Supervised learning events: direct observation of procedural skills pilot.

BACKGROUND: Workplace-based assessment (WBA) is the assessment of specialist competence based on what a trainee doctor actually does in the workplace. Between January 2014 and January 2015, all UK occupational medicine (OM) trainees were invited to test a suite of direct observation of procedural skills (DOPS) tools designed in a supervised learning event (SLE) format. The Faculty of Occupational Medicine (FOM) Workplace-Based Assessment Advisory Group (WBAAG) studied feedback on the new format. AIMS: To assess the utility of the redesigned tools, including their acceptability, feasibility, usability and key aspects of their reliability and validity. METHODS: The face and content validity of the new forms were assessed by a comprehension trial (CT), inter-rater reliability by a video scoring exercise and usability and acceptability by an electronic survey of trainees and trainers. RESULTS: The CT of trainees and trainers indicated that the face and content validity of the revised tools were acceptable. Inter-rater reliability video assessments indicated there was consistency of grading among trainers. Sixty-eight per cent of trainees and 95% of trainers agreed that the redesigned tools were an improvement on the current WBA DOPS tools and 83% of trainees indicated the new tools encouraged them to reflect on their performance. CONCLUSIONS: The results from this pilot study provided evidence to support a request to the General Medical Council (GMC) for the new SLE-DOPS forms to be used for WBA in OM. These changes were accepted by the GMC in January 2016 for implementation in April 2016.

Role of morality in the experience of guilt and shame within the armed forces.

OBJECTIVE: Despite advances in our understanding of mental health issues among military forces, a large proportion of military personnel continue to exhibit deployment-related psychological issues. Recent work has identified symptoms of guilt and shame related to moral injury as contributing significantly to combat-related mental health issues. This systematic scoping review explores the association between morality and symptoms of guilt and shame within military forces. METHOD: A search of the literature pertaining to guilt, shame and morality within military samples was conducted. RESULTS: Nineteen articles were selected for review. There is strong evidence linking exposure to and the perceived perpetration of moral transgressions with experiences of guilt and shame. Critically, symptoms of guilt and shame were related to adverse mental health outcomes, particularly the onset of post-traumatic stress disorder (PTSD). No studies have explored moral judgment in conjunction with assessments of guilt or moral injury. CONCLUSION: These findings have important implications for the prevention and treatment of PTSD-related symptoms in military samples. By measuring moral judgment prior to deployment, it may be possible to predict the likelihood of incurring moral injuries and the development of associated symptoms. Early intervention programmes aimed at ameliorating guilt and shame are required to prevent the long-term development of deployment-related psychological distress.

Comprehension of affective prosody in women with post-traumatic stress disorder related to childhood abuse.

OBJECTIVE: Although deficits in memory and cognitive processing are evident in post-traumatic stress disorder (PTSD), difficulties with social cognition and the impact of such difficulties on interpersonal functioning are poorly understood. Here, we examined the ability of women diagnosed with PTSD related to childhood abuse to discriminate affective prosody, a central component of social cognition. METHOD: Women with PTSD and healthy controls (HCs) completed two computer-based tasks assessing affective prosody: (i) recognition (categorizing foreign-language excerpts as angry, fearful, sad, or happy) and (ii) discrimination (identifying whether two excerpts played consecutively had the 'same' or 'different' emotion). The association of performance with symptom presentation, trauma history, and interpersonal functioning was also explored. RESULTS: Women with PTSD were slower than HCs at identifying happiness, sadness, and fear, but not anger in the speech excerpts. The presence of dissociative symptoms was related to reduced accuracy on the discrimination task. An increased severity of childhood trauma was associated with reduced accuracy on the discrimination task and with slower identification of emotional prosody. CONCLUSION: Exposure to childhood trauma is associated with long-term, atypical development in the interpretation of prosodic cues in speech. The findings have implications for the intergenerational transmission of trauma.

