The changing role of pre-admission work experience (clinical visits) in therapeutic radiography, diagnostic radiography and operating department practice: Academic perspectives (part 2).

INTRODUCTION: A clinical visit (work experience) provides an opportunity for prospective students, prior to registration, to visit a clinical department to observe health professionals in practice. The Covid-19 pandemic interrupted access to clinical visits; this article explores the value of clinical visits and the alternatives implemented as a response to Covid-19 restrictions from an academic perspective. METHODS: This article reports the quantitative phase of a three-phase mixed methods study. A survey was distributed to Higher Education Institution (HEI) education leaders for onward distribution to academics supporting recruitment for diagnostic radiography, therapeutic radiography and operating department practice programmes. Qualtrics online survey software was used to administer the survey which was launched in October 2020. Descriptive statistics summarised the data. RESULTS: Representing 37.7% (n = 18/49) of eligible universities, 34 responses from 18 HEIs across England and Wales were received Seventy-eight percent of respondents strongly agreed that they are vital in confirming career choices. Prior to the Covid-19 pandemic, 64% of respondents' programmes had a clinical visit requirement, yet with improvements in simulation and online learning alternatives, 48% agreed that in the longer-term clinical visits will become obsolete. CONCLUSION: Requirements for clinical visits vary between professions and HEIs; academics welcome an opportunity to standardise work experience. Regardless of prospective student background and selected profession/university, all should have equitable and easily available access to high quality resources to support career decision-making. IMPLICATIONS FOR PRACTICE: The enforced withdrawal of clinical visits may impact upon subsequent attrition associated with 'misinformed career choice'. Alternatives to clinical visits, while less onerous for students, admissions staff and clinical colleagues alike, need to be carefully evaluated to ensure they offer prospective students a realistic understanding of the profession.

The changing role of pre-admission work experience (clinical visits) in Therapeutic Radiography, Diagnostic Radiography and Operating Department Practice: Student perspectives (Part 1).

INTRODUCTION: Clinical visits (work experience opportunities) are a recommended part of admissions processes for many diagnostic and therapeutic radiography courses but not for operating department practice (ODP) where observational visits are challenging for applicants to obtain. The Covid-19 pandemic interrupted access to visits for all prospective students; this study presents a review of the value of clinical visits and alternatives. METHODS: This article reports the initial qualitative phase of a three-phase mixed methods study. Using a critical realist approach, focus groups explored first year student experiences of the 'ideal' pre-admission clinical visit and alternative resources. A structured review of Online Prospectus (OLP) entries was undertaken by two student researchers to ascertain the requirements for clinical visits for the three professions. RESULTS: Four focus groups included 25 first year students interviewed prior to their first clinical placement (14 therapeutic radiography, 5 diagnostic radiography and 6 ODP students). Three themes were constructed, namely: informing career choices, the clinical visit experience, and the value of clinical visits. Clinical visits affirmed rather than inspired career choices. The best timing for a visit was before admission interviews and optimal duration was a full day. Interacting with current students was the most valued aspect. Videos and simulations provided in-depth information about the professional role and allowed replay, but some participants found the videos uninspiring. OLP entries present a confusing picture for applicants who may be researching several Universities and professions. CONCLUSION: Clinical visits were deemed 'vital' to radiography student career choices, yet ODPs who could not access visits were comfortable with videos. Simulated visits are a safe option amidst the pandemic but must capture the dynamic and patient-centred nature of practice to accurately inform career choices.

Neuroprostheses: method to evaluate the information content of stimulation strategies.

We propose a framework to evaluate the information content of different stimulation strategies used in neuroprosthetic implants. We analyze the responses of retinal ganglion cells to electrical stimulation using an information theory framework. This methodology allows us to calculate the information content by looking at the consistency of neural responses generated across multiple repetitions of the same stimulation protocol.

Differences between morphological and electrophysiological retinal ganglion cell classes.

