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BACKGROUND:Cesarean delivery is the most common surgical procedure worldwide. Intrapartum fetal surveillance is routinely offered to improve neonatal outcomes, but the effects of different methods on the risk of emergency cesarean deliveries remains uncertain. We conducted a systematic review and network meta-analysis to evaluate the effectiveness of different types of fetal surveillance.METHODS:We searched MEDLINE, Embase and CENTRAL until June 1, 2020, for randomized trials evaluating any intrapartum fetal surveillance method. We performed a network meta-analysis within a frequentist framework. We assessed the quality and network inconsistency of trials. We reported primarily on intrapartum emergency cesarean deliveries and other secondary maternal and neonatal outcomes using risk ratios (RRs) and 95% confidence intervals (CIs).RESULTS:We included 33 trials (118 863 patients) evaluating intermittent auscultation with Pinard stethoscope/handheld Doppler (IA), cardiotocography (CTG), computerized cardiotocography (cCTG), CTG with fetal scalp lactate (CTG-lactate), CTG with fetal scalp pH analysis (CTG-FBS), CTG with fetal pulse oximetry (FPO-CTG), CTG with fetal heart electrocardiogram (CTG-STAN) and their combinations. Intermittent auscultation reduced the risk of emergency cesarean deliveries compared with other types of surveillance (IA v. CTG: RR 0.83, 95% CI 0.72–0.97; IA v. CTG-FBS: RR 0.71, 95% CI 0.63–0.80; IA v.CTG-lactate: RR 0.77, 95% CI 0.64–0.92; IA v. FPO-CTG: RR 0.75, 95% CI 0.65–0.87; IA v.FPO-CTG-FBS: RR 0.81, 95% CI 0.67–0.99; cCTG-FBS v. IA: RR 1.21, 95% CI 1.04–1.42), except STAN-CTG-FBS (RR 1.17, 95% CI 0.98–1.40). There was a similar reduction observed for emergency cesarean deliveries for fetal distress. None of the evaluated methods was associated with a reduced risk of neonatal acidemia, neonatal unit admissions, Apgar scores or perinatal death.INTERPRETATION:Compared with other types of fetal surveillance, intermittent auscultation seems to reduce emergency cesarean deliveries in labour without increasing adverse neonatal and maternal outcomes.

Delirium has been previously implicated as a risk factor for patient falls. This is a replication study of a 2009 investigation examining the prevalence of diagnosed and undiagnosed delirium in patients who fell during their hospital stay.

Combining a range of assessment parameters into one usable entity has been identified as an important goal in providing a practical, objective and robust assessment of welfare, particularly in laboratory animals. This paper refines and extends one such previously published method. The proposed Extended Welfare Assessment Grid provides for the incorporation of changes in the state of an animal over time, allowing for predictive, retrospective, scheduled, or event monitoring. It enables the numeric, as well as visual, representation of the animal's welfare, placing this in the context of the careful and realistic justification for experimental use of the animal. This assessment method represents a valuable tool for those tasked with ensuring ethical oversight, as well as for those planning the use, or monitoring, of animals in research. It is particularly applicable to animals used in long-term studies, especially non-human primates. It is believed that this system will draw attention to the temporal component of suffering that is often overlooked in the planning of research schedules and allow an assessment of cumulative suffering imposed by the events that occur.

The Clinical Scholar Model serves as an effective framework for investigating and implementing evidence-based practice (EBP) changes by direct care providers. The model guides one in identifying problems and issues, key stakeholders, and the need for practice changes. It provides a framework to critique and synthesize the external and internal evidence. Three EBP projects conducted at a large tertiary care facility in northern New England illustrate the process of using the Clinical Scholar Model.

Responding to agricultural bioterrorism with pathogenic agents that are communicable from animals to humans (zoonotic diseases) requires effective coordination of many organizations, both inside and outside of government. Action must be simultaneously taken to address public health concerns, respond to the agricultural dimensions of the event, and carry out the necessary law enforcement investigation. As part of a project focused on examining public health preparedness in Georgia, an exercise was carried out in July 2005 examining the intentional introduction of avian influenza (H5N1) in commercial poultry operations. The attack scenario, which was written to occur during an already severe human influenza season, enabled exploration of a range of issues associated with public health preparedness for major disease outbreaks including pandemic influenza, coordination of a multiagency response operation at multiple levels of government, and effective management of interdisciplinary response activities. The exercise is described and broader policy lessons regarding preparedness planning are discussed.

