Risk stratification, treatment selection, and transplant eligibility in multiple myeloma: a qualitative study of the perspectives and self-reported practices of oncologists.

BACKGROUND: Since the early 2000s, treatment options for multiple myeloma have rapidly expanded, adding significant complexity to the management of this disease. To our knowledge, no systematic qualitative research on clinical decision-making in multiple myeloma has been published. We sought to characterize how physicians view and implement guidelines and incorporate novel approaches into patient care. METHODS: We designed a semi-structured qualitative interview guide informed by literature review and an expert advisory panel. We conducted 60-minute interviews with a diverse sample of oncology physicians in the southeast United States. We used a constant comparative method to code and analyze interview transcripts. The research team and advisory panel discussed and validated emergent themes. RESULTS: Participants were 13 oncologists representing 5 academic and 4 community practices. Academic physicians reported using formal risk-stratification schemas; community physicians typically did not. Physicians also described differences in eligibility criteria for transplantation; community physicians emphasized distance, social support, and psychosocial capacity in making decisions about transplantation referral; the academic physicians reported using more specific clinical criteria. All physicians reported using a maintenance strategy both for post-transplant and for transplant-ineligible patients; however, determining the timing of maintenance therapy initiation and the response were reported as challenging, as was recognition or definition of relapse, especially in terms of when treatment re-initiation is indicated. CONCLUSIONS: Practices reported by both academic and community physicians suggest opportunities for interventions to improve patient care and outcomes through optimal multiple myeloma management and therapy selection. Community physicians in particular might benefit from targeted education interventions about risk stratification, transplant eligibility, and novel therapies.

Carotidynia Versus Transient Perivascular Inflammation of the Carotid Artery (TIPIC) Syndrome: Finding Common Ground.

Carotidynia remains mired in controversy. Whether to identify this self-limiting unilateral neck pain as a distinct clinical entity or a diagnostic sign associated with a variety of conditions remains a topic of ongoing debate. Adding to the discussion is the occasional finding on imaging studies of a transient inflammatory process surrounding the carotid artery in a number of individuals who present with unilateral neck pain. Although some use carotidynia as the designation of choice by which to identify this inflammatory process, the acronym TIPIC (transient perivascular inflammation of the carotid artery) syndrome is being touted as a far more descriptive and less contentious alternative. Having TIPIC syndrome replace carotidynia, however, need not necessarily signal the latter's outright elimination as some have advocated. When used as a diagnostic sign, carotidynia provides an appreciation of the many conditions that may be associated with idiopathic unilateral neck pain.

Autoantibodies to folate receptors in the cerebral folate deficiency syndrome.

In infantile-onset cerebral folate deficiency, 5-methyltetrahydrofolate (5MTHF) levels in the cerebrospinal fluid are low, but folate levels in the serum and erythrocytes are normal. We examined serum specimens from 28 children with cerebral folate deficiency, 5 of their mothers, 28 age-matched control subjects, and 41 patients with an unrelated neurologic disorder. Serum from 25 of the 28 patients and 0 of 28 control subjects contained high-affinity blocking autoantibodies against membrane-bound folate receptors that are present on the choroid plexus. Oral folinic acid normalized 5MTHF levels in the cerebrospinal fluid and led to clinical improvement. Cerebral folate deficiency is a disorder in which autoantibodies can prevent the transfer of folate from the plasma to the cerebrospinal fluid.

Red ear syndrome: Perspectives for the otolaryngologist.

Red ear syndrome (RES) is an unusual, often unrecognized condition that has rarely been reported in the otolaryngology literature despite the presence of symptoms and associated disorders of relevance to the otolaryngologist. When present, RES may have diagnostic value when uncertainties arise in cases of sinus headache and referred otalgia. Despite the appearance of a distinctive red ear, as well as symptoms and associated disorders relating to otolaryngology, discussion of RES is generally limited to neurology-based publications. A red ear is typically the one constant finding in RES while clinical presentation, rate of occurrence, duration, manner of onset, and response to treatment vary on a case-by-case basis. RES may have value as a diagnostic tool in cases of sinus headache and referred otalgia. In recognizing that RES is commonly associated with migraine and not sinus-related headaches, the presence of RES could help confirm a diagnosis of migraine and remove sinus headache from consideration. Temporomandibular joint (TMJ) disorder and cervical pathology are commonly encountered in both RES and referred otalgia. When identifying the cause of referred otalgia proves problematic, the presence of RES should prompt the clinician to concentrate on either TMJ or cervical pathology as the more likely diagnostic possibilities.