Retinal prostheses work by delivering electrical pulses to the surviving retinal neurons. A pattern of electrical stimulation can generate a perception of vision in blind patients. To improve efficacy of retinal implants, it is important to understand how different classes of retinal neurons respond to electrical stimulation and if a classification can be made based on the electrophysiological properties of neurons. We use previously recorded patch clamp data from retinal ganglion cells classified into morphological classes (A,B,C, D) and functional types (ON, OFF, ON-OFF). We use a machine learning technique to separate data based on the recorded electrophysiological parameters. Results show that the clusters discovered using the machine learning technique do not correspond to the morphological or functional classes used by neuroscientists.

Views and experiences of using integrated care pathways (ICPs) for caring for people in the last days to hours of life: results from a cross-sectional survey of UK professionals.

OBJECTIVES: To determine the views and experiences of health and social care professionals on using integrated care pathways (ICPs)for caring for people in the last days to hours of life. METHODS: Online cross-sectional questionnaire survey of UK professionals working in UK primary and secondary care settings. RESULTS: 1331 professionals returned completed questionnaires. Ninety-three per cent (1138/1228) of respondents used the Liverpool Care Pathway (LCP) or local variant. Eighty-eight (1089/1234) felt ICPs enabled professionals to provide better care for individuals and their families/carers. ICPs were viewed as promoting patient-centred holistic care, improving pain and symptom control, providing guidance and standards and improving communication with patients/families. Sixty-two per cent (770/1234) had no concerns regarding the use of ICPs. Areas of concern included incorrect use and implementation of the ICP, poor communication with families, junior level staff making decisions and insufficient education and support. CONCLUSIONS: There was strong support for using ICPs for caring for people in the last days to hours of life. ICPs were viewed as supporting high-quality patient-centred holistic care. Given the recommendations of the More Care Less Pathway report, those that develop the guidance and support that replace the LCP need to incorporate the aspects of this that have resulted in the benefits seen by professionals within this survey, but also learn from the instances where ICPs have failed to prevent poor care, or worse, have contributed to it.

Developing and testing methods for deriving preference-based measures of health from condition-specific measures (and other patient-based measures of outcome).

OBJECTIVES: Generic preference-based measures such as EQ-5D are widely used to estimate quality-adjusted life-years but may not be available or, more importantly, appropriate in some medical conditions. Condition-specific preference-based measures (CSPBMs) provide an alternative to generic measures that may be more relevant in some conditions. This project conducted five studies to examine issues in the development and use of CSPBMS: (1) literature review of measures; (2) deriving health states values for classifications with highly correlated dimensions; (3) impact of condition labelling; (4) impact of add-on dimensions; and (5) comparative performance of measures. DESIGN: (1) Systematic search and literature review; (2) and (5) psychometric analyses on existing data; (2), (3) and (4) valuation surveys and survey analyses. SETTING: Valuation surveys conducted using face-to-face interviews in the respondents' homes. PARTICIPANTS: Valuation surveys conducted using representative samples of the UK general population. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The project developed a CSPBM CORE-6D and analyses AQL-5D, CORE-6D, EORTC-8D, EQ-5D, OAB-5D and SF-6D data. RESULTS: (1) There was substantial variability in methods used to develop CSPBMs. (2) A new method for generating states using Rasch analysis was undertaken, which successfully dealt with the problem of highly correlated domains. (3) Condition labels affected utility values but this was dependent on the condition and severity of the health state. (4) Adding on an extra dimension affected health-state values and preference weights for other dimensions. (5) The performance of CSPBMs was comparable with that of their parent instrument and of generic preference-based measures with better performance for discrimination between severity groups. CONCLUSIONS: CSPBMs have an important role for economic evaluation, for which generic measures are inappropriate. However, their use in economic evaluation may be compromised by naming the condition; the exclusion of side effects and comorbidities; and focusing effects. Whether a reduction in comparability should be accepted depends on the extent of any gain in validity and responsiveness. This will depend on the condition and measure in question. Research agenda: (1) The appropriateness of generic preference-based measures should be examined in more conditions (and compared with CSPBMs). (2) Further quantitative and qualitative work is requested into the impact of, and reasons for labelling effects. (3) Use of add-ons for condition-specific measures (for side effects and comorbidities) and as a solution to the limitation of generic measures should be explored. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

TP53 mutation profile in chronic lymphocytic leukemia: evidence for a disease specific profile from a comprehensive analysis of 268 mutations.

