Deficiencies in postgraduate training for healthcare professionals who provide diabetes education and support: results from the Diabetes Attitudes, Wishes and Needs (DAWN2) study.

AIMS: To consider the global provision of self-management diabetes education and training for healthcare professionals using data from the second Diabetes Attitudes, Wishes and Needs (DAWN2) study. METHODS: A total of 4785 healthcare professionals caring for people with diabetes were surveyed in 17 countries to assess diabetes healthcare provision, self-management support and training. RESULTS: Of the healthcare professionals surveyed, 33.5% received formal postgraduate training in self-management (19.3-51.4% across countries) and 62.9% received training for medical management of diabetes (47.6-70.6% variation). Training in psychological management was low (19.1%), ranging from 3.6 to 36.5%, while 20.4% (a range of 3.6-36.4% across countries) had received no postgraduate training. Overall, the greatest training need was in the management of psychological aspects of diabetes (59.5%). For some, training in a domain was positively associated with a perceived need for further training. Communication skills, for example, listening (76.9%) and encouraging questions (76.1%), were the skills most widely used. Discussion of emotional issues was limited; 31-60% of healthcare professionals across the different countries reported that this only occurred if initiated by patients. Approximately two-thirds of participants reported a need for major improvements in emotional/psychological support, but few had received training in this area, with consistent findings across professional affiliations. CONCLUSIONS: The present study shows that healthcare professionals report being insufficiently equipped to provide diabetes self-management education, including emotional and psychological aspects of diabetes, and many are not receiving postgraduate training in any part (including medical care) of the management of diabetes. It is paramount that those responsible for the continuing professional development of healthcare professionals address this skills gap.

IgD Subtype But Not IgM or Non-Secretory Is a Prognostic Marker for Poor Survival Following Autologous Hematopoietic Cell Transplantation in Multiple Myeloma. Results From the EBMT CALM (Collaboration to Collect Autologous Transplant Outcomes in Lymphomas and Myeloma) Study.

BACKGROUND: The Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study has provided an opportunity to evaluate the real-world outcomes of patients with myeloma. The aim of this study was to compare the outcome according to the different subtypes of myeloma using CALM data. PATIENTS: This study compared overall survival (OS), progression-free survival (PFS), and complete remission (CR) and the impact of novel versus non-novel drug containing induction regimens prior to autologous hematopoietic cell transplantation (HCT) of 2802 patients with "usual" and "rare" myelomas. RESULTS: Our data suggest that IgM and non-secretory myeloma have superior PFS and OS compared with IgD myeloma and outcomes comparable to those for usual myeloma. Patients who received novel agent induction had higher rates of CR prior to transplant. Non-novel induction regimens were associated with inferior PFS but no difference in OS. Although not the primary focus of this study, we show that poor mobilization status is associated with reduced PFS and OS, but these differences disappear in multivariate analysis suggesting that poor mobilization status is a surrogate for other indicators of poor prognosis. CONCLUSION: We confirm that IgD myeloma is associated with the worst prognosis and inferior outcomes compared with the other isotypes.

Defining metabolically healthy obesity in children: a scoping review.

We conducted a scoping review to identify definitions of metabolically healthy obesity (MHO), describe gaps in the literature, and establish a universal definition of MHO in children. We searched electronic databases from January 1980 to June 2017 and grey literature. Experimental, quasi-experimental, or observational studies were eligible for inclusion if they (i) included a definition of MHO that identified risk factors, cut-off values, and the number of criteria used to define MHO, and (ii) classified 2-18 year olds as overweight or obese. Two reviewers independently screened 1,711 papers for relevance and quality; we extracted data from 39 individual reports that met inclusion criteria. Most (31/39; 79%) definitions of MHO included an absence of cardiometabolic risk factors. Heterogeneity across MHO definitions, obesity criteria, and sample sizes/characteristics resulted in variable prevalence estimates (3-80%). Finally, we convened an international panel of 46 experts to complete a 4-round Delphi process to generate a consensus-based definition of MHO. Based on consensus (≥ 80% agreement), our definition of MHO included: high density lipoprotein-cholesterol > 40 mg/dl (or > 1.03 mmol/l), triglycerides ≤ 150 mg/dl (or ≤ 1.7 mmol/l), systolic and diastolic blood pressure ≤ 90th percentile, and a measure of glycemia. This definition of MHO holds potential universal value to enable comparisons between studies and inform clinical decision-making for children with obesity.

