Vaccines for emerging pathogens: prospects for licensure.

Globally, there are a number of emerging pathogens. For most, there are no licensed vaccines available for human use, although there is ongoing research and development. However, given the extensive and increasing list of emerging pathogens and the investment required to bring vaccines into clinical use, the task is huge. Overlaid on this task is the risk of anti-microbial resistance (AMR) acquisition by micro-organisms which can endow a relatively harmless organism with pathogenic potential. Furthermore, climate change also introduces a challenge by causing some of the insect vectors and environmental conditions prevalent in tropical regions to begin to spread out from these traditional areas, thus increasing the risk of migration of zoonotic disease. Vaccination provides a defence against these emerging pathogens. However, vaccines for pathogens which cause severe, but occasional, disease outbreaks in endemic pockets have suffered from a lack of commercial incentive for development to a clinical standard, encompassing Phase III clinical trials for efficacy. An alternative is to develop such vaccines to request US Emergency Use Authorization (EUA), or equivalent status in the United States, Canada and the European Union, making use of a considerable number of regulatory mechanisms that are available prior to licensing. This review covers the status of vaccine development for some of the emerging pathogens, the hurdles that need to be overcome to achieve EUA or an equivalent regional or national status and how these considerations may impact vaccine development for the future, such that a more comprehensive stockpile of promising vaccines can be achieved.

Excellent long-term results of cardiac valve replacement with the St Jude Medical valve prosthesis.

BACKGROUND: A retrospective review of the performance of the St Jude Medical valve prosthesis over a 12-year period was undertaken. METHODS AND RESULTS: Between 1978 and 1990, 696 St Jude Medical valve prostheses (351 isolated aortic, 191 isolated mitral, 64 double aortic/mitral) were implanted into 616 patients (mean age, 55 years). Concomitant coronary artery graft surgery was performed in 18%. During mid-1991, follow-up was conducted, yielding a 97% completion (16 lost), for a total of 3075 cumulative patient-years (mean, 5.0 years). Early (30-day) mortality rates were 3.1%, 5.2%, and 6.4% after aortic, mitral, and double valve replacements, respectively. The 5-year actuarial survival rates were 94.1 +/- 1.3%, 85.8 +/- 2.7%, and 86.3 +/- 4.6% and those for 10 years were 89.6 +/- 1.9%, 72.9 +/- 6.1%, and 83.0 +/- 5.4%, respectively. There were no structural valve failures. Anticoagulant-related hemorrhage was the most common valve-related complication (28 events, 0.9% per patient-year), with three being fatal. Thromboembolism (13 events) occurred at a rate of 0.5% per patient-year (0.6% aortic, 0.3% mitral, 0.3% double). All of the nonstructural deteriorations (10 events, 0.3% per patient-year) were paravalvular leaks, including 3 aortic valve replacements in patients who developed hemolytic anemia. There was 1 valve thrombosis (0.03% per patient-year). Patients undergoing coronary artery graft surgery had lower survival and higher complication rates than patients without coronary artery graft surgery. There was a significant improvement (P < .001) in New York Heart Association functional class for the entire patient population. CONCLUSIONS: The St Jude Medical valve prosthesis has performed well in all positions over a 12-year period, with an acceptably low incidence of valve-related complications.

An intensive field trial to assess hazards to birds and mammals from the use of methiocarb as a bird repellent on ripening cherries.

: A field trial was carried out in Kent, UK, in 1980, to assess the possible hazards to wildlife of methiocarb used as a spray to protect ripening cherries from damage by birds. A broad range of studies was undertaken on a single site subjected to a series of five applications. Ground deposition was measured by analysis of strips of chromatography paper and petri dishes placed between lines of trees. Airborne drift was measured on targets up to 11 m above the ground, and methiocarb residues were measured in samples of cherries. Birds were captured by intensive mist-netting throughout the trial, and breeding success was monitored in nest boxes and natural nest sites. Livetraps were set to catch small mammals in the orchard on five occasions during the trial. Systematic searches for possible casualties were made, resulting in the discovery of 21 birds found dead or incapacitated. Levels of activity of plasma, liver and brain esterases were measured in samples taken from several species, and liver slices from House Sparrows, Starlings and Thrushes were examined histologically for signs of cell damage. Samples of breast muscle tissue from Starlings and House Sparrows were analysed by GLC for residues of methiocarb and its principal breakdown product, methiocarb sulfoxide. Overall, the trial revealed that many birds and mammals were exposed to methiocarb, but its effects were largely transient and sublethal. Even a heavy repeated programme of spray applications did not cause any serious hazard to wildlife populations.

