General practitioner (GP) prescribing has been identified as an arena that has broad social and political implications, which stretch beyond individual outcomes for patients. This article revisits aspects of the controversy about prescribing benzodiazepines (or 'minor tranquillizers') through an exploration of contemporary views of GPs. In the 1980s the prescribing of these drugs was considered to be both a clinical and social problem, which brought medical decision making under public scrutiny. The legacy of this controversy for recent GPs remains a relatively under-explored topic. This article describes a qualitative study of GPs practising in the north-west of England about their views of prescribing benzodiazepines. The accounts of the respondents highlight a number of points about: blame allocation, past and present; clinical challenges about risk management; and deserving and undeserving patients. These GP views are then discussed in the wider context of psychotropic drug use. It is concluded that, while there has been a recent consensus that the benzodiazepines have been problematic, when they are placed in a longer historical context, a different picture is apparent because other psychotropic drugs have raised similar problems.

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1. The literature concerning attempts to produce macrocytic anemia of the liver-deficiency type in animals by operations on the gastrointestinal tract has been reviewed. Operations on the stomach have failed consistently to produce such an anemia, but success has been achieved by operations on the small intestine with the creation of blind loops or intestinal stenosis. 2. The technic we have used to produce macrocytic anemia in the rat is described in detail. The essentials are that the blind loop should fill with peristalsis and that it should not be too low down in the small intestine. 3. Anemia does not usually develop until an interval of several weeks or months after the operation. It is then macrocytic in type and acute in course. 4. The anemia is probably dependent on stagnation in the blind loop and a change in the bacterial flora of the small intestine.

Structure-guided vaccine design provides a route to elicit a focused immune response against the most functionally important regions of a pathogen surface. This can be achieved by identifying epitopes for neutralizing antibodies through structural methods and recapitulating these epitopes by grafting their core structural features onto smaller scaffolds. In this study, we conducted a modified version of this protocol. We focused on the PfEMP1 protein family found on the surfaces of erythrocytes infected with Plasmodium falciparum. A subset of PfEMP1 proteins bind to endothelial protein C receptor (EPCR), and their expression correlates with development of the symptoms of severe malaria. Structural studies revealed that PfEMP1 molecules present a helix-kinked-helix motif that forms the core of the EPCR-binding site. Using Rosetta-based design, we successfully grafted this motif onto a three-helical bundle scaffold. We show that this synthetic binder interacts with EPCR with nanomolar affinity and adopts the expected structure. We also assessed its ability to bind to antibodies found in immunized animals and in humans from malaria-endemic regions. Finally, we tested the capacity of the synthetic binder to effectively elicit antibodies that prevent EPCR binding and analyzed the degree of cross-reactivity of these antibodies across a diverse repertoire of EPCR-binding PfEMP1 proteins. Despite our synthetic binder adopting the correct structure, we find that it is not as effective as the CIDRα domain on which it is based for inducing adhesion-inhibitory antibodies. This cautions against the rational design of focused immunogens that contain the core features of a ligand-binding site of a protein family, rather than those of a neutralizing antibody epitope. IMPORTANCE Vaccines train our immune systems to generate antibodies which recognize pathogens. Some of these antibodies are highly protective, preventing infection, while others are ineffective. Structure-guided rational approaches allow design of synthetic molecules which contain only the regions of a pathogen required to induce production of protective antibodies. On the surfaces of red blood cells infected by the malaria parasite Plasmodium falciparum are parasite molecules called PfEMP1 proteins. PfEMP1 proteins, which bind to human receptor EPCR, are linked to development of severe malaria. We have designed a synthetic protein on which we grafted the EPCR-binding surface of a PfEMP1 protein. We use this molecule to show which fraction of protective antibodies recognize the EPCR-binding surface and test its effectiveness as a vaccine immunogen.