide antibiotics. General approaches have been explored for modifying glycopeptide antibiotics, typically through the derivatization of the natural products themselves or more recently through chemical total synthesis. In this Perspective, we consider recent efforts to redesign glycopeptide antibiotics for the treatment of resistant microbial infections, including VRE and VRSA, and examine their future potential for providing an even more powerful class of antibiotics that are even less prone to bacterial resistance.

The emergence of bacteria resistant to vancomycin, often the antibiotic of last resort, poses a major health problem. Vancomycin-resistant bacteria sense a glycopeptide antibiotic challenge and remodel their cell wall precursor peptidoglycan terminus from D-Ala-d-Ala to D-Ala-D-Lac, reducing the binding of vancomycin to its target 1000-fold and accounting for the loss in antimicrobial activity. Here, we report [Φ[C(=NH)NH]Tpg4]-vancomycin aglycon designed to exhibit the dual binding to D-Ala-D-Ala and D-Ala-D-Lac needed to reinstate activity against vancomycin-resistant bacteria. Its binding to a model D-Ala-D-Ala ligand was found to be only two-fold less than vancomycin aglycon and this affinity was maintained with a model D-Ala-D-Lac ligand, representing a 600-fold increase relative to vancomycin aglycon. Accurately reflecting these binding characteristics, it exhibits potent antimicrobial activity against vancomycin-resistant bacteria (MIC = 0.31 g/mL, VanA VRE). Thus, a complementary single atom exchange in the vancomycin core structure (O NH) to counter the single atom exchange in the cell wall precursors of resistant bacteria (NH O) reinstates potent antimicrobial activity and charts a rational path forward for the development of antibiotics for the treatment of vancomycin-resistant bacterial infections.