Many captive animals show forms of pelage loss that are absent in wild or free-living con-specifics, which result from grooming or plucking behaviours directed at themselves or at other individuals. For instance, dorsal hair loss in primates such as rhesus macaques (Macaca mulatta) in research facilities, results from excessive hair-pulling or over-grooming by cage-mates. This behaviour appears to be associated with stress, and is controllable to some extent with environmental enrichment. Quantifying alopecia in primates (as in many species) is therefore potentially useful for welfare assessment. A simple system for scoring alopecia was developed and its reliability was tested. Study 1 showed high interobserver reliability between two independent scorers in assessing the state of monkeys’ coats from photographs. Study 2 showed that there were no significant differences between the scores derived from photographs and from direct observations. Thus, where hair loss due to hair pulling exists in captive primates, this scoring system provides an easy, rapid, and validated quantitative method, for use in assessing the success of attempts to reduce it via improved husbandry. In the future, such scoring systems might also prove useful for quantifying barbering in laboratory rodents.

31P‐magnetic resonance spectroscopy (MRS) and a fiberoptic pH meter were used simultaneously to follow the changes in intra‐ (pHi) and extracellular pH (pHe), respectively, of murine RIF‐1 tumors with hyperthermia. Hyperthermia was induced at 34 MHz using the same coil used for MR. The study was carried out until 3.5 hr after hyperthermia. In untreated tumors (n= 29), pHiwas always higher than pHe. pHiwas reduced after hyperthermia (30 min) at both 42°C and 45°C. pHeregistered an increase after 42°C and a decrease after 45°C. The reduction in pHiwas larger than the initial differential between pHiand pHe, and the change in pHewas relatively small. Hyperthermia changed the acidity of the intra‐ and extracellular compartments, such that pHebecame more alkaline than pHiby 0.15 ± 0.13 units after 42°C [pHe(7.20 ± 0.12) and pHi(7.03 ± 0.05)], and by 0.12 ± 0.14 units after 45°C [pHe(6.84 ± 0.24) and pHi(6.72 ± 0.19)]. Simultaneous measurements of pH from the intra‐ and extracellular compartments demonstrated reversal in the pH gradient after hyperthermic treatment. Magn Reson Med 43:1–8, 2000. © 2000 Wiley‐Liss, Inc.

BW12C binds to haemoglobin, shifting the oxygen saturation curve to the left, and is under investigation as an inducer of tumour hypoxia. The intrinsic cellular toxicity of the drug to RIF-1 and EMT6 cells in monolayer culture was studied, and IC50 values of 100 µg ml-1 for 24 h exposure and 10 µg ml-1 for 4-day exposure were measured. The LD50 (95% CL) in C3H mice was shown to be 124 (118-130) mg kg-1 for normal, rapid i.v. injection of the drug, and 173 (164-181) mg kg-1 for slow injection. The well-tolerated dose of 70 mg kg-1, used for all subsequent studies, was shown to produce a maximum haemoglobin modification of 70% 5 min after i.v. administration. This effect decayed with a half-life (± 2 se) of 76 ± 8 min, giving 50% modification at 30 min and 22-25% modification at 2 h after administration. A dose of 70 mg kg-1 BW12C administered 30 min before irradiation protected animals against lethality, and increased the radiation LD50 (95% CL) from 7·16 (7·05-7·27) to 7·86 (7·70-8·02) Gy, representing a DMF of 1·1. In contrast the same drug dose and schedule did not alter normal marrow CFUs radiosensitivity at doses up to 6 Gy. The dose of 70 mg kg-1 did, however, cause marked radioprotection in RIF-1 intramuscular leg tumours. Four- to seven-fold increases in survival were measured by clonogenic cell survival immediately or 24 h after treatment. Protection was maximal 15 to 30 min after administration, and absent by 2 h. The drug did not protect RIF-1 cells in culture against radiation damage, indicating that the in vivo effect is indirect. BW12C is therefore an effective tumour radioprotector in this tumour model, in a manner consistent with an increase in tumour hypoxic fraction, although factors other than changes in blood chemistry may also be involved.