The TP53 mutation profile in chronic lymphocytic leukemia (CLL) and the correlation of TP53 mutations with allele status or associated molecular genetics are currently unknown. We performed a large mutation analysis of TP53 at four centers and characterized the pattern of TP53 mutations in CLL. We report on 268 mutations in 254 patients with CLL. Missense mutations appeared in 74% of cases compared with deletions and insertions (20%), nonsense (4%) and splice site (2%) mutations. The majority (243 of 268) of mutations were located in the DNA-binding domain. Transitions were found in 131 of 268 mutations, with only 41 occurring at methylated CpG sites (15%), suggesting that transitions at CpGs are uncommon. The codons most frequently mutated were at positions 175, 179, 248 and 273; in addition, we detected a common 2-nt deletion in the codon 209. Most mutations (199 of 259) were accompanied by deletion of the other allele (17p-). Interestingly, trisomy 12 (without 17p-) was only found in one of 60 cases with TP53 mutation (without 17p-) compared with 60 of 16 in the cohort without mutation (P=0.006). The mutational profile was not different in the cohorts with and without previous therapy, suggesting that the mechanism underlying the development of mutations may be similar, independent of treatment.

A comprehensive genetic and histopathologic analysis identifies two subgroups of B-cell malignancies carrying a t(14;19)(q32;q13) or variant BCL3-translocation.

The biologic and pathologic features of B-cell malignancies bearing a translocation t(14;19)(q32;q13) leading to a fusion of IGH and BCL3 are still poorly described. Herein we report the results of a comprehensive cytogenetic, fluorescence in situ hybridization (FISH), molecular and histopathological survey of a large series of B-cell malignancies with t(14;19) or variant translocations. A total of 56 B-cell malignancies with a FISH-proven BCL3 involvement were identified with the translocation partners being IGH (n=51), IGL (n=2), IGK (n=2) and a non-IG locus (n=1). Hierarchical clustering of chromosomal changes associated with the t(14;19) indicated the presence of two different groups of IG/BCL3-positive lymphatic neoplasias. The first group included 26 B-cell malignancies of various histologic subtypes containing a relatively high number of chromosomal changes and mostly mutated IgVH genes. This cluster displayed three cytogenetic branches, one with rearrangements in 7q, another with deletions in 17p and a third one with rearrangements in 1q and deletions in 6q and 13q. The second group included 19 cases, mostly diagnosed as B-cell chronic lymphocytic leukemia (B-CLL), and characterized by few additional chromosomal changes (e.g. trisomy 12) and unmutated IgVH genes. In conclusion, our study indicates that BCL3 translocations are not restricted to B-CLL but present in a heterogeneous group of B-cell malignancies.

ZAP-70 by flow cytometry: a comparison of different antibodies, anticoagulants, and methods of analysis.

