Outcomes sensitive to critical care nurse staffing levels: A systematic review.

OBJECTIVE: To determine associations between variations in registered nurse staffing levels in adult critical care units and outcomes such as patient, nurse, organisational and family outcomes. METHODS: We published and adhered to a protocol, stored in an open access repository and searched for quantitative studies written in the English language and held in CINAHL Plus, MEDLINE, PsycINFO, SCOPUS and NDLTD databases up to July 2020. Three authors independently extracted data and critically appraised papers meeting the inclusion criteria. Results are summarised in tables and discussed in terms of strength of internal validity. A detailed review of the two most commonly measured outcomes, patient mortality and nosocomial infection, is also presented. RESULTS: Our search returned 7960 titles after duplicates were removed; 55 studies met the inclusion criteria. Studies with strong internal validity report significant associations between lower levels of critical care nurse staffing and increased odds of both patient mortality (1.24-3.50 times greater) and nosocomial infection (3.28-3.60 times greater), increased hospital costs, lower nurse-perceived quality of care and lower family satisfaction. Meta-analysis was not feasible because of the wide variation in how both staffing and outcomes were measured. CONCLUSIONS: A large number of studies including several with high internal validity provide evidence that higher levels of critical care nurse staffing are beneficial to patients, staff and health services. However, inconsistent approaches to measurement and aggregation of staffing levels reported makes it hard to translate findings into recommendation for safe staffing in critical care.

Hepatic foci of cellular and enzymatic alteration and nodules in rats treated with clofibrate or diethylnitrosamine followed by phenobarbital: their rate of onset and their reversibility.

The histologic appearance and cytochemical characteristics of foci of hepatic cellular alteration, hepatic nodules, and hepatocellular carcinomas occurring in male Sprague-Dawley rats treated with the hypolipidemic agent clofibrate (CAS: 637-07-0), with phenobarbital (CAS: 50-06-6), or with diethylnitrosamine [(DENA) CAS: 55-18-5] followed by phenobarbital were studied after treatment periods from 1 month to 2 years. Rats treated with clofibrate revealed foci of cellular alteration that were more often basophilic and occurred slightly sooner (wk 42) than those in untreated controls (wk 60). Of 36 rats that had received 68 or more weeks of continuous clofibrate, 19 had hepatic nodules. Of the 11 nodules examined cytochemically, none was gamma-glutamyltransferase (gamma-GT) positive and 2 were positive to glucose-6-phosphate dehydrogenase (G-6-PD) under oxygen. In rats withdrawn from clofibrate for 16-18 weeks after 68-95 weeks of clofibrate, 0 of 14 had nodules. In several of these rats zones of hepatic scarring were observed, suggesting the reversibility of the nodules. Phenobarbital alone had little effect on the incidence of foci of cellular alteration, although the number of gamma-GT-positive foci was increased. DENA followed by phenobarbital led to the early appearance of foci of cellular alteration (from wk 4), of nodules (from wk 13), and of hepatocellular carcinomas (from wk 26). gamma-GT activity was raised in most of these nodules and carcinomas, while G-6-PD activity was raised in only 3 of 9 nodules but in all 9 carcinomas examined. DENA-phenobarbital given for 13 or 26 weeks followed by withdrawal of phenobarbital for 28 and 26 weeks, respectively, produced an essentially similar pattern of lesions. In view of the growing recognition of the nonspecificity gamma-GT as a marker of carcinogen-initiated foci, the value of G-6-PD (under oxygen) as a marker merits further investigation.

Two-year carcinogenicity study of tamoxifen in Alderley Park Wistar-derived rats.

