Shared decision-making in peri-operative medicine: a narrative review.

This review on shared decision-making comes at a time when international healthcare policy, domestic law and patient expectation demand a bringing-together of the patient's values and preferences with the physician's expertise to determine the best bespoke care package for the individual. Despite robust guidance in terms of consent, the anaesthetic community have lagged behind in terms of embracing the patient-focused rather than doctor-focused aspects of shared decision-making. For many, confusion has arisen due to a conflation of informed consent, risk assessment, decision aids and shared decision-making. Although they may well be linked, they are discrete entities. The obstacles to delivering shared decision-making are many. Lack of time is the most widely cited barrier from the perspective of physicians across specialties, with little time available to the anaesthetist at the day-of-surgery pre-operative visit. A more natural place to start the process may be the pre-operative assessment clinic, especially for the 'high-risk' patient. Yet shared decision-making is for all, even the 'low-risk' patient. Another barrier is the flow and the focus of the typical anaesthetic consultation; the truncated format presents the danger of a cursory, 'time-efficient' and mechanical process as the anaesthetist assesses risk and determines the safest anaesthetic. As patients have already decided to proceed with therapy or investigation and may be more concerned about the surgery than the anaesthesia, it is often assumed they will accept whatever anaesthetic is offered and defer to the clinician's expertise - without discussion. Furthermore, shared decision-making does not stop at time of anaesthesia for the peri-operative physician. It continues until discharge and requires the anaesthetist to engage in shared decision-making for prescribing and deprescribing peri-operative medicines.

Feasibility and acceptability of a whole-school social-marketing intervention to prevent unintended teenage pregnancies and promote sexual health: evidence for progression from a pilot to a phase III randomised trial in English secondary schools.

BACKGROUND: Reducing unintended teenage pregnancy and promoting adolescent sexual health remains a priority in England. Both whole-school and social-marketing interventions are promising approaches to addressing these aims. However, such interventions have not been rigorously trialled in the UK and it is unclear if they are appropriate for delivery in English secondary schools. We developed and pilot trialled Positive Choices, a new whole-school social marketing intervention to address unintended teenage pregnancy and promote sexual health. Our aim was to assess the feasibility and acceptability of the intervention and trial methods in English secondary schools against pre-defined progression criteria (relating to randomisation, survey follow-up, intervention fidelity and acceptability and linkage to birth/abortion records) prior to carrying out a phase III trial of effectiveness and cost-effectiveness. METHODS: Pilot RCT with integral process evaluation involving four intervention and two control schools in south-east England. The intervention comprised a student needs survey; a student/staff-led school health promotion council; a classroom curriculum for year-9 students (aged 13-14); whole-school student-led social-marketing activities; parent information; and a review of local and school-based sexual health services. Baseline surveys were conducted with year 8 (aged 12-13) in June 2018. Follow-up surveys were completed 12 months later. Process evaluation data included audio recording of staff training, surveys of trained staff, staff log books and researcher observations of intervention activities. Survey data from female students were linked to records of births and abortions to assess the feasibility of these constituting a phase III primary outcome. RESULTS: All six schools were successfully randomised and retained in the trial. Response rates to the survey were above 80% in both arms at both baseline and follow-up. With the exception of the parent materials, the fidelity target for implementation of essential elements in three out of four schools was achieved. Student surveys indicated 80% acceptability among those who reported awareness of the programme and interviews with staff suggested strong acceptability. Linkage to birth/abortion records was feasible although none occurred among participants. CONCLUSIONS: The criteria for progression to a phase III trial were met. Our data suggest that a whole-school social-marketing approach may be appropriate for topics that are clearly prioritised by schools. A phase III trial of this intervention is now warranted to establish effectiveness and cost-effectiveness. Births and terminations are not an appropriate primary outcome measure for such a trial. TRIAL REGISTRATION: ISRCTN65324176.

Pharmacogenetics of antipsychotic treatment response and side effects.