Theory of mind performance in women with posttraumatic stress disorder related to childhood abuse.

OBJECTIVE: Key questions remain unaddressed concerning the nature of interpersonal functioning in trauma survivors, including the ability to understand and interpret other people's thoughts and feelings. Here, we investigate theory of mind (ToM) performance of women with PTSD related to childhood abuse in comparison to healthy controls. METHOD: Participants completed two ToM tasks, the Interpersonal Perception Task-15 (IPT-15) and the Reading the Mind in the Eyes Task - Revised (RMET). RESULTS: Relative to controls, women with a history of childhood trauma had difficulty recognizing familial relationships depicted in the IPT-15 (P = 0.005). No other category of the IPT-15 showed significant group differences. In addition, while healthy women displayed faster RMET reaction times to emotionally valenced mental states (positive: P = 0.003; negative: P = 0.016) compared with neutral mental states, the PTSD group showed similar reaction times across all valences. The presence of dissociative symptoms (e.g., disengagement, amnesia, identity dissociation) was strongly associated with hindered accuracy of complex mental state identification and altered perception of kinship interactions. CONCLUSION: Women with PTSD stemming from childhood trauma show changes in ToM abilities particularly those often involved in the interpretation of family interactions. In addition, individuals with PTSD showed slower reaction times during the recognition of complex mental states from emotionally salient facial/eye expressions in comparison with healthy subjects.

Practice and documentation of palliative sedation: a quality improvement initiative.

BACKGROUND: Palliative sedation (ps), the continuous use of sedating doses of medication to intentionally reduce consciousness and relieve refractory symptoms at end of life, is ethically acceptable if administered according to standards of best practice. Procedural guidelines outlining the appropriate use of ps and the need for rigorous documentation have been developed. As a quality improvement strategy, we audited the practice and documentation of ps on our palliative care unit (pcu). METHODS: A pharmacy database search of admissions in 2008 identified, for a subsequent chart review, patients who had received either a continuous infusion of midazolam (≥10 mg/24 h), regular parenteral dosing of methotrimeprazine (≥75 mg daily), or regular phenobarbital. Documentation of the decision-making process, consent, and medication use was collected using a data extraction form based on current international ps standards. RESULTS: Interpretation and comparison of data were difficult because of an apparent lack of a consistent operational definition of ps. Patient records had no specific documentation in relation to ps initiation, to clearly identified refractory symptoms, and to informed consent in 60 (64.5%), 43 (46.2%), and 38 (40.9%) charts respectively. Variation in the medications used was marked: 54 patients (58%) were started on a single agent and 39 (42%), on multiple agents. The 40 patients (43%) started on midazolam alone received a mean daily dose of 21.4 mg (standard deviation: 24.6 mg). CONCLUSIONS: The lack of documentation and standardized practice of ps on our pcu has resulted in a quality improvement program to address those gaps. They also highlight the importance of conducting research and developing clinical guidelines in this area.

University students' notebook computer use: lessons learned using e-diaries to report musculoskeletal discomfort.

The objective of this pilot study was to identify if notebook accessories (ergonomic chair, desktop monitor and notebook riser) combined with a wireless keyboard, mouse and participatory ergonomics training would have the greatest impact on reducing self-reported upper extremity musculoskeletal discomfort in university students. In addition to pre-post computing and health surveys, the Ecological Momentary Assessment was used to capture change in discomfort over time using a personal digital assistant (PDA) as the e-diary. The PDA was programmed with a survey containing 45 questions. Four groups of university students were randomised to either intervention (three external computer accessories) or to control. Participants reported less discomfort with the ergonomic chair and notebook riser based on the pre-post survey data and the e-diary/PDA ANOVA analysis. However, the PDA data, adjusted for the effect of hours per day of computer use, showed no benefit of the chair and limited benefit from the riser. Statement of Relevance:University students' use of notebook computers has increased. This study found evidence of a positive effect of an adjustable chair or notebook riser when combined with ergonomic training on reducing discomfort. Daily notebook computer use of 4 h was confirmed as a risk factor. Without some form of ergonomic intervention, these students are likely to enter the workforce with poor computing habits, which places them on the road to future injuries as technology continues to play a dominant role in their lives.