Tamoxifen, a nonsteroidal antiestrogen used widely in the treatment of breast cancer, was tested in a conventional 2-year carcinogenicity bioassay in rats, a species in which tamoxifen acts variably as a partial agonist and antagonist on different target tissues. Groups of 51 males and 52 females were given 5, 20, and 35 mg/kg of tamoxifen/day by gastric intubation in 0.5% hydroxypropyl methylcellulose at 5 ml/kg dose volume. There were 102 male and 104 female controls dosed with vehicle alone. Growth rate and food consumption were reduced in all treated groups. The major finding was a dose-related increase in the incidence of hepatocellular tumors which were first observed after 31 weeks of treatment in the top dose group. The majority of the neoplasms were hepatocellular carcinomas showing a well differentiated trabecular pattern. Some tumors were glandular in type. Mortality was increased in the 20 and 35 mg/kg dose groups compared with controls as a result of these tumors. By contrast, survival was greater than controls in rats given 5 mg/kg tamoxifen despite the presence of hepatocellular tumors due to a reduction in the number of pituitary tumors in females and less chronic renal disease in males. The mechanism of hepatic tumor induction by tamoxifen in rats is unclear. In view of the lack of genotoxic activity in conventional genotoxicity studies and lack of similar effect in mice or in humans, the findings may relate to a particular constellation of effects in rats. All other drug-induced changes in this study were nonneoplastic in nature and most appeared to be the result of hormonal perturbation since they were confined to endocrine organs or have been seen previously in rats treated for long periods with tamoxifen.

A twin-reporter vector for simultaneous analysis of expression signals of divergently transcribed, contiguous genes in filamentous fungi.

To analyze the promoter region(s) of divergently transcribed fungal genes, a twin-reporter vector was constructed. This vector contains two divergently oriented reported genes, encoding Escherichia coli beta-glucuronidase (uidA) and E. coli beta-galactosidase (lacZ). Terminator regions of the Aspergillus nidulans nitrate and nitrite reductase-encoding genes, niaD and niiA, respectively, have been cloned 3' to the reporter genes to ensure proficient transcription termination of the reporter genes. The reporter genes have been separated by a unique NotI restriction site, which can be used for the insertion of expression signals. A mutant argB selection marker has been introduced in order to obtain A. nidulans transformants with a single copy of the vector integrated at the argB locus. The use of the vector was demonstrated by insertion of the A. nidulans niaD-niiA intergenic region and analysis of A. nidulans transformants obtained with this construct. Control of expression of both reporter genes was found to be in accordance with previously published data on control of nitrate assimilation [Cove, Biol. Rev. 54 (1979) 291-327].

Isolation and characterisation of the crnA-niiA-niaD gene cluster for nitrate assimilation in Aspergillus nidulans.

Genomic clones containing the entire crnA-niiA-niaD gene cluster of Aspergillus nidulans have been isolated, and the structures of the niiA and niaD genes have been determined by nucleotide sequence analysis. This gene cluster is required for the assimilation of nitrate in A. nidulans, and the three genes encode a product required for nitrate uptake and the enzymes, nitrite reductase and nitrate reductase, respectively. The putative coding sequences, as deduced by comparison to cDNA clones of both niiA and niaD, are interrupted by multiple small introns, and the two genes are divergently transcribed. Identification and characterization of specific mRNAs involved in nitrate assimilation indicates that only monocistronic transcripts are involved, and that the approximate sizes of these transcripts are 1.6 kb, 3.4 kb and 2.8 kb for crnA, niiA and niaD, respectively. The results also indicate that control of niiA and niaD gene expression is mediated by the levels of mRNA accumulation, in response to the source of nitrogen in the growth medium. Two types of transcripts for niiA were observed.

Comparison of the effect of oestradiol, tamoxifen and raloxifene on nerve growth factor-alpha expression in specific neonatal mouse uterine cell types using laser capture microdissection.