Empyema thoracis: 14-year experience in a teaching center.

One hundred two patients with empyema thoracis were managed at the Royal Melbourne Hospital between 1976 and 1989. Fifty-five cases of empyema thoracis were postpneumonic, 8 followed esophageal rupture, and 5 were associated with thoracic trauma. Some form of systemic illness was a major contributing factor in the presentation of 29 patients. A single causal organism was found in 53 patients (the most common being Staphylococcus aureus), multiple organisms in 36, and no growth in 13. During the years 1983 to 1989 there was an increased incidence of empyemas caused by multiple or antibiotic-resistant organisms. Operative drainage was required in 90 patients and 12 were managed by thoracentesis or intercostal tube drainage alone. The in-hospital mortality rate for patients managed nonoperatively was 58% (7 of 12 patients); it was 16% (14 of 90 patients) for those receiving operative drainage. There were seven late deaths, four empyema related and three nonrelated. Early adequate operative drainage is recommended for patients with empyema thoracis.

Combined carotid and coronary surgery.

A retrospective review of 40 consecutive patients undergoing combined coronary artery bypass grafting (CABG) and unilateral carotid endarterectomy (CEA) was carried out to determine the stroke rate for the procedure. Patients presenting with severe coronary artery disease judged to be at risk of imminent myocardial infarction, who had signs of cerebral ischaemia (70%) or asymptomatic carotid bruits (30%), were investigated for extracranial carotid vascular disease. Patients with severe stenotic carotid lesions associated with high risk coronary artery disease underwent combined CEA/CABG. Three patients had a previous contralateral CEA. The average age of the patients was 62 years, and there were 31 males and nine females. CEA was completed prior to CABG under the same general anaesthetic. There were 24 CEAs on the left and 16 on the right. Six patients suffered a postoperative cerebral ischaemic event (15.4%): a reversible ischaemic neurological deficit in three (7.7%), a transient ischaemic cerebral event in two (5.1%), and a permanent stroke occurred in one (2.6%). Two deaths occurred and both were cardiac related. Combined CEA/CABG in patients with stenotic lesions of the coronary and extra-cranial carotid vascular systems who are at risk of cerebral or myocardial infarction, can be performed with a permanent stroke rate within the published range for either CEA or CABG alone and with a mortality of 5%.

Early clinical experience of a new heparinoid, Org 10172, in prevention of deep venous thrombosis.

The potential antithrombotic effect of a new low molecular weight heparinoid, Org 10172, was examined in a randomized, double-blind, placebo-controlled, dose-ranging pilot study of the prevention of deep venous thrombosis (DVT) in 45 high-risk patients having major thoracic or abdominal surgery for cancer. Org 10172 was given in doses of 500, 750 or 1000 U bd subcutaneously. DVT occurred in 9 of 14 patients given placebo and in 4 of 11 patients given 500 U bd but in none of the 20 patients given 750 or 1000 U bd. Operative blood loss and post-operative bleeding were not significantly different between the groups but one patient given 1000 U bd had major post-operative bleeding. Average mid-interval and trough plasma anti-Xa levels reached 0.26 and 0.20 U/ml respectively following the highest dose. It is concluded that Org 10172 is a potentially useful antithrombotic agent and that the effective and safe dose appears to be between 500 and 1000 U bd for prevention of DVT in high-risk patients.

Psychiatric aspects of coronary artery surgery. A prospective study.

A psychiatric assessment was carried out before operation, and at three months and 12 months after operation, in 77 men undergoing coronary artery bypass graft surgery. Neither psychiatric assessment before the operation nor perioperative surgical assessment could predict the physical outcome of surgery. The physical results of surgery were good, but there was a 20% decrease in the number of patients who were in employment after the operation. Abnormally high scores on measures of anxiety and depression were present in about 50% of patients before the operation, and in about one-third of patients after the operation. Impairment in various aspects of personality-functioning since surgery was reported by 7%-29% of patients. These complaints were not correlated with the surgical result. Attention is drawn to this area of persisting postoperative morbidity.