Antipsychotic drugs are particularly interesting in pharmacogenetic studies as they are associated with a large interindividual variability in terms of response and side effects and, therefore, frequently need to be discontinued, requiring switches to other antipsychotics. Any information that allows the prediction of outcome to a given antipsychotic in a particular patient will, therefore, be of great help for the clinician to minimize time and find the right drug for the right patient, thus optimizing response and minimizing side effects. This will also have a substantial impact on compliance and doctor-patient relationships. Moreover, antipsychotic drug treatments are often required for life-long treatment and are also frequently prescribed to the more 'vulnerable' populations: children, adolescents and the elderly. This article focuses on some important studies performed with candidate gene variants associated with antipsychotic response. In addition, important findings in pharmacogenetic studies of antipsychotic-induced side effects will be briefly summarized, such as antipsychotic treatment induced tardive dyskinesia and weight gain.

The distribution of anionic sites on the surface of the Golgi complex.

The distribution of anionic binding sites has been investigated in the isolated Golgi complex using cationic ferritin. The greatest density of anionic sites occurs on the tubular network and small vesicles, and this binding is accompanied by increased levels of galactosyltransferase activity. The density of anionic sites on the cisternae is less than on the tubules and shows anisotropic distribution, with higher density on the convex surface and lower density on the concave surface. The distribution of anionic sites may reflect the functional activity of the Golgi complex and possibly the interaction or cohesion between cisternae in this organelle.

Study of Flare Assessment in Systemic Lupus Erythematosus Based on Paper Patients.

OBJECTIVE: To determine the level of agreement of disease flare severity (distinguishing severe, moderate, and mild flare and persistent disease activity) in a large paper-patient exercise involving 988 individual cases of systemic lupus erythematosus. METHODS: A total of 988 individual lupus case histories were assessed by 3 individual physicians. Complete agreement about the degree of flare (or persistent disease activity) was obtained in 451 cases (46%), and these provided the reference standard for the second part of the study. This component used 3 flare activity instruments (the British Isles Lupus Assessment Group [BILAG] 2004, Safety of Estrogens in Lupus Erythematosus National Assessment [SELENA] flare index [SFI] and the revised SELENA flare index [rSFI]). The 451 patient case histories were distributed to 18 pairs of physicians, carefully randomized in a manner designed to ensure a fair case mix and equal distribution of flare according to severity. RESULTS: The 3-physician assessment of flare matched the level of flare using the 3 indices, with 67% for BILAG 2004, 72% for SFI, and 70% for rSFI. The corresponding weighted kappa coefficients for each instrument were 0.82, 0.59, and 0.74, respectively. We undertook a detailed analysis of the discrepant cases and several factors emerged, including a tendency to score moderate flares as severe and persistent activity as flare, especially when the SFI and rSFI instruments were used. Overscoring was also driven by scoring treatment change as flare, even if there were no new or worsening clinical features. CONCLUSION: Given the complexity of assessing lupus flare, we were encouraged by the overall results reported. However, the problem of capturing lupus flare accurately is not completely solved.

The effect of turpentine-induced inflammation on rat liver glycosyltransferases and Golgi complex ultrastructure.

Turpentine-induced inflammation in the rat caused a 1.6--2.3-fold increase in liver homogenate sialyl-, galactosyl- and N-acetylglucosaminyltransferase total and specific enzyme activities. Peak transferase activities were achieved at about 40 h after turpentine injection; the rise and fall of these activities corresponded to a similar rise and fall in serum haptoglobin levels. Sialyl- and N-acetylglucosaminyltransferase activities were measured in both liver homogenates and Golgi-enriched membranes at 24 h after turpentine injection; both total and specific enzyme activities doubled in the homogenates following turpentine treatment but in the Golgi-enriched membranes only the total enzyme activities doubled while the specific enzyme activities increased only by about 20%. These findings suggest that turpentine injection results in an increase of Golgi complex protein relative to total cellular protein. This conclusion was supported by electron microscopic studies of rat liver at various times after turpentine injection. The increased glycosylation potential of the liver and the proliferation of liver Golgi complex may play an important role in the turpentine-induced secretion of acute-phase glycoproteins.