Potassium transport was measured in equine red blood cells, using 86Rb+ influx as a convenient assay. A significant component of volume‐ and pH‐sensitive K(+)‐Cl‐ cotransport to the overall K+ flux was observed in all blood samples studied, although fluxes were variable between animals, and within individuals when measured at intervals over a period of weeks. The aryloxyacetic acid [(dihydroindenyl)oxy]alkanoic acid (DIOA), at a final concentration of 100 microM, inhibited most (> 95%) of the Cl(‐)‐dependent K+ flux, and DIOA sensitivity was therefore used to define the activity of the K(+)‐Cl‐ cotransport. K(+)‐Cl‐ cotransport was also sensitive to protein phosphatase inhibition with calyculin A or okadaic acid, with inhibition constants of 9 +/− 1 nM for calyculin and about 100 nM for okadaic acid. Peak fluxes were observed at an external pH of 6.7–7.0, with inhibition at higher and lower values. Volume‐sensitive K+ fluxes assayed in autologous plasma, controlled for osmolaity, pH and potassium concentration, were significantly lower (28 +/− 8% of control values, n = 6) than those measured in saline. This inhibition was mimicked by the culture medium RPMI, but disappeared following dialysis of the plasma. Phosphate (5.6 mM) inhibited volume‐sensitive K+ fluxes by 48 +/− 2%, n = 3; no significant effect was observed by increasing external magnesium concentrations to 0.5 or 2 mM. Thus, inhibition by RPMI, but not that by plasma, may be due to phosphate. Finally, volume‐ and pH‐sensitive K+ fluxes were sensitive to oxygen tension and were abolished reversibly by equilibrating solutions with nitrogen, as opposed to air. Use of solutions equilibrated with different values of Po2 may account for some of the variability in equine red blood cell KCl fluxes. The importance of these observations to equine red blood cell homeostasis and haemodynamics is discussed.

The mechanism of the potentiation of thermal damage by hydralazine (HDZ) has been investigated. Using the KHT sarcoma in the leg of C3H mice, it was shown that 5 mgikg of HDZ given i.v. 15-20 min before irradiation or heat exposure: (i) increased the radiobiological hypoxic fraction from 1 to 32%; (ii) produced a greater than additive growth delay when combined with heating for 30 rnin at either 43 or 43.5°C, or 60 rnin at 43°C; (iii) produced only additive cell killing when combined with 30 rnin heating at 43, 43.5. or 44°C. assayed by clonogenic cell survival immediately or 24 h after treatment; and (iv) produced a prolonged (> 72 h) reduction in relative tissue perfusion (RTP) in the tumour when combined with heating for 30 rnin at 43.5°C. The effects of HDZ or heat alone lasted for less than 24 and 48 h, respectively. The RTP in skin was unaffected by either agent or combination of agents at the times assayed. The results show that this 30-fold increase in hypoxia does not increase the intrinsic thermosensitivity of KHT tumour cells, and that the prolonged reduction in RTP caused by the combined treatment is probably responsible, at least in part, for the greater than additive component of the measured growth delay in this system. The data suggest that non-perfused turnour vessels are more heat sensitive than perfused vessels.

In the course of herpes simplex virus 1 (HSV-1) replication in human epidermoid carcinoma no. 2 cells, the synthesis and glycosylation of host cell proteins ceases and is replaced by the synthesis and glycosylation of virus-specified polypeptides. Analyses of the synthesis of viral glycoproteins show that the glycosylation of viral polypeptides occurs late in the virus growth cycle and that certain of the precursors to major vital glycoproteins are members of the gamma group of polypeptides, i.e., polypeptides synthesized at increasing rates until 12 to 15 h postinfection. Viral glycoproteins are formed by stepwise additions of heterosaccharide chains to completed precursor polypeptides. The precursor and the highly glycosylated product are separable by gel electrophoresis and are localized in different fractions of infected cells. Within 15 min of their synthesis, precursor polypeptides acquire heterosaccharide chains of about 2,000 molecular weight, which contain glucosamine but little or nor fucose or sialic acid. Both precursor and product of this first stage of glycosylation are absent or present in low concentrations in the surface membranes of the infected cell and in the virion. The partially glycosylated product is then conjugated further in a slow, discontinuous process to form the mature glycoprotein of the virion and plasma membrane. These mature products bear large heterosaccharide units with molecular weights greater than 4,000 to 5,000; these contain fucose and sialic acid as well as glucosamine. Heterosaccharide chains from infected and uninfected cells are distributed among discrete size classes and the smallest chains consist of multiple saccharide residues.