The ORION statement: guidelines for transparent reporting of outbreak reports and intervention studies of nosocomial infection.

The quality of research in hospital epidemiology (infection control) must be improved to be robust enough to influence policy and practice. In order to raise the standards of research and publication, a CONSORT equivalent for these largely quasi-experimental studies has been prepared by the authors of two relevant systematic reviews, following consultation with learned societies, editors of journals, and researchers. The ORION (Outbreak Reports and Intervention Studies Of Nosocomial infection) statement consists of a 22 item checklist, and a summary table. The emphasis is on transparency to improve the quality of reporting and on the use of appropriate statistical techniques. The statement has been endorsed by a number of professional special interest groups and societies. Like CONSORT, ORION should be considered a "work in progress", which requires ongoing dialogue for successful promotion and dissemination. The statement is therefore offered for further public discussion. Journals and research councils are strongly recommended to incorporate it into their submission and reviewing processes. Feedback to the authors is encouraged and the statement will be revised in 2 years.

Autoantibodies against folate receptors in women with a pregnancy complicated by a neural-tube defect.

BACKGROUND: In the absence of clinical folate deficiency, periconceptional supplementation with folic acid reduces a woman's risk of having an infant with a neural-tube defect. Since antiserum to folate receptors induces embryo resorption and malformations in rats, we hypothesized that autoantibodies against folate receptors in women may be associated with pregnancy complicated by a neural-tube defect. METHODS: Serum from 12 women who were or had been pregnant with a fetus with a neural-tube defect and from 24 control women (20 with current or prior normal pregnancies and 4 who were nulligravid) was analyzed for autoantibodies by incubation with human placental folate receptors radiolabeled with [3H]folic acid. The properties of these autoantibodies were characterized by incubating serum and the autoantibodies isolated from serum with placental membranes, ED27 cells, and KB cells, which express the folate receptors. RESULTS: Serum from 9 of 12 women with a current or previous affected pregnancy (index subjects) and 2 of 20 control subjects contained autoantibodies against folate receptors (P<0.001). The autoantibodies blocked the binding of [3H]folic acid to folate receptors on placental membranes and on ED27 and KB cells incubated at 4 degrees C and blocked the uptake of [3H]folic acid by KB cells when incubated at 37 degrees C. CONCLUSIONS: Serum from women with a pregnancy complicated by a neural-tube defect contains autoantibodies that bind to folate receptors and can block the cellular uptake of folate. Further study is warranted to assess whether the observed association between maternal autoantibodies against folate receptors and neural-tube defects reflects a causal relation.

Does bone quality predict loosening of cemented total hip replacements?

We matched 78 patients with a loose cemented Charnley Elite Plus total hip replacement (THR) by age, gender, race, prosthesis and time from surgery with 49 patients with a well-fixed stable hip replacement, to determine if poor bone quality predisposes to loosening. Clinical, radiological, biomechanical and bone mineral density indicators of bone quality were assessed. Patients with loose replacements had more pain, were more likely to have presented with atrophic arthritis and to have a history of fragility fracture, narrower femoral cortices and lower peri-prosthetic or lumbar spine bone mineral density (all t-test, p < 0.01). They also tended to be smokers (chi-squared test, p = 0.08). Vitamin-D deficiency was common, but not significantly different between the two groups (t-test, p = 0.31) In this series of cemented hip replacements performed between 1994 and 1998, aseptic loosening was associated with poor bone quality. Patients with a THR should be screened for osteoporosis and have regular radiological surveillance.

Primary B cell lymphoma of the external auditory canal.

Temporal bone lymphomas are rare and typically metastatic neoplasms. We describe a case of primary B cell lymphoma that originated in the external auditory canal of an elderly woman. The diagnosis was based on histopathologic examination supplemented by immunophenotypic analysis. The patient was treated with external-beam radiation and remained disease-free throughout 9 years of follow-up. We also point out that the presence of non-Hodgkin's lymphoma in an unusual site may be an indication that the patient has an acquired immunodeficiency syndrome.

Bridging the gap between pragmatic intervention design and theory: using behavioural science tools to modify an existing quality improvement programme to implement "Sepsis Six".