The effect of temperature on the galactosyl- and sialyltransferases and on the ultrastructure of Golgi membranes.

The effect of temperature on the activity of galactosyl- and sialyltransferases of rat liver Golgi membranes and the galactosyltransferase of serum has been studied. Arrhenius plots for three enzymes were different. Sharp breaks in the curves, indicative of phase transitions were observed for sialyltransferase (28 degree C) of Golgi and galactosyltransferase (34 degree C) of serum but not for galactosyltransferase of Golgi. The activation energy was greater above the break (above 28 degree C) than below for sialyltransferase of Golgi; The activation energy was lower (above 34 degree C) for galactosyltransferase of serum than below. Electron microscopic freeze replicas showed a patchy distribution of particles which increased as the temperature was raised accompanied by smooth areas. This was interpreted as representing lateral phase separation of the membrane components.

The effect of cycloheximide on galactosyltransferase of rat liver Golgi membranes.

An inhibitory effect of cycloheximide on the initial rate of galactosyltransferase of rat liver Golgi membranes has been demonstrated. Cycloheximide was effective in inhibiting the activity of the enzyme when added directly to the assay medium or after pre-incubation of the membranes with the drug. The inhibition observed with different concentrations of nucleotide sugar was shown to be competitive at higher concentrations of the nucleotide sugar (0.10-1.0 mumol). The inhibition observed with different concentrations of acceptor, N-acetylglucosamine was complex and could not be analysed further with the present data. Washing the Golgi membranes previously incubated with cycloheximide with water failed to reverse the inhibition. Washing with UDPgalactose partially reversed the inhibition only. These results, together with the observation that serum galactosyltransferase was not inhibited by cycloheximide supported the view that the cycloheximide effect may be primarily on the membrane system.

Clinical expressions of immotile cilia syndrome.

To date three distinct morphologic types of immotile cilia disorder in man have been recognized. Patients with the disorder have variable clinical manifestations of disease of the upper and lower respiratory tract. Twenty-one patients with immotile cilia syndrome have been evaluated from the standpoint of history, clinical presentation, radiologic changes, pulmonary function tests, and mucociliary clearance. The results have been compared to the pathologic changes noted on ultrastructural examination of the cilia. Although clinical severity does not correlate with the type of abnormality found, a profile of clinical signs and symptoms suggestive of immotile cilia syndrome has emerged. The triad of productive cough, sinusitis, and otitis was a consistent finding in all. Situs inversus occurred in only half of the patients.

Cystic fibrosis in Ontario.

The incidence of cystic fibrosis in Ontario, Canada has been determined from clinical data, from the cystic fibrosis database of the Hospital for Sick Children, Toronto, and from population statistics in the Province of Ontario. The survey included 420 confirmed cases of cystic fibrosis born during the period 1966-1980. The mean incidence during this period was one in 2,927. In the last 5-year period, a decline was noted in incidence that may have reflected in part the effectiveness of early diagnosis and genetic counseling in affected families. During the period of the survey, over 60% of cases were diagnosed within the first year of life, 74% by age 2 years, and 90% by age 5 years. Clinical diagnosis in the first year of life was more common in males (65%) than in females (54%), a consistent finding during the period of the survey. The incidence of meconium ileus was 15.7% of ascertained cases of cystic fibrosis, with similar incidences in males (16.4%) and females (14.4%). Although survival has not been the subject of this survey, mortality in the neonatal period was significantly higher in males than in females with cystic fibrosis.

Genetic aspects of immotile cilia syndrome.