We have characterized the virus progeny and its DNA from plaque-purified and undiluted passages of herpes simplex virus 1 in HEp-2 cells. Secifically, (i) infectious virus yields declined progressively in passages 1 through 10 and gradually increased at passages 11 through 14. The yields correlated with PFU/particle ratios. (ii) In cells infected with virus from passages 6 through 10, there was an overproduction of an early viral polypeptide (no. 4) and a delay in the synthesis of late viral proteins. In addition, the virus in these passages interfered with the replication of a nondefective marker virus. Cells infected with passage 14 virus produced normal amounts of polypeptide 4 and, moreover, this virus showed minimal interfering capacity. (iii) In addition to DNA of density 1.726 g/cm-3, which was the sole component present in viral progeny of passage 0, passages 6 through 14 contained one additional species (p 1.732) and in some instances (passages 6 and 10) also DNA of an intermediate buoyant density. The ratio of p 1.732 to p 1.726 DNA increased to a maximum of 4 in passages 6 through 9 and gradually decreased to 1 in passages 10 through 14. (iv) p 1.732 DNA cannot be differentiated from p 1.726 DNA with respect to size; however, it has no Hin III restriction enzyme cleavage sites and yields only predominantly two kinds of fragments with molecular weights of 5.1 x 10-6 and 5.4 x 10-6 upon digestion with EcoRI enzyme. (v) Partial denaturation profiles of purified p 1.732 DNA from passage 14 revealed the presence of two types of tandemly repeated units corresponding roughly in size to the EcoRI fragments and situated in different molecules. (vi) In addition to the two kinds of p 1.732 molecules consisting of tandem repaeat units of different sizes, other evidence for the diversity of defective DNA molecules emerged from comparisons of specific infectivity and interfering capacity of the progeny from various passages. The data suggest that some of the particles with DNA of normal buoyant density (1.726) must also be defective since the capacity to interfere and to produce an excess of polypeptide 4 did not appear to be proportional to the amount of high-buoyant-density defective DNA. The data suggest that defective interfering particles are replaced by defective particles with diminished capacity to interfere and that more than one species of defective DNA molecules evolves on serial preparation of HSV.

The time course and dose response of 600 mm3 subcutaneous RIF-1 tumours to pentoxifylline was measured in terms of relative tumour perfusion, assayed by 86Rb extraction, and pO2 distribution measured by the Eppendorf histograph. Both perfusion and pO2 distribution were maximally increased by 20 mg/kg pentoxifylline 15 min after administration, perfusion to 141 ± 15% (2 SE) of control, and median pO2 from 3 to 15 mmHg, with the percentage of values <2.5 mmHg falling from 44 ± 8% to 22 ± 7%. Fifteen minutes after administration the pO2 increases were linearly dose-dependent up to 20 mg/kg. Correlation coefficients for perfusion data with the percentages of low values were, for time course and dose response data respectively, 0.76 and 0.84 for median pO2, 0.84 and 0.97 for percentage < 2.5 mmHg and 0.81 and 0.87 for percentage < 10 mmHg. The data show good correlation between changes in perfusion and pO2 distribution parameters, with better correlation for percentage of low values than for median pO2.

The magnitude of potentiation by whole body hyperthermia (45 min at 41°C) of cis-platinum (DDP), CCNU, BCNU, chlorambucil and melphalan (Mel) on two tumours was compared with that on marrow in C3H mice. Drug damage was assayed in the KHT tumour by growth delay and in the RIF-1 tumour by clonogenic cell survival 24 h after treatment and/or by growth delay. Toxicity to marrow stem cells was assayed 24 h after treatment, by the spleen colony technique. When drug was given at the start of heating, all drugs were potentiated both in tumour and marrow to varying degrees. However, there was no therapeutic gain for the combined treatment with DDP on RIF-1, with CCNU or BCNU on KHT, or with CHL on either RIF-1 or KHT. Therapeutic ratios for Mel of 1.9 to 2.0 for KHT and of 1.1 to 1.8 in RIF-1 were measured over the dose range 7.5 to 15.0 mg/kg in unheated animals, indicating net therapeutic gain under these conditions. An absolute therapeutic gain was found for Mel in KHT when Mel was given 30 min before the start of heat.