BACKGROUND: Sepsis has a mortality rate of 40 %, which can be halved if the evidence-based "Sepsis Six" care bundle is implemented within 1 h. UK audit shows low implementation rates. Interventions to improve this have had minimal effects. Quality improvement programmes could be further developed by using theoretical frameworks (Theoretical Domains Framework (TDF)) to modify existing interventions by identifying influences on clinical behaviour and selecting appropriate content. The aim of this study was to illustrate using this process to modify an intervention designed using plan-do-study-act (P-D-S-A) cycles that had achieved partial success in improving Sepsis Six implementation in one hospital. METHODS: Factors influencing implementation were investigated using the TDF to analyse interviews with 34 health professionals. The nursing team who developed and facilitated the intervention used the data to select modifications using the Behaviour Change Technique (BCT) Taxonomy (v1) and the APEASE criteria: affordability, practicability, effectiveness, acceptability, safety and equity. RESULTS: Five themes were identified as influencing implementation and guided intervention modification. These were:(1) "knowing what to do and why" (TDF domains knowledge, social/professional role and identity); (2) "risks and benefits" (beliefs about consequences), e.g. fear of harming patients through fluid overload acting as a barrier to implementation versus belief in the bundle's effectiveness acting as a lever to implementation; (3) "working together" (social influences, social/professional role and identity), e.g. team collaboration acting as a lever versus doctor/nurse conflict acting as a barrier; (4) "empowerment and support" (beliefs about capabilities, social/professional role and identity, behavioural regulation, social influences), e.g. involving staff in intervention development acting as a lever versus lack of confidence to challenge colleagues' decisions not to implement acting as a barrier; (5) "staffing levels" (environmental context and resources), e.g. shortages of doctors at night preventing implementation. The modified intervention included six new BCTs and consisted of two additional components (Sepsis Six training for the Hospital at Night Co-ordinator; a partnership agreement endorsing engagement of all clinical staff and permitting collegial challenge) and modifications to two existing components (staff education sessions; documents and materials). CONCLUSIONS: This work demonstrates the feasibility of the TDF and BCT Taxonomy (v1) for developing an existing quality improvement intervention. The tools are compatible with the pragmatic P-D-S-A cycle approach generally used in quality improvement work.

3-Oxoacyl-[ACP] reductase from oilseed rape (Brassica napus).

3-Oxoacyl-[ACP] reductase (E.C. 1.1.1.100, alternatively known as beta-ketoacyl-[ACP] reductase), a component of fatty acid synthetase has been purified from seeds of rape by ammonium sulphate fractionation, Procion Red H-E3B chromatography, FPLC gel filtration and high performance hydroxyapatite chromatography. The purified enzyme appears on SDS-PAGE as a number of 20-30 kDa components and has a strong tendency to exist in a dimeric form, particularly when dithiothreitol is not present to reduce disulphide bonds. Cleveland mapping and cross-reactivity with antiserum raised against avocado 3-oxoacyl-[ACP] reductase both indicate that the multiple components have similar primary structures. On gel filtration the enzyme appears to have a molecular mass of 120 kDa suggesting that the native structure is tetrameric. The enzyme has a strong preference for the acetoacetyl ester of acyl carrier protein (Km = 3 microM) over the corresponding esters of the model substrates N-acetyl cysteamine (Km = 35 mM) and CoA (Km = 261 microM). It is inactivated by dilution but this can be partly prevented by the inclusion of NADPH. Using an antiserum prepared against avocado 3-oxoacyl-[ACP] reductase, the enzyme has been visualised inside the plastids of rape embryo and leaf tissues by immunoelectron microscopy. Amino acid sequencing of two peptides prepared by digestion of the purified enzyme with trypsin showed strong similarities with 3-oxoacyl-[ACP] reductase from avocado pear and the Nod G gene product from Rhizobium meliloti.

Fatal Legionnaires' disease coincident with initiation of immunosuppressive therapy.

A fatal relapse of legionnaires' disease occurred coincidental with the initiation of chemotherapy in a patient who had received previous parenteral erythromycin gluceptate therapy for 30 days. Sputum examinations utilizing the direct fluorescent antibody test for Legionella pneumophila suggested persistence of infection during the course of antibiotic therapy. This case suggests that administration of immunosuppressive agents should be delayed in patients whose sputum is positive on direct fluorescent antibody testing, regardless of previous antibiotic therapy.

