Implementation of duty of candour within neurosurgery: a national survey and framework for improved application in clinical practice.

INTRODUCTION: Statutory duty of candour was introduced in November 2014 for NHS bodies in England. Contained within the regulation were definitions regarding the threshold for what constitutes a notifiable patient safety incident. However, it can be difficult to determine when the process should be implemented. The aim of this survey was to evaluate the interpretation of these definitions by British neurosurgeons. MATERIALS AND METHODS: All full (consultant) members of the Society of British Neurological Surgeons were electronically invited to participate in an online survey. Surgeons were presented with 15 cases and asked to decide in the case of each one whether they would trigger the process of duty of candour. Cases were stratified according to their likelihood and severity. RESULTS: In all, 106/357 (29.7%) members participated in the survey. Responses varied widely, with almost no members triggering the process of duty of candour in cases where adverse events were common (greater than 10% likelihood) and required only outpatient follow-up (7/106; 6.6%), and almost all members doing so in cases where adverse events were rare (less than 0.1% likelihood) and resulted in death (102/106; 96.2%). However, there was clear equipoise in triggering the process of duty of candour in cases where adverse events were uncommon (0.1-10% likelihood) and resulted in moderate harm (38/106; 35.8%), severe harm (57/106; 53.8%) or death (49/106; 46.2%). CONCLUSION: There is considerable nationwide variation in the interpretation of definitions regarding the threshold for duty of candour. To this end, we propose a framework for the improved application of duty of candour in clinical practice.

Potential applications of next generation DNA sequencing of 16S rRNA gene amplicons in microbial water quality monitoring.

The applicability of next generation DNA sequencing (NGS) methods for water quality assessment has so far not been broadly investigated. This study set out to evaluate the potential of an NGS-based approach in a complex catchment with importance for drinking water abstraction. In this multi-compartment investigation, total bacterial communities in water, faeces, soil, and sediment samples were investigated by 454 pyrosequencing of bacterial 16S rRNA gene amplicons to assess the capabilities of this NGS method for (i) the development and evaluation of environmental molecular diagnostics, (ii) direct screening of the bulk bacterial communities, and (iii) the detection of faecal pollution in water. Results indicate that NGS methods can highlight potential target populations for diagnostics and will prove useful for the evaluation of existing and the development of novel DNA-based detection methods in the field of water microbiology. The used approach allowed unveiling of dominant bacterial populations but failed to detect populations with low abundances such as faecal indicators in surface waters. In combination with metadata, NGS data will also allow the identification of drivers of bacterial community composition during water treatment and distribution, highlighting the power of this approach for monitoring of bacterial regrowth and contamination in technical systems.

Influence of monocaprin on the permeability of a diacidic drug BTA-243 across Caco-2 cell monolayers and everted gut sacs.

This study explores the potential of the monoglyceride monocaprin as an enhancer of the epithelial permeability of the beta(3)-adrenoceptor agonist BTA-243, as an approach to improving the bioavailability of this drug. The permeabilities of BTA-243 and mannitol (paracellular marker) in Caco-2 cell monolayer and everted gut sac models in aqueous buffer (pH 6.8) in the presence of 1.3 and 2.0 mM monocaprin were compared with control (monocaprin-free) solutions over a period of 1 h. The transepithelial electrical resistance (TEER) of the Caco-2 cell monolayers was measured at regular time intervals throughout the experiment and after a recovery period of 30 h. Toxicological damage to the biological models associated with exposure to monocaprin was assessed by scanning electron microscopy and by the measurement of lactate dehydrogenase (LDH) release from everted gut sacs. The permeability of BTA-243 in epithelial monolayers was enhanced in the presence of 1.3 and 2.0 mM monocaprin. Measurements of TEER and mannitol permeability showed partial recovery of barrier properties after a 30 h period following exposure to 1.3 mM monocaprin. No structural damage was evident in these monolayers. Enhancement of Caco-2 permeability to BTA-243 by 2.0 mM monocaprin was significantly greater than by 1.3 mM but was irreversible; monolayers failed to recover their barrier properties after 30 h and changes in their gross morphology were observed. The mucosal to serosal transfer of BTA-243 in everted gut sac was enhanced but to a lesser extent than in the Caco-2 model. LDH release from everted gut sacs exposed to monocaprin was significantly less than that after exposure to Triton X-100, a nonionic surfactant known to cause membrane disruption.