An interleukin 5 mutant distinguishes between two functional responses in human eosinophils.

Interleukin 5 (IL-5) is the key cytokine involved in regulating the production and many of the specialized functions of mature eosinophils including priming, adhesion, and survival. We have generated a point mutant of human IL-5, IL-5 (E12K), which is devoid of agonist activity in both a TF-1 cell proliferation assay and a human eosinophil adhesion assay. However, IL-5 (E12K) is a potent and specific antagonist of both these IL-5-dependent functional responses. In both receptor binding and cross-linking studies the wild-type and IL-5 (E12K) mutant exhibit virtually identical properties. This mutant protein was unable to stimulate tyrosine phosphorylation in human eosinophils, and blocked the phosphorylation stimulated by IL-5. In contrast, IL-5 (E12K) is a full agonist in a human eosinophil survival assay, although with reduced potency compared to the wild-type protein. This IL-5 mutant enables us to clearly distinguish between two IL-5-dependent functional responses and reveals distinct mechanisms of receptor/cellular activation.

Cytokine-specific transcriptional regulation through an IL-5Ralpha interacting protein.

Cytokine receptors consist of multiple subunits, which are often shared between different receptors, resulting in the functional redundancy sometimes observed between cytokines. The interleukin 5 (IL-5) receptor consists of an IL-5-specific alpha-subunit (IL-5Ralpha) and a signal-transducing beta-subunit (betac) shared with the IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors. In this study, we sought to find a role for the cytoplasmic domain of IL-5Ralpha. We show that syntenin, a protein containing PSD-95/Discs large/zO-1 (PDZ) domains, associates with the cytoplasmic tail of the IL-5Ralpha. Syntenin was found to directly associate with the transcription factor Sox4. Association of syntenin with IL-5Ralpha was required for IL-5-mediated activation of Sox4. These studies identify a mechanism of transcriptional activation by cytokine-specific receptor subunits.

Communicating biosecurity information to Australian-registered veterinarians.

OBJECTIVE: Updating veterinarians (vets) on the latest biosecurity resources, information and alerts is important to ensure protection of domesticated and native animals. This preliminary questionnaire aimed to better understand the communication preferences of Australian-registered vets for biosecurity information, and their trust of these sources. METHODS: An online questionnaire asking vets about their current communication preferences for biosecurity information, and their level of trust of these was created and distributed to Australian-registered vets. RESULTS: Survey respondents (158) use and highly trust communication from (in order) vet and animal health organisations, vet surgeons' boards, the scientific literature, and government agencies. CONCLUSIONS: This preliminary study identifies that using vet surgeon's boards, government agencies and vet and animal health organisations may be an effective means for communicating biosecurity information to vets. Future research should consider which sources vets trust and why, to facilitate effective communication to them and the clients they serve.

Congenital Hypothalamic "Hamartoblastoma" Versus "Hamartoma": Suggestions for Neuropathologic Terminology Emanating From a Mid-gestational Autopsy Case of Pallister-Hall Syndrome.