BACKGROUND: The clinical course of chronic lymphocytic leukaemia (CLL) is variable. ZAP-70 expression is believed to provide prognostic information. The flow cytometric detection of ZAP-70 is difficult because it is an intracellular antigen with weak expression in CLL. Consensus has not been reached as to the best method for measurement. METHODS: We analyzed 72 CLL patient samples for ZAP-70 expression and IgVH mutational status. Sensitivity and specificity of ZAP-70 expression against IgVH mutational status were assessed for two clones (2F3.2 and 1E7.2) and for four methods of analysis: percentage positivity (PP), comparing test to isotype control, ratio of geometric means of test and isotype control, and percentage and ratiometric methods comparing test and T/NK cell populations. The effects of anticoagulant, collection times, and time to analysis were also evaluated. RESULTS: Sensitivity and specificity were 85 and 88%, respectively, for Upstate PP; 70 and 88% for Caltag PP; 89 and 91% for Upstate ratio; 89 and 88% for Caltag ratio. Intraobserver variability was smaller when ZAP-70 expression was assessed using a ratiometric approach rather than the percentage method. By 48 h, we observed an average decrease of 13% in the Caltag ratio in the heparin preserved samples compared to an increase of 3% in those collected in EDTA. Within the first 24-h period, a greater percent variability was observed in those samples collected into EDTA compared with heparin. CONCLUSION: Our data support a rapid method for ZAP-70 measurement using commercially available fixation/permeabilization reagents, a conjugated antibody, and a ratiometric method of analysis that minimizes subjective interpretation of the results. This is a method of ZAP-70 assessment that could be included in a routine diagnostic CLL panel; however, the choice of anticoagulant and time of analysis after collection are critical factors in accurate assessment of ZAP-70 expression.

Ultralong Raman fiber lasers as virtually lossless optical media.

By transforming the optical fiber span into an ultralong cavity laser, we experimentally demonstrate quasilossless transmission over long (up to 75 km) distances and virtually zero signal power variation over shorter (up to 20 km) spans, opening the way for the practical implementation of integrable nonlinear systems in optical fiber. As a by-product of our technique, the longest ever laser (to the best of our knowledge) has been implemented, with a cavity length of 75 km. A simple theory of the lossless fiber span, in excellent agreement with the observed results, is presented.

P2X7 polymorphism and chronic lymphocytic leukaemia: lack of correlation with incidence, survival and abnormalities of chromosome 12.

The P2X7 receptor, a plasma membrane ATP-gated ion channel that plays a role in lymphocyte apoptosis, has been suggested as an important contributory factor to the pathogenesis of chronic lymphocytic leukaemia (CLL). The P2X7 gene resides on chromosome 12 and is polymorphic in the population at large (1513A/C) with the A and C alleles encoding fully active and nonfunctional proteins, respectively. We have evaluated the significance of this polymorphism by genotyping 144 patients with CLL and 348 healthy controls using a tetraprimer ARMS assay. We found no significant difference in allele frequency between patients and controls. Although patients with the C allele (A/C heterozygotes or C/C homozygotes) had a marginally shorter survival than those who were homozygous for the A allele, this difference was not significant for either the patient group considered as a whole or for IgVH-mutated/unmutated subsets. Finally, no association was found between trisomy 12 and P2X7 genotype. We conclude that the influence, if any, of P2X7 genotype on susceptibility to CLL or clinical outcome is small.

0(+)(gs) --> 2(+)(1) excitations in the mirror nuclei 32Ar and 32Si.

We measured the strength of the 0(+)(gs)-->2(+)(1) excitations in the radioactive mirror nuclei 32Ar and 32Si using the techniques of intermediate-energy Coulomb excitation for 32Ar and inelastic proton scattering in inverse kinematics for 32Si. The 32Ar measurement, taken together with previously existing Coulomb excitation data for 32Si, yields the isoscalar and isovector multipole matrix elements for the 0(+)(1)-->2(+)(1) transition between T = 2 states in the A = 32 system. The proton scattering measurement for 32Si, when combined with the Coulomb excitation data for this nucleus, yields a ratio of neutron and proton matrix elements, M(n)/M(p), for 32Si.

Dysregulation of cyclin dependent kinase 6 expression in splenic marginal zone lymphoma through chromosome 7q translocations.

