Is conservative management of the indeterminate thyroid nodule [Thy3f or Bethesda category IV] safe?

PURPOSE: The histological diagnosis after diagnostic thyroidectomy for indeterminate thyroid nodules is often non-malignant and some cancers detected are considered 'indolent'. The safety and effectiveness of conservative management in these patients are unclear. The aim of this study was to determine the safety of conservative management of indeterminate thyroid nodules and to explore association between clinical features and pathology in patients undergoing surgery. METHODS: This is a retrospective cohort study of patients presenting to a single centre over a 4-year period (2013-2016) with thyroid nodules that were considered indeterminate (thy3f in the UK RCPath classification) on cytology. Demographic data, ultrasound features, follow-up details (in those undergoing conservative management) and histology details (in those undergoing surgery) were collected. RESULTS: Of 164 patients that had Thy3f cytology, 34 were initially managed conservatively; however, 4 of these eventually had surgery (due to patient preference). No patient on conservative management had significant disease progression on ultrasound at a median (interquartile range) of 27 (16-40) months. Of the 134 patients that underwent surgery, 26 had thyroid malignancy. The BTA 'U' classification, gender and age (> 55) were not associated with malignancy in these nodules, but larger nodules (> 40 mm) were more likely to be malignant (p = 0.042). CONCLUSIONS: Conservative management of indeterminate (Thy3f or Bethesda stage IV) thyroid nodules is safe in the short term and may be indicated in selected cases after appropriate discussion of risks and benefits of surgery.

Immunoglobulin G4-related disease in a dog.

Immunoglobulin G4-related disease (IgG4-RD), which affects many organ systems, has been recognized as a distinct clinical entity in human medicine for just over a decade but has not been previously identified in dogs. In humans, IgG4-RD is characterized by diffuse IgG4-positive lymphoplasmacytic infiltrates that commonly lead to increased serum concentrations of IgG4 and IgE, peripheral eosinophilia, tumorous swellings that often include the parotid salivary glands, obliterative phlebitis, and extensive fibrosis. Herein we describe the diagnosis, clinical progression, and successful treatment of IgG4-RD in an 8-year-old female spayed Husky mixed breed dog. Immunoglobulin G4-related disease should be considered as a differential diagnosis for dogs with vague clinical signs, lymphoplasmacytic swellings, restricted polyclonal gammopathy, eosinophilia or some combination of these findings.

Smoking Predicting Physical Activity in an Aging America.

OBJECTIVES: Tobacco smoking and physical inactivity are among leading behavioral risk factors for ill health in older adults. This study considers how smoking is associated with physical activity. DESIGN: Using a Life-Course model, data are analyzed regarding this relationship, controlling for, and interacted with, life-course and other factors. Daily smokers and sometimes smokers were hypothesized to engage in less leisure-time physical activity than those who never smoked, while those who stopped smoking were expected to do more than never smokers. Analyses were performed using SAS-Callable SUDAAN. SETTING AND PARTICIPANTS: Secondary data from ten years of a national sample of adults aged 18 and over of the National Health Interview Survey, 2001-2010, are used (N = 264,945, missing data excluded, of 282,313 total cases). MEASUREMENTS: Daily smokers, occasional smokers, and smoking quitters are compared to never smokers with regard to requisite physical activity (150 minutes per week of moderate, 100 of vigorous, and/or 50 of strengthening activity). Life-course measures include birth cohorts, age, and year of survey, as well as gender, race/ethnicity, and education. RESULTS: Overall, hypotheses are supported regarding daily smokers and quitters; but the hypothesis is strongly rejected among sometimes smokers, who are much more likely to do requisite physical activity. Findings differ by age, sometimes smokers age 65 and over being less likely to do physical activity. Findings among all men are similar to the overall findings, while those among all women are similar to those for older respondents. Associations of smoking status with physical activity vary greatly by race/ethnicity. CONCLUSIONS: Daily smokers may be most in need of both smoking cessation and leisure-time physical activity interventions. Smoking-cessation efforts may pay greater physical activity benefits among women and the aged, while smoking-reduction efforts may provide better outcomes among men. Smoking reduction efforts may pay more exercise benefits among African-Americans and Hispanics.

Evaluation of the biological differences of canine and human factor VIII in gene delivery: implications in human hemophilia treatment.