Pallister-Hall syndrome (PHS) is a rare malformative disorder that is due to truncating functional repressor mutations in GLI3. Since the seminal publication in 1980, hypothalamic tumors have been recognized to be a cardinal feature of PHS. In their original description of the neuropathologic features of PHS, Clarren et al. coined the term "hamartoblastoma" to characterize what they deemed to be a dual malformative and neoplastic mass of the hypothalamus. In subsequent published cases/series of PHS, the term "hamartoma" was often substituted for hamartoblastoma given what appeared to be a benign natural history of this lesion. Additional confusion in the literature has ensued since most hypothalamic hamartomas (HH) encountered on the clinical neuropathology service are "isolated" in nature (ie, no other congenital malformations) and present in a very different and stereotypical fashion with gelastic seizures and/or precocious puberty. While genomic investigations of isolated HH have begun to uncover a mutational profile of these cases, GLI3 mutations have only been recognized in a small subset of isolated HH. Herein, we describe the autopsy findings from a 21-week gestational age fetus with features of PHS. Moreover, we provide a detailed description of the hypothalamic tumor affecting this fetus and propose a novel subclassification of HH, distinguishing syndromic from isolated forms based upon the presence or absence of neocortical-like areas.

A collaborative hit-to-lead investigation leveraging medicinal chemistry expertise with high throughput library design, synthesis and purification capabilities.

High throughput screening (HTS) campaigns, where laboratory automation is used to expose biological targets to large numbers of materials from corporate compound collections, have become commonplace within the lead generation phase of pharmaceutical discovery. Advances in genomics and related fields have afforded a wealth of targets such that screening facilities at larger organizations routinely execute over 100 hit-finding campaigns per year. Often, 10(5) or 10(6) molecules will be tested within a campaign/cycle to locate a large number of actives requiring follow-up investigation. Due to resource constraints at every organization, traditional chemistry methods for validating hits and developing structure activity relationships (SAR) become untenable when challenged with hundreds of hits in multiple chemical families per target. To compound the issue, comparison and prioritization of hits versus multiple screens, or physical chemical property criteria, is made more complex by the informatics issues associated with handling large data sets. This article describes a collaborative research project designed to simultaneously leverage the medicinal chemistry and drug development expertise of the Novartis Institutes for Biomedical Research Inc. (NIBRI) and ArQule Inc.'s high throughput library design, synthesis and purification capabilities. The work processes developed by the team to efficiently design, prepare, purify, assess and prioritize multiple chemical classes that were identified during high throughput screening, cheminformatics and molecular modeling activities will be detailed.

Base transitions dominate the mutational spectrum of a transgenic reporter gene in MSH2 deficient mice.

Tumors derived from individuals with hereditary nonpolyposis colorectal cancer syndrome frequently demonstrate mutations in both alleles of hMSH2, a key gene in DNA mismatch repair (MMR). Sporadic tumors also frequently exhibit MMR deficiency. In keeping with the role of MMR in the maintenance of genome integrity, mice deficient in MSH2 via gene targeting demonstrate a high incidence of thymic lymphomas and small intestinal adenocarcinomas. To investigate the effects of MSH2 deficiency in normal tissues, mice containing a retrievable transgenic lacI reporter gene for mutation detection were crossed with MSH2-/- mice. Mice homozygous for MSH2 deficiency revealed 4.8, 11.0 and 15.2-fold elevations in spontaneous mutation frequency in DNA obtained from brain, small intestine, and thymus, respectively, as compared to heterozygous or wild-type mice. Mutations most frequently recovered from MSH2-/- mice were single base substitutions (77%), particularly base transitions (64%). Frameshifts occurred less frequently (19%) and fell within very short (3-5 bp) mononucleotide runs. Thus the number of key growth control genes potentially impacted by MMR deficiency extends beyond those containing repetitive sequences. These results highlight the capacity for MSH2 deficiency to serve as a potent driving force during the multi-step evolution of tumors.

Phospholipase-D activation can be negatively regulated through the action of protein kinase C.

Transient activation of COS-1 cell phospholipase-D (PLD) in response to the protein kinase C (PKC) agonist tetradecanoyl phorbol acetate (TPA) was demonstrated by monitoring the ethanol-dependent accumulation of phosphatidylethanol (PtdEth). Transfection of COS-1 cells with PKC-alpha (wild type and constitutively activated mutants) produced no detectable ptdEth on incubation of transfected cells in the presence of ethanol. However, the response of transfected cells to subsequent TPA stimulation was inhibited, consistent with a role for the PKC-alpha in the suppression of PLD activity.