Herpesvirus saimiri (HVS) is the prototype member of a distinctive subset of lymphotropic herpesviruses (the gamma 2 subgroup) with A+T-rich coding sequences. In this paper, we show that cells productively infected with HVS contain high concentrations of a virus-specified thymidylate synthase (5,10-methylenetetrahydrofolate:dUMP C-methyltransferase, EC 2.1.1.45); we identify the active polypeptide and present the sequence of the virus gene. The predicted amino acid sequence of the 294-residue subunit of the virus enzyme is 70% homologous with the sequence of the human enzyme and about 50% homologous with prokaryotic thymidylate synthases, illustrating the remarkable structural constraints imposed by the thymidylate synthase function. However, the presence of the enzyme is not a conserved property of herpesviruses. We find no evidence for a virus-encoded thymidylate synthase activity (or a homology to a thymidylate synthase sequence) in G+C-rich representatives of alpha 1 (e.g., herpes simplex viruses, 66-68% G+C), beta (i.e., human cytomegalovirus, 58-59% G+C), and gamma 1 (i.e., Epstein-Barr virus, 60% G+C) herpesvirus subgroups. The production of excess thymidylate by a virus thymidylate synthase in cells infected with an A+T-rich herpesvirus would provide one plausible source of biased mutations by the virus-encoded replicative enzymes, which we have previously suggested as the likely general cause of differences in the mean nucleotide compositions of herpesvirus genomes.

To understand the relationship between the primary structure and function of varicella-zoster virus thymidine kinase (VZV TK; EC 2.7.1.21), we established rapid screening and phenotypic selection of mutant VZV TK genes in TK-deficient Escherichia coli C600 by using a constitutive pKK223-3 expression plasmid. In this screening system, mutant TK genes generated by random mutagenesis were identified by the sensitivity of E. coli-expressing VZV TKs to 5-bromo-2'-deoxyuridine and 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl) uracil. Twenty-four mutant clones with amino acid substitutions were isolated, and their nucleotide sequence and enzymatic activities were determined. Of the 24 clones, 20 had single amino acid substitutions, 2 clones had double amino acid substitutions, and 1 clone had triple amino acid substitutions. In 17 cases of single amino acid substitution, six mutations led to lost enzyme activity, and four of these six mutations centered in the ATP-binding site. The other 11 mutations resulted in reduction of both TK and thymidylate kinase activities or only thymidylate kinase activity and were located in scattered positions in the VZV TK gene, although 5 mutations showed a tendency to cluster in the region between positions 251 and 260.

Cytomegalovirus virions and dense bodies were purified by sucrose velocity and equilibrium centrifugation from the medium of fibroblasts infected with the strain AD169. The final virus preparations were purified more than 228-fold with respect to cellular proteins as determined by double-isotopic labeling and at least 1,600-fold on the basis of changes in the ratio of total protein to virus particles. The protein content of purified particles approximated that found for purified preparations of other herpesviruses. Twenty polypeptides ranging from 22,000 to greater than 230,000 molecular weight were detected in purified virus preparations by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Polypeptides of virions and dense bodies were allocated on the basis of analyses of preparations containing differing percentages of virions and dense bodies. Six polypeptides were represented predominantly or exclusively in virions, and four polypeptides were represented predominantly or exclusively in dense bodies, whereas the remainder appeared to be shared by both types of particles. Four polypeptides were glycosylated, and at least three of these appeared to be shared by both particles. Four polypeptides were glycosylated, and at least three of these appeared to be shared by both particle types. The protein composition of cytomegalovirus differs profoundly from that of herpes simplex virus.

The effect of preheating EMT6 cells in vitro on their response to cytotoxic agents of either 43 degrees C or 37 degrees C has been investigated. Preheating for 3 h at 40 degrees C produced measurable protection (thermal tolerance) to subsequent treatment for 1 h at 43 degrees C. This preheat treatment was further found to reduce cell killing by BLM and BCNU (drug tolerance) present during 1 h at 43 degrees C. In contrast, no such heat-induced drug tolerance was seen with ADR. An additional effect with ADR was the apparent elimination of heat-induced thermal tolerance at toxic drug doses. However, preheating under these conditions had no effect on the subsequent cytotoxicity of any of these drugs at 37 degrees C. Also, preheating for 1 h at 43 degrees C was found to sensitize cells to BLM and BCNU toxicity at 37 degrees C but to protect against ADR toxicity. The results are discussed in relation to known mechanisms of cell killing by heat and of thermal tolerance.