Computational design of a specific heavy chain/κ light chain interface for expressing fully IgG bispecific antibodies.

The use of bispecific antibodies (BsAbs) to treat human diseases is on the rise. Increasingly complex and powerful therapeutic mechanisms made possible by BsAbs are spurring innovation of novel BsAb formats and methods for their production. The long-lived in vivo pharmacokinetics, optimal biophysical properties and potential effector functions of natural IgG monoclonal (and monospecific) antibodies has resulted in a push to generate fully IgG BsAb formats with the same quaternary structure as monoclonal IgGs. The production of fully IgG BsAbs is challenging because of the highly heterogeneous pairing of heavy chains (HCs) and light chains (LCs) when produced in mammalian cells with two IgG HCs and two LCs. A solution to the HC heterodimerization aspect of IgG BsAb production was first discovered two decades ago; however, addressing the LC mispairing issue has remained intractable until recently. Here, we use computational and rational engineering to develop novel designs to the HC/LC pairing issue, and particularly for κ LCs. Crystal structures of these designs highlight the interactions that provide HC/LC specificity. We produce and characterize multiple fully IgG BsAbs using these novel designs. We demonstrate the importance of specificity engineering in both the variable and constant domains to achieve robust HC/LC specificity within all the BsAbs. These solutions facilitate the production of fully IgG BsAbs for clinical use.

Consistency of retrospective triage decisions as a standardised instrument for audit.

OBJECTIVES: To determine the level of agreement between senior medical staff when asked to perform retrospective case note review of nursing triage decisions, both before and after development of a consensus approach. METHODS: Four medical reviewers independently allocated triage categories to 50 emergency department patients after review of their case notes. They were blind to the identity of the triage nurse and their triage categorisation. The process was repeated twice, firstly after agreement on a consensus approach and then using formal guidelines. RESULTS: Agreement between reviewers was initially fair to moderate (kappa = 0.27 to 0.53). This failed to improve after development of a consensus approach (kappa = 0.29 to 0.57). There was a trend towards better agreement when guidelines were used but agreement was still only moderate (kappa = 0.31 to 0.63). CONCLUSIONS: Audit of nurse triage categorisation by senior medical staff performing case note review has only fair to moderate consistency between reviewers. Use of this technique will result in frustration among those whose performance is being audited if they recognise inconsistency in the standard they are compared against.

Excessive morphine requirements after pre-hospital nalbuphine analgesia.

Nalbuphine hydrochloride is an opioid agonist-antagonist that has gained acceptance as a pre-hospital analgesic agent. Nalbuphine has equal analgesic properties to morphine, has a low addiction potential, and can be stored and administered without restrictions, unlike morphine. To date no clinical evidence has been published to support the theoretical difficulty that the action of opioids administered after nalbuphine could be altered or negated. The following case reports highlight 10 patients who received nalbuphine pre-hospital and subsequently required higher doses of opioid analgesia than expected. The discussion summarises the properties of nalbuphine and identifies potential reasons why excessive amounts of opioid analgesia were required.

An evaluation of paramedic activities in prehospital trauma care.

The object of the study was to identify the effect paramedics have on prehospital trauma care and evaluate their influence on outcome compared to that of ambulance technicians. A prospective review of ambulance and hospital records was conducted over 2 years from 1 August 1993 to 31 July 1995. The setting for the study was the Royal Infirmary of Edinburgh and its primary response catchment area served by the South-East Region of the Scottish Ambulance Service central control room. The study involved 1090 patients brought to hospital by ambulance who met the entry criteria for the Scottish Trauma Audit Group study. The results show that paramedics spend significantly longer at scene than the ambulance technicians; however, there was no difference in total prehospital times between the groups. Paramedics direct a significantly higher proportion of patients to the resuscitation room and significantly more of these patients go to theatre, intensive care or the mortuary. There is no reduction in mortality or length of stay in intensive care in the paramedic group. The authors conclude that paramedics deliver an improved process of care but their activities do not significantly reduce mortality or length of stay in intensive care.

Women's health and social change: the case of lay midwives.

One reaction to the medicalization of birth has been the comeback of lay midwives in the past 10 years. While many practice alone as did midwives 80 years ago, now midwives are networking and organizing in regional and statewide groups, an important new distinction in the light of increasing regulatory policy formation by many states. Are these groups the beginnings of traditional bureaucratic health professional organizations or are they better described as alternative women's health groups that espouse nonhierarchical philosophies of women's health? In this article, we describe an empirical study of one such group, the Michigan Midwives' Association, and explore the philosophies and practices of individual members as well as the internal organization of the group and its influence on members. Data were collected using individual telephone interviews with 48 of 50 members, group newsletters and documents, and two spokespersons who developed an oral history of the Association since its origin in 1978. Results suggest that the group plays an important role in reinforcing individually held philosophies about women-controlled birth and in providing social support to health workers practicing outside the traditional system.

PIP: An empirical study of the Michigan Midwives Association (MMA), a lay midwife group, was undertaken, and a oral history was developed; interviews were conducted with 48 of the 50 members. Their ages cluster in the 30s. 27 (56%) of these women considered themselves full-time midwives. They usually meet their clients by word-of-mouth. Their practice patterns are characterized by client-centered care and continuity of care. The midwives' socioeconomic backgrounds are similar; but their political attitudes include many views. The words "natural" or "normal" were used by the midwives to describe birth. The MMAs origin was informal. Originally there were 8 members, but the group grew rapidly. Currently there are 50 members. Authority is shared equally among members. Work is done through committees. MMA members share common views about birth and women's right to make decisions about it. Members are spread out geographically all over Michigan, so frequent meetings are impossible. Many members have changed their practice ways since they started midwifery. About 75% of the midwives thought that client relationships had changed since they began practicing. Several felt that their attitudes toward their profession had changed. The MMA holds peer review sessions whenever a midwife requests it. An internal certification process has been developed.