Photoreactivation of ultraviolet radiation-induced basic fibroblast growth factor (bFGF) and the role of bFGF in corneal lesion formation in Monodelphis domestica.

Chronic ultraviolet radiation (UVR) exposure to the eyes of Monodelphis domestica causes corneal opacification, neovascularization, and fibrosarcoma induction. By immunohistochemistry and Western blotting, we have shown that one to four exposures of the eyes of this opossum to UVR enhances basic fibroblast growth factor (bFGF) expression by the corneal epithelium. Treatment with photoreactivating light, which selectively removes UVR-induced pyrimidine dimers, suppresses bFGF induction, indicating that UVR induction of bFGF is ultimately due to DNA damage. Furthermore, UVR-induced corneal tumors derived from corneal keratocytes express bFGF mRNA and protein, as determined by immunohistochemistry and in situ hybridization. Taken together, these findings suggest that bFGF acts in both an autocrine and a paracrine manner to stimulate corneal fibroplasia, neovascularization, and tumor development.

Respiratory psychophysiology and behavior modification.

This article was written as an introduction to a special issue of Behavior Modification dedicated to studies in the field of respiratory psychophysiology. Although the invited articles that constitute this special issue cover a fairly broad range of topics, priority was given to articles that focus on the role of respiration in panic disorder. Attention is directed to the fundamental role of breathing in applied psychophysiology and to the encouragement of research in the modification of breathing behavior. The connection between respiratory psychophysiology and behavior modification is explained by reference to (a) a recent article on Pavlovian and operant control of breathing behavior and (b) four published volumes of selected articles dedicated exclusively to the field of respiratory psychophysiology. The present special issue of Behavior Modification marks the fifth volume.

Dyspnea during panic attacks. An Internet survey of incidences of changes in breathing.

This article presents the results of a survey that investigated breathing-related symptoms of panic attacks together with the frequency of other symptoms reported by active panickers. All the participants of this study experienced naturally occurring panic attacks and sought treatment guidance by visiting a Web site devoted to the treatment of panic. The results of a symptom questionnaire showed that 195 respondents (95.1%) reported breathing changes during panic attacks, and remarkable dyspnea was reported by more than two thirds (68%) of respondents. These findings are consistent with earlier studies but are contrary to conclusions that only a small number of panickers report shortness of breath as a symptom. This study concludes that outside of the laboratory, a large majority of people who suffer from panic attacks experience symptoms of dyspnea.

Dose response for ultraviolet radiation A-induced focal melanocytic hyperplasia and nonmelanoma skin tumors in Monodelphis domestica.

Four groups of 30 dorsally shaved opossums (Monodelphis domestica) were exposed to graded doses of ultraviolet radiation A (UVA) (320-400 nm) three times per week for 90 weeks. Animals were monitored for the appearance of focal melanocytic hyperplasia (FMH) and nonmelanoma skin tumors (NMST) during the course of the exposures and for an additional 20 weeks following termination of exposures. FMH is the putative precursor for melanoma in the opossum. The lowest dose of UVA (2.5 x 10(3) J/m2) used in this study was selected based on the action spectrum for the induction of melanoma in a fish model. The prediction was that 2.5 x 10(3) J/m2 would induce FMH in the opossum if the action spectra for the induction of FMH in the opossum and melanoma in the fish were the same. The highest UVA dose was 2.5 x 10(5) J/m2. Only the highest dose of UVA gave a statistically significant induction of FMH and NMST in the opossum. As in previous studies, the FMH appeared earlier than the NMST during the course of exposures and the final prevalence of FMH was lower than the final prevalence of NMST. Overall, the results of this study indicate that the efficacy of UVA to induce FMH in the opossum is not as great as would be predicted from the action spectrum for melanoma induction in a fish model.

Physicochemical and biopharmaceutical characterization of BTA-243, a diacidic drug with low oral bioavailability.