The canine is the most important large animal model for testing novel hemophilia A (HA) treatment. It is often necessary to use canine factor VIII (cFIII) gene or protein for the evaluation of HA treatment in the canine model. However, different biological properties between cFVIII and human FVIII (hFVIII) indicated that the development of novel HA treatment may require careful characterization of non-human FVIII. To investigate whether the data obtained using cFVIII can translate to HA treatment in human, we analyzed the differential biological properties of canine heavy chain (cHC) and light chain (cLC) by comparing with human heavy chain (hHC) and light chain (hLC). The secretion of cHC was 5-30-fold higher than hHC, with or without light chains (LCs). cHC+hLC group exhibited ~18-fold increase in coagulation activity compared with hHC+hLC delivery by recombinant adeno-associated viral vectors. Unlike hHC, the secretion of cHC was independent of LCs. cLC improves the specific activity of FVIII by two- to threefold compared with hLC. Moreover, the cLC, but not cHC, contributes to the higher stability of cFVIII. Our results suggested that the cFVIII expression results in the canine model should be interpreted with caution as the cHC secreted more efficiently than hHC and cLC exhibited a more active and stable phenotype than hLC.

Awake videolaryngoscopy-assisted tracheal intubation of the morbidly obese.

Awake videolaryngoscopy may be useful for the tracheal intubation of the morbidly obese. This prospective, observational study enrolled 50 patients undergoing bariatric surgery. After sedation and topical anaesthesia of the airway, awake tracheal intubation was attempted, assisted by videolaryngoscopy, and terminated if there was severe gagging, coughing, or inadequate laryngeal view. After three attempts the procedure was considered a failure. Twenty-seven intubations were successful on the first attempt, fifteen on the second, six on the third and two were not successful, giving a success rate of 96% (95% CI 86-100%). In one failure, inserting the tracheal tube caused severe gagging in spite of an adequate view of the larynx, and the trachea was intubated with the videolaryngoscope after induction of anaesthesia. The second failure was due to gagging, with subsequent tracheal intubation successful using fibreoptic bronchoscopy. When managing the morbidly obese airway, awake tracheal intubation using videolaryngoscopy may be considered.

Unintentional subdural catheter placement during labor analgesia shows typical radiological pattern but atypical response to the Tsui test.

Subdural injection may be associated with abnormally extensive or limited spread of local anesthetics during neuraxial anesthesia. This complication is difficult to diagnose clinically. Radiological imaging is the gold standard for confirming the location of subdural catheter, but electrical stimulation of the catheter has also been described as a useful diagnostic tool. We present the case of an obstetric patient with unintentional subdural catheter placement that presented as a failed epidural block associated with severe upper back and scapular pain on catheter injection. Electrical stimulation of the catheter did not elicit muscle contractions until a current of 4 mAmp was attained, which is the response pattern of epidural placement. Subdural location of the catheter was subsequently confirmed by contrast radiography. This case adds to the evidence that subdural catheters are difficult to identify clinically, and that electrical stimulation may not differentiate them from epidural catheters.

Accuracy and reproducibility of conformal radiotherapy using data from a randomised controlled trial of conformal radiotherapy in prostate cancer (MRC RT01, ISRCTN47772397).

AIMS: The MRC RT01 trial used conformal radiotherapy to the prostate, a method that reduces the volume of normal tissue treated by 40-50%. Because of the risk of geographical miss, the trial used portal imaging to examine whether treatment delivery was within the required accuracy. MATERIAL AND METHODS: In total, 843 patients were randomly assigned to receive 64 Gy in 32 fractions over 6.5 weeks or 74 Gy in 37 fractions over 7.5 weeks. Field displacements and corrections were recorded for all imaged fractions. Displacement trends and their association with time, disease and treatment set-up characteristics were examined using univariate and multivariate analyses. A Radiographer Trial Implementation Group (RTIG) was set up to inform the quality assurance process and to promote the development of best practice. RESULTS: Treatment isocentre positioning was within 5 mm in every direction on 6238 (83%) of the 7535 fractions imaged. In total, 532 (81%) of 695 included patients had at least one > or = 3 mm displacement and 415 (63%) had at least one > or = 5 mm displacement. Univariate, multivariate and stepwise models of > or =5 mm displacements showed an increased likelihood of displacement in weeks 1 and 2 with low melting point alloy (LMPA) blocks compared with multileaf collimators, film verification compared with electronic portal imaging (EPI) and increased number of fractions imaged. Except for LMPA, this was also seen for > or = 5 mm displacements in weeks 3-6. CONCLUSIONS: Accurate conformal treatment was delivered. The use of EPI was associated with increased reported accuracy. The RTIG was a crucial part of the quality assurance process.