Oral dosing of CD-1 mice on days 2-5 after birth with tamoxifen but not raloxifene disrupts the development of the myometrium, resulting in adult uterine adenomyosis. Using laser capture microdissection and RT-PCR we have investigated nerve growth factor (NGF) and cognate receptor expression in uterine cells of 6-day-old pups that may be important in early developmental changes that give rise to adenomyosis. NGF down-regulation is known to occur during terminal myogenic differentiation. NGF was found exclusively in endometrial luminal epithelium of controls. It was up-regulated 18-fold in the luminal epithelium following dosing with tamoxifen but not raloxifene. Western blotting for NGF protein in the whole uterus showed a 25-fold increase after tamoxifen treatment. Expression of the low affinity p75 neutrophin receptor (p75(NTR)) was twofold higher in the myometrium compared with luminal epithelium or stroma. This was not altered following tamoxifen treatment. There was no detectable expression of high affinity tyrosine kinase receptor (trkA(NGFR)). This study shows luminal epithelial cells of the endometrium primarily form NGF. This suggests that NGF normally regulates the differentiation of the mesenchyme into uterine myocytes through paracrine mechanisms and that an early disturbance of this process plays a key role in the subsequent development of adenomyosis.

Comparisons of the effects of tamoxifen, toremifene and raloxifene on enzyme induction and gene expression in the ovariectomised rat uterus.

This study compares the actions of oestradiol, tamoxifen, toremifene and raloxifene on enzyme and gene expression in uterine tissues of ovariectomised rats over 72 h. The time-course for the induction of ornithine decarboxylase by the compounds showed a rapid biphasic response, while for creatine kinase brain type (BB) there was a continued increase over 72 h. The efficacy of induction showed that, with both markers, oestradiol gave the highest induction level, followed by tamoxifen or toremifene and then raloxifene. RT-PCR demonstrated that all compounds decreased oestrogen receptor (ER) alpha, ERbeta and ERbeta2 gene expression, 8-24 h after the first dose, suggesting that down-regulation of ER is not the primary cause of the difference in efficacy between these compounds. Using cDNA arrays, expression of 512 genes was examined in the uteri of oestradiol- or tamoxifen-treated rats. Both compounds resulted in the up-regulation of heat-shock protein 27, telomerase-associated protein 1 and secretin. However, most surprising was the marked down-regulation of Wilms' tumour and retinoblastoma genes. We speculate that this may result in a loss of regulation of the transition from the G1 to the S phase in the cell cycle and may make cells more vulnerable to the carcinogenic effects of tamoxifen in this tissue.

New methods for the isolation of Legionella pneumophila.

Some new methods for the isolation of Legionella pneumophila are described which have been successful in recovering this organism from 6/10 patients with clinical evidence of Legionnaires' disease. The increased sensitivity of these methods combined with speedier isolation of the organisms than has hitherto been possible will hopefully lead to eventual isolation of this organism as a routine procedure in diagnostic microbiology laboratories.

Selectagerm: a new approach to clinical bacteriology.

A method of processing clinical specimens received at the laboratory on cotton wool swabs is described. The method uses a range of selective culture media to assist in the isolation of potential pathogens from mixed cultures. Because the culture media are distributed in 2 millilitre volumes in the small squares of divided plastic petri dishes it is economically possible to use the same series for every specimen. This facilitates the rapid processing of large numbers of swabs and allows the isolation of pathogens from sites where they might otherwise go unnoticed.

Electron microscopic evidence of flagella and pili on Legionella pneumophila.

Twenty-one strains of Legionella pneumophila, representing the six known serotypes of the organism, cultured on various bacteriological media and in the yolk sacs of fertile hens' eggs were examined by negative stain electron microscopy for flagella and pili. These appendages were usually observed after cultivation on media capable of inducing an early profuse growth of the organisms.

A cytochemical study of the livers of rats treated with diethylnitrosamine/phenobarbital, with benzidine/phenobarbital, with phenobarbital, or with clofibrate.