The genetics of the immotile cilia syndrome has been analyzed in a series of 46 affected individuals from 38 families. Both sexes were equally affected: there were 20 males and 26 females in this series. All patients had upper and lower respiratory disease with chronic sinusitis, otitis, and chronic cough from early childhood. Bronchiectasis was common in older children and adults. Situs inversus occurred randomly, affecting 11 males and 15 females. Biopsies of nasal and bronchial mucosa from these subjects have been investigated by electron microscopy and identified as having specific ultrastructural defects of respiratory tract cilia including deficiencies in outer dynein arms (19), inner dynein arms (3), both inner and outer dynein arms (15), radial spoke defect (5); and microtubular transposition anomaly (4). Segregation analysis of proband sibships was consistent with autosomal recessive inheritance. However, the different ultrastructural defects that underly the immotile cilia syndrome involve presumably different genetic determinants, and the different types have not been analyzed separately. Examination of paternal age and birth order gave no evidence of new autosomal dominant mutation in the series.

Genital mycoplasma infection. Intrauterine infection: pathologic study of the fetus and placenta.

Mycoplasma infection was present in the fetuses from three spontaneous abortions and in one second-trimester newborn. Gross examination revealed in most cases a severely infected placenta and membranes, with a fetus of normal appearance. The fetal infection presumably followed placental involvement and appeared to have been acquired shortly prior to delivery. Genital mycoplasmas, Ureaplasma urealyticum or Mycoplasma hominis, were isolated from the placentas and the fetal tissues, and from the genital tracts of the mothers. Isolation of mycoplasmas from the liver indicated that bloodstream dissemination of these organisms occurred in the fetus. In the fetus, the pathologic changes were variable. Lesions were identified in the lung by scanning electron microscopy of the bronchial tree in two cases and were accompanied by interstitial pneumonia. An abnormally dilated left ventricle suggestive of cardiomyopathy was observed in one case.

Parkinson-like syndrome in nonhuman primates receiving a tetrahydropyridine derivative.

Antipsychotic drugs, while ameliorating symptoms in schizophrenia, evoke extrapyramidal effects which resemble parkinsonism. We studied the potential of 1- (4,4-bis(4-fluorophenyl)butyl)-4-(4-fluorophenoxy)-1,2,3,6-tetrahydropyr idine d-tartrate to induce extrapyramidal side effects in Rhesus monkeys. This agent shares neurochemical effects of known antipsychotic agents in its ability to antagonize cerebral dopamine action by competing for (3H)-Haloperidol binding of the dopamine receptors and inhibiting limbic and striatal adenylate cyclase in rat brain. The compound was administered orally to monkeys for 18 days, starting at 2 mg/kg and increasing to 20 mg/kg. Additional groups of monkeys received the drug for 29 consecutive days at 5 and 7.5 mg/kg/day. In both studies, extrapyramidal signs were associated with neuropathological changes in the brains of treated monkeys. The findings resemble those reported in Rhesus monkeys and in drug addicts after repeated intravenous administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The findings also suggest a structure/activity relationship of tetrahydropyridine analogs with neurologic and associated neuropathologic manifestations produced in monkeys. The experimental model is useful to study the pathogenesis and possibly therapeutic approaches for Parkinson's disease.

Recurrent respiratory infections in a child with fucosidosis: is the mucus too thin for effective transport?

Fucosidosis is caused by a deficiency of the lysosomal enzyme alpha-L-fucosidase (ALF) leading to an accumulation of glycoproteins in a variety of cells. Infants and young children with this disorder are prone to recurrent sinus and pulmonary infections and often die of pneumonia. We studied the mucociliary and systemic immune function in a 6 year old girl with fucosidosis and recurrent respiratory infections. All measurements of systemic immune function were normal. Sweat chloride was normal when measured on angiokeratotic skin but was greater than 65 mg/L on uninvolved areas. During the placement of tympanic ventilation tubes, tracheal mucus was gently aspirated and a mucosal biopsy was taken. Tracheal mucus transport was not measured. The biopsy material was examined under phase contrast microscopy and revealed ciliated cells with apparently normal beating. TEM of these cells showed a characteristic pattern of vacuoles in the cytoplasm as described in other tissues from patients with fucosidosis. Ciliary ultrastructure was normal. Mucus viscoelasticity was measured in a magnetic microrheometer. The loss tangent was 2 SD above the mean for normal mucus and mechanical impedance was about 2 SD below the mean. These changes are similar in direction but double in magnitude to what has been described with methacholine administration in dogs. The high compliance of the mucus may be due to incomplete assembly of mucus glycoprotein or to decreased secretion of glycoproteins in respiratory secretions. This leads to mucus that is abnormally watery and thus difficult to clear from the airway.