Developing ethical strategies to assist oncologists in seeking informed consent to cancer clinical trials.

Randomised clinical trials have come to be regarded as the gold standard in treatment evaluation. However, many doctors see the discussion of a clinical trial as an intrusion into the doctor-patient relationship and find these discussions difficult to initiate. Detailed informed consent is now a requirement of patient participation in trials; however, it is known that patients commonly fail to understand and recall the information conveyed. These difficulties for doctors and patients raise questions about the ethical integrity of the informed consent process. In this study, we have developed a set of communication strategies underpinned by ethical, linguistic and psychological theory, designed to assist doctors in this difficult task. Initially, audiotape transcripts of 26 consultations in which 10 medical oncologists invited patients to participate in clinical trials were analysed by expert ethicists, linguists, oncologists and psychologists, using rigorous qualitative methodology. A subset of seven of these was subjected to detailed linguistic analysis. A strategies document was developed to address themes which emerged from these analyses. This document was presented to relevant expert stakeholders. Their feedback was incorporated into the final document. Four themes emerged from the analysis; (a) shared decision-making, (b) the sequence of moves in the consultation, (c) the type and clarity of the information provided and (d) disclosure of controversial information and coercion. Detailed strategies were developed to assist doctors to communicate in these areas. We have developed a set of ethical strategies which may assist health professionals in this difficult area. A training package based on these strategies is currently being evaluated in a multi-centre randomised controlled trial.

Hyaluronan--a review of the recent patent literature.

A review of patent literature surrounding the use of hyaluronan (HA) and its derivatives, or agents capable of modulating endogenous levels, is presented. Indications are many and varied and include arthritis, abnormal wound healing, neoplasia, prevention of surgical adhesions and dermatological disorders. In many cases, it is the physicochemical and biological properties of HA itself that have been exploited. For example, HA and/or its derivatives have been suggested as a synovial fluid replacement, a vehicle for topical application of drugs, a matrix for sustained drug release and a putative drug delivery system (targeting HA receptors at sites of pathology). In each of these examples, the lack of toxicity of HA and its biocompatability are important considerations.

Drug-induced cognitive impairment in the elderly.

Elderly people are more likely than younger patients to develop cognitive impairment as a result of taking medications. This reflects age- and disease-associated changes in brain neurochemistry and drug handling. Delirium (acute confusional state) is the cognitive disturbance most clearly associated with drug toxicity, but dementia has also been reported. The aetiology of cognitive impairment is commonly multifactorial, and it may be difficult to firmly establish a causal role for an individual medication. In studies of elderly hospital patients, drugs have been reported as the cause of delirium in 11 to 30% of cases. Medication toxicity occurs in 2 to 12% of patients presenting with suspected dementia. In some cases CNS toxicity occurs in a dose-dependent manner, often as a result of interference with neurotransmitter function. Drug-induced delirium can also occur as an idiosyncratic complication. Finally, delirium may occur secondary to iatrogenic complications of drug use. Almost any drug can cause delirium, especially in a vulnerable patient. Impaired cholinergic neurotransmission has been implicated in the pathogenesis of delirium and of Alzheimer's disease. Anticholinergic medications are important causes of acute and chronic confusional states. Nevertheless, polypharmacy with anticholinergic compounds is common, especially in nursing home residents. Recent studies have suggested that the total burden of anticholinergic drugs may determine development of delirium rather than any single agent. Also, anticholinergic effects have been identified in many drugs other than those classically thought of as having major anticholinergic effects. Psychoactive drugs are important causes of delirium. Narcotic agents are among the most important causes of delirium in postoperative patients. Long-acting benzodiazepines are the commonest drugs to cause or exacerbate dementia. Delirium was a major complication of treatment with tricyclic antidepressants but seems less common with newer agents. Anticonvulsants can cause delirium and dementia. Drug-induced confusion with nonpsychoactive drugs is often idiosyncratic in nature, and the diagnosis is easily missed unless clinicians maintain a high index of suspicion. Histamine H2 receptor antagonists, cardiac medications such as digoxin and beta-blockers, corticosteroids, non-steroidal anti-inflammatory agents and antibiotics can all cause acute, and, less commonly, chronic confusion. Drug-induced confusion can be prevented by avoiding polypharmacy and adhering to the saying 'start low and go slow'. Special care is needed when prescribing for people with cognitive impairment. Early diagnosis of drug-induced confusion, and withdrawal of the offending agent or agents is essential.