Prophylaxis of venous thrombosis after major thoracic surgery.

The high incidence (50-60%) of deep venous thrombosis of the legs (DVT) after major thoracic surgery is reduced only by about half with routine low-dose heparin prophylaxis. The present study compared the efficacy of a higher dose of heparin (7500 U twice daily) with the commonly used dose of 5000 U twice daily in preventing scan-detected DVT in 100 consecutive patients having thoracotomy for carcinoma of the lung or oesophagus. After the higher dose of heparin, postoperative DVT was not significantly less frequent (22% compared with 33% for total DVT) but was significantly less extensive (8% and 14%, respectively, for bilateral calf DVT, and 0% and 4% for popliteal DVT). Despite prophylaxis, DVT was especially common after oesophagogastrectomy (41% total DVT, 30% extensive DVT). No excessive postoperative bleeding was noted in either group. It is concluded that an increased dose of heparin safely offers increased prophylaxis against DVT in patients undergoing major thoracic surgery for cancer.

Cost analysis and cost justification of automated data processing in the clinical laboratory.

Prospective cost analysis of alternative data processing systems can be facilitated by proper selection of the costs to be analyzed and realistic appraisal of the effect on staffing. When comparing projects with dissimilar cash flows, techniques such as analysis of net present value can be helpful in identifying financial benefits. Confidence and accuracy in prospective analyses will increase as more retrospective studies are published. Several accounts now in the literature describe long-term experience with turnkey laboratory information systems. Acknowledging the difficulty in longitudinal studies, they all report favorable effects on labor costs and recovery of lost charges. Enthusiasm is also expressed for the many intangible benefits of the systems. Several trends suggest that cost justification and cost effectiveness will be more easily demonstrated in the future. These are the rapidly decreasing cost of hardware (with corresponding reduction in service costs) and the entry into the market of additional systems designed for medium to small hospitals. The effect of broadening the sales base may be lower software prices. Finally, operational and executive data management and reporting are destined to become the premier extensions of the LIS for cost justification. Aptly applied, these facilities can promote understanding of costs, control of costs, and greater efficiency in providing laboratory services.

The effects of 1,1-di(p-chlorophenyl)-2-chloroethylene (DDMU) on hepatic morphology of Japanese quail.

The effects of dietary administration of 1,1-di(p-chlorophenyl)-2-chloroethylene (DDMU) to Japanese quail at a concentration of 100 ppm were investigated for periods of up to 32 days. Hepatic morphology was studied by light microscopy. Histologic changes observed included cytoplasmic and nuclear degeneration in the hepatocytes followed by severe lipid accumulation and hepatocellular hypertrophy. There was a progressive increase in cytoplasmic vacuoles containing lipid up to Day 24 followed by a decrease by Day 32 when the numbers of vacuoles remained greater than those in untreated quail livers. The vacuoles showed a distribution which followed the functional acinar units of the liver. Increased numbers and hypertrophy were observed in Kupffer cells and fibrocytes. There was an occasional necrotic hepatocyte observed but this lesion was not a prominent feature. Hepatocellular hyperplasia occurred as the lipid accumulation decreased. The histologic findings are compared with the biphasic response previously described.

Control enzyme levels in the plasma, brain and liver from wild birds and mammals in Britain.

Brain from 47 avian and 17 mammalian species and the liver from 19 avian and 7 mammalian species has been examined for acetyl cholinesterase and nitrophenyl acetate esterase activities. Plasma from 27 avian and 7 mammalian species has been examined for acetyl cholinesterase, cholinesterase, nitrophenyl acetate esterase, glutamate, oxaloacetate transaminase, glutamate pyruvate transaminase, glutamate dehydrogenase, sorbitol dehydrogenase and lactate dehydrogenase activities. The studies have revealed that variations in enzyme activities occur between species but that there are discernible trends within families. The results indicate that comprehensive control enzyme data is necessary in order to assess the effects of exposure to agricultural chemicals in wildlife.