Characterising an implementation intervention in terms of behaviour change techniques and theory: the 'Sepsis Six' clinical care bundle.

BACKGROUND: Sepsis is a major cause of death from infection, with a mortality rate of 36 %. This can be halved by implementing the 'Sepsis Six' evidence-based care bundle within 1 h of presentation. A UK audit has shown that median implementation rates are 27-47 % and interventions to improve this have demonstrated minimal effects. In order to develop more effective implementation interventions, it is helpful to obtain detailed characterisations of current interventions and to draw on behavioural theory to identify mechanisms of change. The aim of this study was to illustrate this process by using the Behaviour Change Wheel; Behaviour Change Technique (BCT) Taxonomy; Capability, Opportunity, Motivation model of behaviour; and Theoretical Domains Framework to characterise the content and theoretical mechanisms of action of an existing intervention to implement Sepsis Six. METHODS: Data came from documentary, interview and observational analyses of intervention delivery in several wards of a UK hospital. A broad description of the intervention was created using the Template for Intervention Description and Replication framework. Content was specified in terms of (i) component BCTs using the BCT Taxonomy and (ii) intervention functions using the Behaviour Change Wheel. Mechanisms of action were specified using the Capability, Opportunity, Motivation model and the Theoretical Domains Framework. RESULTS: The intervention consisted of 19 BCTs, with eight identified using all three data sources. The BCTs were delivered via seven functions of the Behaviour Change Wheel, with four ('education', 'enablement', 'training' and 'environmental restructuring') supported by the three data sources. The most frequent mechanisms of action were reflective motivation (especially 'beliefs about consequences' and 'beliefs about capabilities') and psychological capability (especially 'knowledge'). CONCLUSIONS: The intervention consisted of a wide range of BCTs targeting a wide range of mechanisms of action. This study demonstrates the utility of the Behaviour Change Wheel, the BCT Taxonomy and the Theoretical Domains Framework, tools recognised for providing guidance for intervention design, for characterising an existing intervention to implement evidence-based care.

Diffraction-Enhanced Computed Tomographic Imaging of Growing Piglet Joints by Using a Synchrotron Light Source.

The objective of this project was to develop and test a new technology for imaging growing joints by means of diffraction-enhanced imaging (DEI) combined with CT and using a synchrotron radiation source. DEI-CT images of an explanted 4-wk-old piglet stifle joint were acquired by using a 40-keV beam. The series of scanned slices was later 'stitched' together, forming a 3D dataset. High-resolution DEI-CT images demonstrated fine detail within all joint structures and tissues. Striking detail of vasculature traversing between bone and cartilage, a characteristic of growing but not mature joints, was demonstrated. This report documents for the first time that DEI combined with CT and a synchrotron radiation source can generate more detailed images of intact, growing joints than can currently available conventional imaging modalities.

A genetic polymorphism in the coding region of the gastric intrinsic factor gene (GIF) is associated with congenital intrinsic factor deficiency.

Congenital intrinsic factor (IF) deficiency is a disorder characterized by megaloblastic anemia due to the absence of gastric IF (GIF, GenBank NM_005142) and GIF antibodies, with probable autosomal recessive inheritance. Most of the reported patients are isolated cases without genetic studies of the parents or siblings. Complete exonic sequences were determined from the PCR products generated from genomic DNA of five affected individuals. All probands had the identical variant (g.68A>G) in the second position of the fifth codon in the coding sequence of the gene that introduces a restriction enzyme site for Msp I and predicts a change in the mature protein from glutamine(5) (CAG) to arginine(5) (CGG). Three subjects were homozygous for this base exchange and two subjects were heterozygous, one of which was apparently a compound heterozygote at positions 1 and 2 of the fifth codon ([g.67C>G] + [g.68A>G]). The other patient, heterozygous for position 2, had one heterozygous unaffected parent. Most parents were heterozygous for this base exchange, confirming the pattern of autosomal recessive inheritance for congenital IF deficiency. cDNA encoding GIF was mutated at base pair g.68 (A>G) and expressed in COS-7 cells. The apparent size, secretion rate, and sensitivity to pepsin hydrolysis of the expressed IF were similar to native IF. The allelic frequency of g.68A>G was 0.067 and 0.038 in two control populations. This sequence aberration is not the cause of the phenotype, but is associated with the genotype of congenital IF deficiency and could serve as a marker for inheritance of this disorder.