The increased or inappropriate expression of genes with oncogenic properties through specific chromosome translocations is an important event in the pathogenesis of B-cell lymphoproliferative diseases. Recent studies have found deletions or translocations of chromosome 7q to be the most common cytogenetic abnormality observed in SLVL, a leukemic variant of SMZL, with the q21-q22 region being most frequently affected. In three patients with translocations between chromosomes 2 and 7, the cloning of the breakpoints at 7q21 revealed that each was located within a small region of DNA 3.6 kb upstream of the transcription start site of cyclin dependent kinase 6 (CDK6). In each case the translocation event was consistent with aberrant VJ recombination between the immunoglobulin light chain region (Ig kappa) on chromosome 2p12 and DNA sequences at 7q21, resembling the heptamer recombination site. The t(7;21) breakpoint in an additional patient with splenic marginal zone lymphoma (SMZL), resided 66 kb telomeric to the t(2;7) breakpoints juxtaposing CDK6 to an uncharacterized transcript. In two of the SLVL patient samples, the CDK6 protein was found to be markedly over expressed. These results suggest that dysregulation of CDK6 gene expression contributes to the pathogenesis of SLVL and SMZL.

Reduced quality of clot formation with gelatin-based plasma substitutes.

We have studied, over a wide range of dilutions using techniques of clot weight, thrombelastography and scanning electron microscopy, the physical properties of a blood clot formed in vitro when fresh blood was diluted with gelatin-based colloid solutions compared with crystalloid controls. The colloid solutions tested (3.5% polygeline (Haemaccel) and 4% succinylated gelatin (Gelofusine)) produced clots that had reduced median weight (P < 0.001 and P = 0.018, respectively) and reduced mean shear modulus (P < 0.001) compared with crystalloid controls. Scanning electron microscopy showed that the fibrin formed a less extensive mesh in the presence of the gelatin-based colloids compared with crystalloid. Reduction in clot quality with gelatin-based colloids has not been noted previously and further work is needed to ascertain if this occurs in vivo as these solutions are used frequently in patients who require full haemostatic competence.

A cosmid and cDNA fine physical map of a human chromosome 13q14 region frequently lost in B-cell chronic lymphocytic leukemia and identification of a new putative tumor suppressor gene, Leu5.

B-cell chronic lymphocytic leukemia (B-CLL) is a human hematological neoplastic disease often associated with the loss of a chromosome 13 region between RB1 gene and locus D13S25. A new tumor suppressor gene (TSG) may be located in the region. A cosmid contig has been constructed between the loci D13S1168 (WI9598) and D13S25 (H2-42), which corresponds to the minimal region shared by B-CLL associated deletions. The contig includes more than 200 LANL and ICRF cosmid clones covering 620 kb. Three cDNAs likely corresponding to three different genes have been found in the minimally deleted region, sequenced and mapped against the contigged cosmids. cDNA clone 10k4 as well as a chimeric clone 13g3, codes for a zinc-finger domain of the RING type and shares homology to some known genes involved in tumorigenesis (RET finger protein, BRCA1) and embryogenesis (MID1). We have termed the gene corresponding to 10k4/13g3 clones LEU5. This is the first gene with homology to known TSGs which has been found in the region of B-CLL rearrangements.

Detailed molecular delineation of 13q14.3 loss in B-cell chronic lymphocytic leukemia.

A region of chromosome 13q14.3, telomeric to the Retinoblastoma gene RB-1 is frequently deleted in patients with B-cell chronic lymphocytic leukemia (B-CLL). A cosmid and P1-derived artificial chromosome (PAC) contig spanning over 600 kb has been constructed, which encompasses this locus. The contig clones have been used to order a number of markers along the minimally deleted region and to localize a series of CpG islands corresponding to possible candidate genes. A novel polymorphic dinucleotide repeat, 6E3.2, present in one of the ordered cosmid clones has been isolated for use in deletion mapping studies of patient DNA. Leukemic samples from 229 CLL patients have been screened for loss of heterozygosity using microsatellite markers and analyzed for hemizygous and homozygous deletions by Southern blot techniques using genomic probes selected from cosmids across the region. Hemizygous deletions were found in 31% of cases with an additional 10% showing homozygous loss. The use of these probes has defined the commonly deleted area to less than 130 kb, centromeric to the locus D13S272.