This investigation has examined possible causes of the poor bioavailability of the beta(3)-adrenoceptor agonist BTA-243. The aqueous solubility of BTA-243 is pH dependent with a solubility minimum at pH 1.5. However, the dissolution rate of the disodium salt of BTA-243 is similar at both pH 2.0 and 7.4 indicating that dissolution rate is unlikely to be the controlling factor in the absorption of BTA-243. The apparent permeability coefficient of BTA-243 across Caco-2 monolayers at pH 6 was lower than that of mannitol and therefore the epithelial permeability of the molecule in vivo is predicted to be very low and potentially bioavailability limiting. Apparent permeability coefficients were not dependent on BTA-243 concentration over the concentration range 0.5 to 12 mM, indicating that epithelial transport is unlikely to occur via a saturable mechanism. They were of similar magnitude in both directions across the monolayers, indicative of no significant effluxing of BTA-243 by components of the cell membrane. Apparent octanol/water distribution coefficients increased with decrease of pH between 2 and 6; the relatively low values at pH 4 and 6 suggest that the limited intestinal absorption predicted in vivo will occur predominantly via paracellular passive diffusion. Everted gut sac experiments performed at pH 2.0 and 6.8 suggest that at pH 2.0 a significant proportion of the BTA-243 transport occurs via the transcellular route confirming that the ionization state of the BTA-243 molecule influences the route and rate of epithelial permeability.

UVAI-induced edema and pyrimidine dimers in murine skin.

The induction of edema and pyrimidine dimers in epidermal DNA was determined in the skin of SKH:HR1 mice exposed to graded doses of ultraviolet radiation AI (UVAI; 340-400 nm). Exposure to UVAI induced 1.6 +/- 0.08 x 10(-6) (mean +/- standard error of mean) pyrimidine dimers per 10(8) Da of DNA per J/m2. Edema in irradiated animals was determined as an increase in skinfold thickness. A dose of 1.8 x 10(6) J/m2 of UVAI that resulted in a 50% increase in skinfold thickness (SFT50%) would have induced 1.0 x 10(5) dimers per basal cell genome. A similar increase in SFT induced by full spectrum solar ultraviolet radiation (290-400 nm) would accompany the induction of 11.0 x 10(5) pyrimidine dimers per basal cell genome. These results support a hypothesis that UVAI-induced pathological changes of the skin are mediated through the formation of nondimer photoproducts.

Photobiology of Monodelphis domestica.

The gray, short-tailed opossum, Monodelphis domestica, has been used for photobiologic studies since 1984. The presence of a light-activated DNA repair pathway in the tissues of Monodelphis has been used to identify pyrimidine dimers in DNA as initiating events for a number of ultraviolet radiation (UVR)-induced pathologies of the skin and cornea. Furthermore, Monodelphis, unlike common laboratory rodents, is susceptible to the induction of melanoma by UVR alone.

The modification of breathing behavior. Pavlovian and operant control in emotion and cognition.

The purpose of this article is to bring attention to breathing as a behavior that can be modified by means of Pavlovian and operant principles of control. With this aim in mind, this paper (a) reviews a selection of early and recent conditioning studies (Pavlovian and operant paradigms) in respiratory psychophysiology, (b) discusses the bidirectional relationship between breathing and emotion/cognition, and (c) discusses theoretical and applied implications that point to new directions for research in the laboratory and clinic. Emphasis is placed on dyspnea/suffocation fear and the acquisition of anticipatory dyspnea/suffocation fear in panic, anxiety, and stress disorders and their concomitant cognitive deficits. Discussions throughout the article focus on research relevant to theory and application, especially applications in programs of remedial breathing (breathing retraining) designed for the treatment of psychophysiological disorders (e.g., panic, anxiety, and stress) and the accompanying cognitive deficits that result from cerebral hypoxia induced by conditioned hyperventilation.

Cloning and characterization of the CDKN2A and p19ARF genes from Monodelphis domestica.