Effects of hyaluronan on models of immediate and delayed hypersensitivity in the rat.

Others have previously shown that superoxide dismutase conjugated with hyaluronan (HA) retains enzymic activity but is non-immunogenic. Whether HA could be widely used to prevent sensitisation to protein/polypeptide therapeutics is not known. In this study we investigated the effects of HA on bovine serum albumin (BSA) and methylated BSA pleural reactions in sensitised rats (active Arthus and delayed hypersensitivity reactions respectively) and on a reverse passive Arthus reaction in which rats received an intravenous injection of rabbit immunoglobulin and intrapleural challenge with goat anti rabbit immunoglobulin. HA suppressed the active Arthus and delayed hypersensitivity models when administered at the time of sensitisation but only the delayed hypersensitivity model at the time of intrapleural challenge. HA did not modulate the reverse passive Arthus reaction. The results show no evidence that simple mixing of HA with antigens masks antigenic determinants. However, HA appeared to have suppressive effects on both antibody and cell-mediated immune reactions. Therefore it may not be necessary to conjugate protein/polypeptide therapeutics to HA in order to prevent immune sensitisation.

Effects of diacerhein on granuloma induced cartilage breakdown in the mouse.

OBJECTIVE: Diacerhein, an anti-osteoarthritic agent, was tested for its ability to suppress synthesis of proinflammatory cytokines in a model of granuloma-induced cartilage breakdown. DESIGN: 50 TO mice received a subcutaneous implant of cotton-wrapped rat femoral head cartilage for a period of 2 weeks. Animals (N = 10/group) were dosed daily with either 6 mg/kg p.o. diclofenac or diacetylrhein at 5, 15 or 50 mg/kg p.o. in 0.1.ml 1% gum tragacanth which served as a control. Implanted cartilages were assayed for glycosaminoglycan (GAG) and hydroxyproline content. The surrounding granulomas were assayed for interleukin-1 alpha (IL-1 alpha), tumour necrosis factor-alpha (TNF-alpha) and IL-6. Statistical analysis was by Mann-Whitney U test. RESULTS: Diclofenac had no significant effect on GAG or hydroxyproline content of implanted cartilage or on granuloma cytokine concentrations. Diacerhein protected implanted cartilages against hydroxyproline loss, implanted control cartilages contained 220 micrograms hydroxyproline compared with diacerhein at 5, 15 and 50 mg/kg which produced a 21, 16 and 59% decrease in hydroxyproline loss compared with non-implanted controls (P < 0.05, 0.05 and 0.001) respectively. Diacerhein also protected against GAG loss at 5 mg/kg and 50 mg/kg, control cartilages contained 134 micrograms GAG compared with diacerhein at 5 mg/kg and 50 mg/kg which produced a 24 and 38% decrease in GAG loss respectively (P < 0.05 for both). Diacerhein significantly reduced granuloma interleukin-1 alpha content at 5 mg/kg (control level of 2.4 micrograms/ml reduced by 58%; P < 0.05), reduced TNF-alpha at 5 mg/kg and 15 mg/kg (reduced by 61%: P < 0.01 and 49%: P < 0.05 respectively; control level of 469 pg/ml) and reduced IL-6 at 15 mg/kg and 50 mg/kg (control level of 537 pg/ml reduced by 60 and 51%, respectively; P < 0.01 for both). CONCLUSIONS: The mechanism of the chondroprotective effects of diacerhein is not understood but may be explained by a reduction in the concentrations of proinflammatory cytokines.

Single-patient data meta-analysis of 3453 postoperative patients: oral tramadol versus placebo, codeine and combination analgesics.