Male Sprague-Dawley rats were treated with clofibrate (CLOF) in the diet for 2 years or with 4 i.p. injections of either diethylnitrosamine (DEN) or benzidine (BZ) followed by phenobarbital (PB) in the diet for 67 weeks, or just with PB for 41 weeks. Animals were killed at frequent intervals, some while still on treatment and others after 3 or 6 months withdrawal of treatment. The livers were subjected to cytochemical measurements of the parenchyma, foci, nodules and carcinomas. The parenchyma of the CLOF groups showed, in general, increases in glucose-6-phosphate dehydrogenase (G-6PD), alpha-glycerophosphate dehydrogenase (alpha-GPD), 5'-nucleotidase (5'-Nu), acid phosphatase (AP) and catalase and decreases in uricase and glutathione (GSH). CLOF induced a low incidence of GSH positive foci; nodules showed universally lower levels of catalase and GSH. In the DEN/PB and BZ/PB groups the parenchyma showed increases (even before PB treatment started) in G-6PD and in gamma-glutamyl transpeptidase (gamma-GT) and decreases in GSH. DEN raised and BZ lowered 5'-Nu. Neither initiator affected alpha-GPD. Both initiators caused a high incidence of foci positive for G-6PD and for gamma-GT; nodules induced by DEN/PB were mainly positive for gamma-GT and showed an erratic response to the other parameters. Carcinomas, found only after DEN/PB, were all positive for G-6PD and, with one exception, all were negative for alpha-GPD, 5'-Nu, AP and GSH. All changes regressed within 3 months of withdrawal of CLOF but not after withdrawal of PB from DEN-initiated animals. In conclusion G-6PD, alpha-GPD and 5'-Nu may be useful histocytochemical parameters for studying the precarcinogenic hepatic changes and nodules induced by peroxisome proliferators and by genotoxic hepatocarcinogens.

Renal and hepatic toxicity of a benzopyran-4-one in the Cynomolgus monkey.

The administration of PD 119819, a novel benzopyran-4-one brain dopamine autoreceptor agonist, to Cynomolgus monkeys was followed by deposition of needle-like drug crystals in the bile canaliculi, hepatocytes, proximal renal tubules and renal parenchyma. The crystals were associated with a granulomatous inflammation, and histological and biochemical evidence of hepatic and renal cell damage. Although metabolism differences may be the reason why primates, but not rodents, developed these changes, this form of crystallization appeared to be primarily a result of the insolubility of PD 119189 at alkaline pH.

Patterns of cardiovascular pathology induced by diverse cardioactive drugs.

In the beagle dog, exaggerated hypotension and tachycardia following administration of high doses of vasodilating antihypertensive drugs are associated with vascular injury and characteristic patterns of myocardial necrosis and haemorrhage. Cardiac and vascular inflammation and necrosis also occur in dogs in association with different functional changes including severe hypertension and the effects that follow treatment with high doses of vasoconstrictor and pressor drugs. More recently, cardioactive drugs of novel classes such as the endothelin antagonists have also been shown to produce vascular damage in the beagle dog but in the absence of ischaemic myocardial damage or significant haemodynamic alterations that typically follow administration of high doses of vasodilating antihypertensive or pressor drugs. This underlines the importance of a careful analysis of the patterns of cardiovascular pathology, their dose, temporal and spatial relationships in the context of functional changes.

First-postgraduate-year resident clinical time use on three specialty rotations.