A comparison of demethoxyviridin and wortmannin as inhibitors of phosphatidylinositol 3-kinase.

The mammalian Ptdlns 3-kinase is shown to be inhibited by low nanomolar concentrations of demethoxyviridin, an antifungal agent structurally related to wortmannin. The inhibitory potency of both compounds could be observed in purified Ptdlns 3-kinase whether or not the regulatory subunit (p85 alpha) was present, suggesting that the inhibitors bind to the catalytic subunit (p110) of the Ptdlns 3-kinase. These inhibitors also show similar potency against the intrinsic p85-phosphorylating activity of the p110-kinase. However, the structurally related Ptdlns 3-kinase from Saccharomyces cerevisiae (Vps34p) is not inhibited by either compound. Both inhibitors target the mammalian Ptdlns 3-kinase in vitro and in vivo, implying that these compounds should be useful in suppressing Ptdlns 3-kinase in mammalian systems. The inhibitors did not affect the mammalian Ptdlns 4-kinase, but they are able to inhibit a membrane-associated Ptdlns 4-kinase from Schizosaccharomyces pombe.

Reliability of a comorbidity measure: the Index of Co-Existent Disease (ICED).

The reliability of an established comorbidity index (the Index of Co-Existent Disease) was tested using retrospective data from the case notes of elderly patients who had undergone total hip replacement. Inter-rater reliability was examined twice, first with two raters (n = 39) and then with three (n = 49). Intra-rater reliability was assessed using one rater (n = 45). Reasons for any lack of reliability were explored. The inter-rater reliability of the ICED was moderate (kappa 0.5-0.6). While the Functional Severity index performed well (kappa 0.6-1.0), the Index of Disease Severity subindex was less reliable (kappa 0.4-0.5). Differences between raters had an impact on the observed association between comorbidity and serious post-operative complications. Intra-rater reliability was excellent (kappa 0.9). Several reasons why inter-rater reliability was only moderate were identified, mostly related to uncertainties in applying the ICED. The reliability of the ICED needs to be improved before it is used more widely with retrospective data. This might be achieved by further clarification of the instructions for its use.

Does the Hawksley random zero sphygmomanometer underestimate blood pressure, and by how much?

The study objective was to compare blood pressure (BP) measurement by the Hawksley random-zero sphygmomanometer and the standard mercury sphygmomanometer. Comparison of simultaneous 'blind' BP measurements were made using the Hawksley random-zero sphygmomanometer and the standard mercury sphygmomanometer linked by a Y-connector to a single cuff, in the general practice and office environments. Sixty five healthy volunteers and general practice patients, aged between 20 and 50 years (SBP range 82-184 mm Hg, DBP range 38-112 mm Hg), were studied. Each had three blood pressure measurements taken. Mean BPs recorded by the Hawksley random-zero sphygmomanometer were lower than those recorded by the standard mercury sphygmomanometer. The Hawksley random-zero sphygmomanometer underestimated SBP by 1.3 mm Hg (95% CI 0.9-1.8 mm Hg) and DBP by 1.7 mm Hg (95% CI 1.1-2.3 mm Hg). These differences between instruments were independent of BP level both for systolic and diastolic measurements. An overview including this study and six other published reports describing nine studies examining the performance of the Hawksley random-zero sphygmomanometer suggested a similar degree of underestimation for SBP (mean difference 1.35 mm Hg, 95% CI 1.24-1.46 mm Hg). Underestimation of DBP appeared greater (mean difference 2.54 mm Hg, 95% CI 2.43-2.65 mm Hg) but was reduced when two outlying studies were removed from analysis (mean 1.97, 95% CI 1.85-2.09 mm Hg). We conclude that the Hawksley random-zero sphygmomanometer underestimates systolic and diastolic pressure, when compared with the standard mercury sphygmomanometer. However, the degree of underestimation is small and appears consistent across a wide range of blood pressure levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Name that tune: identifying popular recordings from brief excerpts.