Systemic lupus erythematosus: considerations for a genetic approach.

There is a powerful evidence suggesting that etiology and pathogenesis of systemic lupus erythematosus has both genetic and environmental components. Unfortunately, understanding the genetics of lupus has been impeded by knowing the pattern of inheritance. Indeed, a complex mode of inheritance for the lupus disease phenotype is suggested by the known characteristics of this disorder. Twenty-five multiplex pedigrees for lupus have been enrolled and have been used to evaluate power to reveal linkage. The power to find linkage in these pedigrees is greater for autosomal recessive than for autosomal dominant modes of inheritance. Once 100 similar pedigrees are available for analysis our results predict that linkage is likely to be present for genetic models with relatively relaxed requirements. At loci operating by autosomal recessive inheritance linkage should be detectable despite genetic homogeneity as low as 40% and penetrance as low as 50%. For loci operating by autosomal dominant inheritance genetic homogeneity must be 60% or more when penetrance is as low as 50% to be able to establish linkage. Available preliminary data are also consistent with a possible genetic linkage of Fc gamma RIIIPMN with lupus in American Black pedigrees multiplex for lupus.

The half-life of the transcript encoding the folate receptor alpha in KB cells is reduced by cytosolic proteins expressed in folate-replete and not in folate-depleted cells.

The KB cell, a transformed human cell line, constitutively expresses a high level of the glycosylphosphatidylinositol (GPI) anchored folate receptor protein alpha (FR alpha) and thereby can grow in medium containing <1 nM folate. When transferred from a folate-replete (FR) medium to one folate-deficient (FD), intracellular folate diminishes about 50-fold and expression of the FR alpha increases 6-fold. This up-regulation is mediated by a 4.5-fold increase in the initial transcription rate and a 2.4-fold prolongation of the mRNA half-life that together provide a higher level of the steady-state mRNA abundance. An RNA gel -shift assay of a 5' region of the mRNA that includes all of the non-coding and 24 nt of coding sequence, and a 3' region comprised only of coding sequence, identified unique complexes with cytosolic proteins from the FR-KB cells that were not observed with the cytosol from FD-KB cells. It appears, therefore, that expression of these folate-dependent cytosolic trans-active proteins function to maintain a shorter half-life of the mRNA in the FR-KB cells by binding to 5' and 3' cis elements, reducing the stability of this transcript.

A method for the selective beta-irradiation of individual lymphocyte microcultures and its application in a preliminary study of radiation sensitivity.

A method that permits high energy beta-irradiation to be applied to individual lymphocyte microplate cultures is described. The principle involves the introduction of single energy sources (in this case 32P) contained within tubes which rest inside wells containing the lymphocyte cultures. Cell viability and mitogen-induced transformation were studied under these conditions. Dose-response effects were clearly demonstrated. The method is simple and, provided the precautions described are adhered to, safe. It should be applicable to studies of radiation sensitivity of putative target cells in various clinical situations.

Human erythrocyte rosette formation with mitogen-stimulated human lymphocytes--a marker for the demonstration of activated T-cells.

Human lymphocytes after stimulation by various mitogens could be shown to make rosettes with washed uncoated human Group O rhesus negative erythrocytes (H-rosettes). Using purified T- and B-cell populations and exposing them to the action of mitogens it has been demonstrated that the cell responsible is the activated T-lymphocyte. The H-rosette is thus presented as a new marker for the demonstration of activated human T-cells.

A method for measuring cyto-adherence on frozen tissue sections.

A simple method for quantifying the cells adhering to frozen sections of mouse spleen using a microscope equipped with a drawing tube attachment, and a planimeter is described. It is a straightforward and reproducible technique which was been preliminarily employed to study optimal binding conditions for Esheep and EoxAC.

Potentiation in vivo of melphalan activity by nitroimidazole compounds.

Many nitroimidazole compounds have been shown to potentiate the activity of melphalan against the murine anaplastic MT tumor. The degree of potentiation achieved by these compounds probably depends on their octanol-water partition coefficient and electron affinity: for the greater the partition coefficient of electron affinity, the greater the potentiation. The mechanism of this potentiation remains uncertain. However, it is not due to either nitroimidazole-induced hypothermia, or to the elimination of the recovery from melphalan-induced potentially lethal damage (PLD).