OBJECTIVE: To compare in-hospital time uses by first-postgraduate-year (PGY1) residents during rotations in emergency medicine (EM), internal medicine (IM), and surgery (S). This article reports the clinical components of residency time use. METHODS: A cross-sectional, observational study of the clinical activities of EM PGY1 residents was performed while the residents were on duty during the three specialty rotations. The activities were recorded by an observer using a log with predetermined categories for clinical activities. A time-blocked, convenience sample of resident shifts was observed for each service rotation. The sample was proportional to the total number of hours for which a PGY1 resident was expected to be in the hospital during a rotation on that service. No attempt was made to sample the same resident at all time periods or on all rotations. Proportions were compared by chi2; alpha = 0.0001. RESULTS: Twelve PGY1 residents were observed for a total of 166 hours on S, 156 hours on IM, and 120 hours on EM. These hourly amounts were representative of a typical two-week span of service on each rotation for the residents. On average, the residents spent 57% of their time on clinical or service-oriented activities. During EM and IM rotations, the residents spent most of their time performing clinical information gathering and engaging in case management and data synthesis (52% of total clinical effort). Within this category, residents on EM were more involved with case discussion and review of ancillary test results than on IM (34% vs 20% of time in this category). Conversely, proportionately less time in this category was devoted to documentation on the EM vs IM rotation (56% vs 80%; p < 0.0001). The greatest opportunity to perform procedures was on the S rotation (31% of total clinical time vs 6% for other specialties; p < 0.0001). CONCLUSION: Awareness of the clinical activities performed on PGY1 rotations can help residency directors anticipate educational needs to balance their residents' experience. Since 29% and 42% of total clinical time on PGY1 EM and IM rotations, respectively, is focused on documentation, efforts to enhance charting skills and efficiency are warranted. Also, efforts to enhance PGY1 procedural experience outside of the S rotation appear warranted.

Periarteritis in a beagle colony.

Primary periarteritis, an uncommon necrotizing vasculitis in the dog, was found to affect, almost exclusively, the major branches of the coronary arteries in a number of young beagle dogs. The arteritis was mainly distributed in the proximal segment of the right coronary artery. Immunocytochemical studies failed to identify immunoglobulin deposits in the lesions and the cause of the arteritis remains unknown. It is important to be aware of this spontaneous condition and its regional distribution since certain cardiovascular drugs may also produce necrotizing arteritis at similar sites.

The evaluation of potential human carcinogens: a histopathologist's point of view.

Over 100 marketed drugs induce neoplasia when administered at high doses to rats and mice for periods of up to two years. Despite their diverse chemical structures and biological activities, these compounds produce a relatively limited range of tumour types in rodents, most commonly in the liver. Tumours usually develop only after long periods of time following high exposure to drug. The main exceptions are DNA-reactive anticancer drugs such as alkylating agents which produce tumours rapidly in rodents in several organs. In this laboratory, mouse carcinogenicity studies are performed using the C57BL/10J strain. This strain infrequently develops hepatic tumours spontaneously but it is sensitive to the effects of DNA-reactive carcinogens. Moreover, hepatic neoplasms regularly develop in male but not female C57BL/10J mice following long-term treatment with nongenotoxic drugs that produce hepatic enlargement associated with diverse hepatocellular effects. Studies in this strain with the tumorigenic liver enlarger, phenobarbitone, have shown that although such liver enlargement is characterised by a brief burst of hepatocyte replication, this is associated with persistent regional modulation of hepatic growth stimulatory and inhibitory factors and their associated receptors. These findings indicate that there is a sustained alteration to the internal hepatic environment characterised by regional alterations to the balance of hepatocyte mitogens and inhibitors of replication and their respective receptors. Thus, the development of hepatocellular tumours in C57BL/10J mice following two-year treatment with nongenotoxic drugs appears to be a regular response of an organ to an exaggerated and long-term disruption of its homeostasis. Agents that produce tumours in rodents in this way seem likely to pose little or no risk to humans if administered under appropriate clinical circumstances at doses which show no significant disruption of organ homeostasis. However, drugs that produce this type of response need to be distinguished from those that induce unusual and rapid patterns of tumour development because these agents may have high tumorigenic potency of potential hazard to humans.

Patterns of drug-induced cardiovascular pathology in the beagle dog: relevance for humans.