The tumor suppressor gene, CDKN2A (p16), encodes a cyclin-dependent kinase inhibitor and functions as a negative regulator in the retinoblastoma pathway that blocks cell cycle progression from the G1 phase. The gene has been found to be deleted, truncated, mutated, or silenced by promoter methylation in a wide range of tumor types. Where melanoma CDKN2A mutations have been characterized, C --> T and CC --> TT transitions were found, indicating a direct role for ultraviolet radiation (UVR)-induced pyrimidine dimers in the formation of some tumors. The South American opossum, Monodelphis domestica, has been shown by our group and others to be susceptible to the induction of melanoma on chronic exposure to UVR alone. The CDKN2A gene and its exon 1beta alternate transcript p19ARF were cloned and sequenced from M. domestica to investigate the role of these genes in the development of UVR-induced melanoma and non-melanoma tumors. Both genes were first amplified by polymerase chain reaction (PCR) using cDNA from an opossum corneal-tumor cell-line library and degenerate primers based on human, mouse, and rat CDKN2A gene sequences. To verify these as normal sequences, both genes were then RT-PCR amplified from cultured normal opossum melanocyte mRNA. When comparing the tumor and melanocyte sequences, we found a UVR signature point mutation, a C --> T transition, within exon 2 in the corneal tumor cell line. The same mutation at this site in other tumors has been shown to alter the CDKN2A protein's ability to bind CDK4 kinase, which may lead to uncontrolled cell cycling. A comparison of the amino acid sequence of opossum CDKN2A showed identities relative to human, mouse, and rat between 57% and 63%, and when conserved amino acid substitutions are considered (similarity), the range is 63% to 67%. The amino acid identity and similarity for p19ARF ranged from 39% to 49%.

Fractional end-tidal CO2 as an index of the effects of stress on math performance and verbal memory of test-anxious adolescents.

The research reported here was derived from the hypothesis that hyperventilation contributes to the decrement in performance observed in test-anxious students. From this point of view, students identified as test-anxious would be expected to hyperventilate to a greater extent than non-test-anxious students when confronted with the stress of testing. The experiment reported here tested this hypothesis by continuous capnographic monitoring of end-tidal CO2 and respiration frequency of 16 high- and 16 low-test-anxious boys and girls (ages 12-14 years) before and during tests of math and word-recall memory under conditions of high- and low-stress (i.e. 'strong' motivational instruction versus 'weak' motivational instructions). Consistent with predictions, high test-anxious students displayed lower levels of end-tidal CO2 (under the high-stress condition) and faster respiration frequencies than low test-anxious students. Both high- and low-test-anxious students scored higher on the math test under high-stress conditions, but differences between recall scores were not significant. Collateral data revealed a positive relationship between scores on the Nijmegen Hyperventilation Questionnaire and the Revised Suinn Test Anxiety Behavior Scale, and a negative relationship between the questionnaire scores (self reports of frequency of symptoms of hypocapnia) and drop in level of end-tidal CO2 during testing, i.e. high-test-anxiety group reported a greater frequency of symptoms of hyperventilation and a larger drop in level of end-tidal CO2 during testing than low-test-anxiety group.

Pulmonary function and dyspnea/suffocation theory of panic.

This article presents a brief discussion of pulmonary function and panic attacks in the context of respiratory psychophysiology. Ley's (Behaviour Research and Therapy, 27, 549-554, 1989) earlier dyspnea/suffocation theory of panic is contrasted with Klein's (Archives of General Psychiatry, 50, 306-316, 1993) later false suffocation alarm theory. The distinction between "dyspnea" (the sensation of difficulty in breathing) and "suffocation" (a condition that sometimes gives rise to dyspnea) is emphasized. The brief discussion is followed by a critical comparison of two recent studies on pulmonary function and panic. Asmundson and Stein (Journal of Anxiety Disorders, 8, 63-69, 1994) reported an association between forced expiratory flow rate (a measure of pulmonary function) in panic disorder patients and the severity of panic-related symptoms. They interpreted their findings as support for the dyspnea/suffocation theory of panic since severity of dyspnea is a consequence of pulmonary function. Spinhoven et al. (Behaviour Research and Therapy, 33, 457-460, 1995) failed to replicate the findings of Asmundson and Stein. The present paper provides a critical analysis of the study by Spinhoven et al. and concludes that the failed attempt to replicate may have been a consequence of a flawed methodology (the subjects of the two studies are not comparable on a crucial pulmonary test) and a statistical anomaly (disproportionately small differences between means that exceed predictions based on sampling error). A recommendation is made that future attempts to replicate should pay special care to avoid the possibility of experimenter-demand effects.

Ultraviolet A radiation (320-400 nm) protects hairless mice from immunosuppression induced by ultraviolet B radiation (280-320 nm) or cis-urocanic acid.