The analgesic effectiveness and safety of oral tramadol were compared with standard analgesics using a meta-analysis of individual patient data from randomised controlled trials in patients with moderate or severe pain after surgery or dental extraction. Calculation of %maxTOTPAR from individual patient data, and the use of > 50%maxTOTPAR defined clinically acceptable pain relief. Number-needed-to-treat (NNT) for one patient to have > 50%maxTOTPAR compared with placebo was used to examine the effectiveness of different single oral doses of tramadol and comparator drugs. Eighteen randomised, double-blind, parallel-group single-dose trials with 3453 patients using categorical pain relief scales allowed the calculation of %maxTOTPAR. The use of > 50%maxTOTPAR was a sensitive measure to discriminate between analgesics. Tramadol and comparator drugs gave significantly more analgesia than placebo. In postsurgical pain tramadol 50, 100 and 150 mg had NNTs for > 50%maxTOTPAR of 7.1 (95% confidence intervals 4.6-18), 4.8 (3.4-8.2) and 2.4 (2.0-3.1), comparable with aspirin 650 mg plus codeine 60 mg (NNT 3.6 (2.5-6.3)) and acetaminophen 650 mg plus propoxyphene 100 mg (NNT 4.0 (3.0-5.7)). With the same dose of drug postsurgical patients had more pain relief than those having dental surgery. Tramadol showed a dose-response for analgesia in both postsurgical and dental pain patients. With the same dose of drug postsurgical pain patients had fewer adverse events than those having dental surgery. Adverse events (headache, nausea, vomiting, dizziness, somnolence) with tramadol 50 mg and 100 mg had a similar incidence to comparator drugs. There was a dose response with tramadol, tending towards higher incidences at higher doses. Single-patient meta-analysis using more than half pain relief provides a sensitive description of the analgesic properties of a drug, and NNT calculations allow comparisons to be made with standard analgesics. Absolute ranking of analgesic performance should be done separately for postsurgical and dental pain.

The cell surface of Aeromonas salmonicida determines in vitro survival in cultured brook trout (Salvelinus fontinalis) peritoneal macrophages.

Aeromonas salmonicida strains phenotypically differing in their A-layer, lipopolysaccharide, and macrophage cytotoxicity were tested in vitro for survivability in brook trout (Salvelinus fontinalis) serum with or without antibodies, and in vivo following intraperitoneal injection. The ability of brook trout peritoneal macrophages to phagocytize and kill the different phenotypes was investigated in an in vitro assay. The virulent strain, A. salmonicida 80204, which has the full complement of known virulence factors, as well as the recently described macrophage cytotoxin, was resistant in vitro to both the bactericidal activity of normal and immune serum, and to brook trout peritoneal macrophages. A. salmonicida SS-70.1, which possesses the A-layer but lacks the cytotoxin, was resistant to the bactericidal activity of normal and immune serum but was avirulent and killed by macrophages. Phenotypes lacking the A-layer, regardless of whether or not they possessed the macrophage cytotoxin were avirulent, susceptible to normal and immune serum and the bactericidal activity of peritoneal macrophages. A. salmonicida virulence expression requires both the A-layer and the macrophage cytotoxin.

OM-89 modulation of chronic inflammation: relevance to clinical use.

The modulatory effects of a glycoprotein-rich endotoxin-free extract of Escherichia coli (OM-89) have been studied using the cotton pellet model of chronic inflammation in the male Wistar rat. OM-89 had a suppressive effect on the size of granuloma surrounding implanted cotton pellets at both 4 and 40 mg/kg given three times weekly. The lower dosage of 4 mg was effective throughout and there was little to be gained by increasing the dose as further reduction of granuloma size was not obtained. Whether given prior to, at the same time as, or after an inflammatory stimulus, OM-89 had suppressive effects. However, if given before, animals at first went through a phase of 'sensitization' before suppressive effects were seen on further exposure to OM-89 antigens, a phenomenon which might have bearing on clinical findings in rheumatoid arthritis. In animals presensitized to a cotton pellet, OM-89 was statistically as effective as indomethacin in suppressing a second granuloma. OM-89 combined with indomethacin showed additive effects and was highly effective. The results indicate that OM-89 could be efficacious in the treatment of chronic inflammatory conditions and there is the possibility that in appropriate circumstances OM-89 might replace some drugs currently used and in others reduce their dosage.

Hyaluronan as a drug delivery system for diclofenac: a hypothesis for mode of action.

Hyaluronan (HA) in combination with diclofenac is currently undergoing clinical trials as a topical preparation in the management of osteoarthritic pain, basal-cell carcinoma and actinic keratosis. These are clearly diverse pathologies, but in all cases substance P plays a central role either directly or through secondary mediators such as prostaglandin E2 and nitric oxide. A common mechanism for HA in combination with diclofenac in these conditions may be through ameliorating the direct and indirect effects of substance P. Additionally, HA appears to depot and hold diclofenac in the epidermis, thereby prolonging its pharmacokinetic half-life. In rabbits, stenosis following balloon angioplasty is prevented by a subcutaneous dose of HA, probably through blockade of cell-surface HA receptors (ICAM-1, CD44 & RHAMM). The physicochemical properties of HA, and the binding of HA to HA receptors, suggests that HA will have value as a novel drug delivery system.