We tested listeners' ability to identify brief excerpts from popular recordings. Listeners were required to match 200- or 100-msec excerpts with the song titles and artists. Performance was well above chance levels for 200-msec excerpts and poorer but still better than chance for 100-msec excerpts. Performance fell to chance levels when dynamic (time-varying) information was disrupted by playing the 100-msec excerpts backward and when high-frequency information was omitted from the 100-msec excerpts; performance was unaffected by the removal of low-frequency information. In sum, successful identification required the presence of dynamic, high-frequency spectral information.

Community studies of the health service implications of low back pain.

STUDY DESIGN: Retrospective study using primary care physician case notes and a self-report questionnaire on the same randomly selected population sample. OBJECTIVES: To assess the prevalence, management, and outcomes of low back pain in the community, comparing, in the same random sample of registered patients, self-report questionnaire data and primary care physicians' records. SUMMARY OF BACKGROUND DATA: The financial and resource implications of low back pain are extensive. Data on consultations, investigations, and the management of low back pain are fragmentary and there are no comparisons estimating prevalence from case notes and self-report. METHODS: A retrospective study of prevalence, management, referral, and outcome covering the previous 12 months was carried out in three general practices using case notes and a self-report postal questionnaire on a sample of 900 patients over 18 years. RESULTS: Lifetime prevalence of low back pain was 62%. Annual prevalence was 48%, with 16% reporting low back pain at the time of report. Twenty-four percent consulted their primary care physician for low back pain, of whom 17% were referred to a hospital specialist. The annual consultation rate of patients with low back pain was similar to the rate for patients with chronic conditions. The activities of daily living were restricted in less than half, with few taking sick leave. The general health status of those reporting recent low back pain was significantly lower than those not reporting low back pain. Most felt that low back pain was self-limiting and would not consult health professionals for future episodes. There were substantial discrepancies between case notes recorded at consultation with the primary care physician and self-report regarding consultation and investigations. CONCLUSIONS: Prevalence rates were comparable with those reported in other studies. The significant discrepancies between data sources suggest patient recall bias or underrecording in case notes. The low consultation rate, time off, and day-to-day disability indicate that most episodes are self-limiting.

Birthweights and growth of infants in five Aboriginal communities.

OBJECTIVES: To improve, by culturally appropriate means, birthweights and growth of children up to three years of age over 14 months in five Aboriginal communities in north-western Australia. METHODS: Frequent individual nutritional assessment of infants and children with counselling of mothers and carers and of pregnant women and the introduction of the Aboriginal-controlled Strong Women, Strong Babies, Strong Culture maternal support program. Outcomes compared with those in the same communities for the five years preceding intervention. RESULTS: By international standards, pre-intervention birthweights of full-term infants (37-42 weeks) were only moderately depressed and recovered to exceed standard weight-for-age within two weeks of birth. Growth of full-term infants slowed abruptly after six months. Prevalence and duration of breastfeeding were very high. Prevailing low average birthweight was chiefly attributable to a prevalence of pre-term birth approaching 20%. Intervention was not accompanied by any change in full-term birth weight but was associated with increased weight gain after six months. From 12 to 36 months growth rose by 30 g per month (p = 0.001). Average birthweights of pre-term infants were < 2,500 g and average weight-for-age did not improve during intervention. CONCLUSIONS: Both low birthweight and a disproportionate part of intransigent failure to grow by Aboriginal infants were associated with pre-term birth. Depressed average growth of full-term infants appeared to respond to nutritional counselling accompanied by a community support program. IMPLICATIONS: Investigation of the causes of the exceptionally high rate of Aboriginal pre-term birth in the region is urgently required.