The Golgi complex. III. The effects of puromycin on ultrastructure and glycoprotein synthesis.

The effect of puromycin has been investigated on protein and glycoprotein synthesis and on ultrastructure of the Golgi complex from rat liver. Incorporation of [14C]leucine into protein in Golgi fractions and into serum proteins was depressed rapidly after puromycin treatment. In the serum proteins, incorporation returned to normal levels at 2 h whereas in Golgi fractions it continued to rise to 200% of the control levels at 3 h and was still elevated at 24 h after puromycin treatment. Incorporation of [14C]glucosamine into glycoprotein was depressed in Golgi and serum fractions in a similar manner but slightly later than that of leucine. Leucine labelled material found at 3 h was a poor acceptor for carbohydrate, since [14C]glucosamine incorporation was not elevated above control values. Galactosyl transferase activity was not depressed in the Golgi membranes and, at 3 h, was elevated implying that an adequate supply of enzyme was available at all times. The activity of the galactosyl transferase in serum appeared to be depressed suggesting that transport of enzyme from Golgi complex to serum was defective. Ultrastructural changes in the Golgi complex were observed to occur rapidly after puromycin treatment. The cisternae became irregular, compressed, and degenerated progressively from central region towards the periphery. Irregular tubular structures formed at the expense of cisternal membrane and showed accumulation of low density lipoprotein. Vesiculation and degenerative changes of the Golgi membranes continued from 2-12 h while more typical arrangements of the Golgi complex were observed between 24-48 h. The morphological changes correlated with changes in glycoprotein synthesis.

The secretory response in dissociated acini from the rat submandibular gland.

Rat submandibular gland was dissociated by enzymatic digestion with collagenase and hyaluronidase, followed by mild mechanical shearing and filtration through a nylon mesh. The dissociated cell populations contained predominantly groups of acinar cells which maintained their acinar arrangement. The morphological and functional viability of the cells was confirmed by electron microscopic examination and a normal secretory response to beta-adrenergic or cholinergic stimulation was observed. Both isoproterenol (IPR) and carbachol caused the fusion of secretory granules into large vacuoles which were also continuous with the lumen, and into which the secretory product was released. Secretion was assessed quantitatively from the incorporation of 14C-glucosamine into the acinar cells and its subsequent release into the culture medium as labelled glycoprotein. IPR stimulated secretion to 125% of untreated controls in the concentration range t x 10(-5) to 5x 10(-7) M and to 110% of controls at 5 x 10(-8) M, after 40 min incubation. Carbachol stimulated secretion to 131% of controls at 5 x 10(-5) M and to 115% at 5 x 10(-6) M but had no effect at 5 x 10(-7) or 5 x 10(-8) M. The secretory response was blocked by the respective beta-adrenergic and cholinergic antagonists, propranolol and atropine. These findings show that dissociated rat submandibular acinar cells provide a useful in vitro model for the study of mucus synthesis and secretion.

Histiocytic sarcoma in Wistar rats. A light microscopic, immunohistochemical, and ultrastructural study.

Histiocytic sarcoma, a recently described tumor entity in rats, was studied by light microscopy in 20 male and female Wistar rats. The tumors originated from subcutaneous tissues; metastasis involved primarily the liver with sinusoidal spread and the lungs with peribronchiolar distribution. The characteristic features of this tumor were the uniform population of tumor cells, palisading necrosis, and abundant multinucleated giant cells. Immunocytochemical and ultrastructural findings confirmed the histiocytic nature of the tumor cells.