In toxicity studies, the examination of tissue sections for pathological changes is the principle method for the identification of organ toxicity and characterisation of the hazard of novel drugs for humans. Study of the patterns of pathological alterations also represents an important means of developing an understanding of the mechanism of toxicity. However as pathological change frequently represents a final common expression of diverse processes, additional functional information is often required for a clear understanding of the mechanisms of toxicity. This is exemplified in the evaluation of the effects of drugs on the beagle dog cardiovascular system where an understanding of mechanisms is crucial in the assessment of human risk. Particular patterns of drug-induced structural change in the myocardium or blood vessels are frequently linked to specific mechanisms of toxicity. However, assessment based on the interpretation of patterns of cardiovascular pathology alone may be misleading. Quite different changes in cardiac and vascular function or direct cellular toxicity may also be manifest by pathological features in common. Therefore, a clear understanding of mechanism frequently requires additional in vivo or in vitro physiological, pharmacological, biochemical or other mechanistic information. The beagle dog remains an important model for the study of cardiovascular toxicity because in this species, haemodynamic changes and pathological alterations can be related in a way that provides the basis for the safe study in humans of novel drugs with cardiovascular activity.

Polyarteritis in a beagle.

A 13-month-old Beagle became anorectic and had fever, stiff gait, and tenderness in the inguinal region. Clinical signs of disease were associated with neutrophilia and a decrease in the albumin-to-globulin ratio. The dog became clinically normal for 5 days after 3 days of treatment with penicillin G and dihydrostreptomycin. Clinical signs of disease recurred, and the dog was euthanatized after failing to respond to administration of a trimethoprim-sulfamethoxazole combination for 9 days. Disseminated arteritis was seen in the testes, epididymides, mesentery, coronary arteries, aorta, and thyroid gland. Lesions were seen in large and medium-sized arteries and varied from acute necrotizing arteries to a chronic lesion with organization and recanalization of thrombi. The clinical signs of disease resembled those of Beagle pain syndrome, described in laboratory Beagles.

Adolescent sexuality and public policy.

In recent decades, various attempts have been made to determine the level of sexual activity among adolescents. This information has been used in the planning and evaluation of sex-related programs. However, there is a flaw in using only the initial estimates of the behavior--that a sexually active person is defined as one who has had sexual intercourse. This narrow definition distorts the perception of adolescent sexual behavior. Sexual activity can more accurately be designated by focusing on the actual frequency with which teenagers have sex. In this research report, adolescents were considered sexually active if they had had sex within the last four weeks. Using this definition, adolescents were found to be substantially less sexually active than has been previously reported. This finding was then used to look at various policy decisions in the areas of sex education, family planning, and sexually transmitted disease prevention.

PIP: This analysis of national surveys of teenage sexual behavior in the US provides a more useful and precise estimate of teenage sexual activity for policy and program decisions. Data were taken from the 1979 National Survey of Men (NSYM), and Women (NSYW), and the 1982 National Survey of Family Growth (NSFG). Analysis was based on 1) the % of unmarried respondents who were sexually experienced and the % who were sexually active, and 2) the % sexually experienced who were sexually active. The distinction between sexual activity vs. experience shows considerable differences; i.e., for women 15-19 in 1979, 46% were sexually experienced but only 26% were sexually active at the time of the survey. Further delineation is made for never, seldom, monthly, and currently active by race. Black women 15-19 in 1982 were shown to be no more sexually active than white women. However, from the NSYM black males followed the traditional pattern of higher sexual activity, with 68.2% for blacks vs. 60.1% for whites. The data dispute the typical image of rampant sexual portrayed by the popular press. The public policy response to this epidemic was to adopt a family planning (FP) approach to teenage pregnancy prevention. Reduced adolescent pregnancy rates as a measure of program effectiveness have not been shown, and program effectiveness must be based on other measures. Sex education also has had limited success in reducing adolescent pregnancy. The suggestion is that access to accurate information, student liking, parental support, and knowledge acquisition are more reasonable criteria for demonstrating success of sex education programs. Abstinence programs help reduce the risks of teenage pregnancy by emphasizing skills in decision making and resisting pressures to be sexually involved. The example is given of an Atlanta-based program, Postponing Sexual Involvement, which reported that 84% resisted becoming sexually involved after completion of the program. Other abstinence programs show promise and are an inexpensive alternative to FP, albeit evaluations are needed. Contraceptive approaches are appropriate for the already sexually active population.