T cell-mediated immune function, here measured as the contact hypersensitivity reaction, is readily suppressed by moderate exposure of mice to ultraviolet B (UVB) or solar-simulated radiation (SSUV), or by topical application of cis-urocanic acid. The effect of ultraviolet A (UVA) radiation on immune function has been unclear. Here we have demonstrated that when UVA radiation from a fluorescent tube source was rigorously filtered to remove contaminating UVB radiation, it was immunologically innocuous at physiologically relevant doses. Furthermore, we have found that mice exposed to UVA radiation, either immediately after, or up to 24 h before, immunosuppressive treatment with either UVB radiation, SSUV or cis-urocanic acid, became refractory to the immunosuppression and retained more normal contact hypersensitivity. A greater UVA exposure reversed the immunosuppression more effectively. The results suggest that there are immunologically significant interactions between UV wavebands, and that UVA exposure may induce a relatively long-lived immunoprotective photoproduct, as yet unidentified, that can inhibit the activity of epidermal cis-urocanic acid and thus provide protection from photoimmunosuppression.

H-ras oncogene activation in invasive UVR-induced corneal sarcomas of the opossum Monodelphis domestica.

Chronic exposure to ultraviolet radiation (UVR) induces corneal sarcomas in the South American opossum Monodelphis domestica. Cell lines are readily established from these tumors. Northern blotting of mRNA from six such cell lines revealed high expression of the H-ras oncogene. H-ras cDNA from an eye tumor cell line was cloned and characterized; the germline sequence of codons 12, 13, and 61 was confirmed by examination of H-ras sequences amplified from liver DNA by the polymerase chain reaction. The Monodelphis H-ras coding sequence is 84-89% identical to that of other vertebrates at the nucleotide level, and the predicted 189-amino-acid sequence differs by 2-12 amino acids from that of other vertebrates. Analysis of 12 primary invasive corneal sarcomas induced by chronic UVR exposure revealed no evidence of H-ras gene amplification or rearrangement. One tumor was heterozygous for an activating point mutation in codon 61 of the H-ras gene; the tumor was also homozygous for a point mutation at an adjacent site in codon 62. These results provide additional evidence for the functional importance and consequent evolutionary conservation of the ras oncogenes.

Ultraviolet radiation A-induced precursors of cutaneous melanoma in Monodelphis domestica.

Two groups of 30 dorsally shaved opossums (Monodelphis domestica) were exposed three times per week for 81 weeks to 250 J/m2 of UV radiation from FS40 sunlamps (approximately 150 J/m2 of UV radiation B; UV-B), or to 2.5 x 10(4) J/m2 of UV radiation A (UV-A) from filtered F40BLB fluorescent lamps (black lights). Animals were monitored for the appearance of nonmelanoma skin tumors (NMSTs) and melanocytic hyperplasia (MH). After 81 weeks of exposures, the prevalence of NMSTs was 71% and 4% for animals exposed to UV-B and UV-A, respectively. The difference between the treatment groups was statistically significant (P < 0.001). However, the prevalence of MH in the treatment groups, 31% for UV-B-exposed animals and 22% for UV-A-exposed animals, was not significantly different (P > 0.05). Thus, a dose of UV-A that was relatively ineffective in producing NMSTs, compared to UV-B, was as effective as UV-B in the induction of MH. If, as shown previously, MH is the precursor lesion for melanoma in this model, these results suggest that the action spectra for the induction of melanoma and NMSTs in the opossum are different.

S-100 immunoreactivity in melanomas of the South American opossum Monodelphis domestica.

S-100 immunoreactivity was determined 1) in foci of melanocytic hyperplasia, 2) in naturally occurring, ultraviolet radiation-induced, and 9,10-dimethyl-1,2-benzanthracene (DMBA)-induced primary melanomas, and 3) in metastatic melanoma lesions in the South American opossum Monodelphis domestica. Preneoplastic lesions of melanocytic hyperplasia contained scattered cells with S-100-positive nuclei. All primary melanomas, with the exception of a single DMBA-induced tumor, contained cells with S-100-positive nuclei. The pattern of S-100 reactivity in tumors varied from large foci of S-100-positive cells to scattered individual S-100-positive cells. Lymph node metastases were S-100 positive, but metastatic masses in internal organs were usually S-100 negative. Although S-100 reactivity did not distinguish preneoplastic lesions from tumors or benign melanomas from malignant melanomas, identification of metastatic tumor cells clearly demonstrated malignancy.