A brief eHealth tool delivered in primary care to help parents prevent childhood obesity: a randomized controlled trial.

OBJECTIVES: To determine the feasibility and preliminary impact of an electronic health (eHealth) screening, brief intervention and referral to treatment (SBIRT) delivered in primary care to help parents prevent childhood obesity. METHODS: Parents of children (5-17 years) were recruited from a primary care clinic. Children's measured height and weight were entered into the SBIRT on a study-designated tablet. The SBIRT screened for children's weight status, block randomized parents to one of four brief interventions or an eHealth control and provided parents with a menu of optional obesity prevention resources. Feasibility was determined by parents' interest in, and uptake of, the SBIRT. Preliminary impact was based on parents' concern about children's weight status and intention to change lifestyle behaviours post-SBIRT. RESULTS: Parents (n = 226) of children (9.9 ± 3.4 years) were primarily biological mothers (87.6%) and Caucasian (70.4%). The proportion of participants recruited (84.3%) along with parents who selected optional resources within the SBIRT (85.8%) supported feasibility. Secondary outcomes did not vary across groups, but non-Caucasian parents classified as inaccurate estimators of children's weight status reported higher levels of concern and intention to change post-SBIRT. CONCLUSIONS: Our innovative, eHealth SBIRT was feasible in primary care and has the potential to encourage parents of unhealthy weight children towards preventative action.

High dose melphalan or intermediate dose melphalan can be well tolerated and result in good response rates in selected elderly patients with myeloma.

We have used two strategies for treating myeloma patients aged 65-75 years. Those fit enough underwent Cyclophosphamide mobilisation and PBSCT using melphalan 200mg/m(2) (HDM) (n=15, median 67 years). Those less fit were mobilised with G-CSF and received melphalan 70mg/m(2) (IDM) (n=15, median 69 years). Where possible sufficient PBSC were collected so that patients not in CR after their first IDM, underwent a second IDM procedure (n=6). The treatment was well tolerated with zero day+100 TRM. Median cell dose was 4.85x10(6)CD34+cells/kg and 2.7x10(6) in the HDM and IDM groups, respectively. Neutrophil engraftment was faster in the HDM group but despite this there was a trend to earlier discharge in the IDM group (13 days versus 15 days) and lower antibiotic and anti-fungal usage, suggesting better tolerability. Response rates were similar with CRs achieved in 7/15 patients receiving HDM and 9/15 receiving IDM (6 after the first and 3 after the second procedure). Three patients did not undergo a second IDM due to insufficient cells. In the IDM group 11/15 remain alive at a median follow up of 14 months with 5 in CR, whilst in the HDM group 12/15 are alive with 5 in CR at a median follow up of 15.5m. We conclude both approaches have comparable efficacy but that IDM may be better tolerated in an older age group.

Clinical impact of MRSA in a stem cell transplant unit: analysis before, during and after an MRSA outbreak.

Meticillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial pathogen, with an increased incidence in the UK since 1993, causing serious morbidity and mortality in immunosuppressed patients. We analysed the frequency and outcome of MRSA infection in a single-centre transplant population over a 5-year period. The total number of patients infected was 41/776 (5%). The frequency in autologous, sibling and unrelated donor transplants was 3, 6 and 9%, respectively. Prior to 2004, the incidence was <4%/year; however, an outbreak in the day unit resulted in 22 patients becoming newly infected. Over 90% of infections were clinically relevant, half (49%) being bacteraemia. Three patterns were seen: known MRSA positive at any time before transplant (n=15), MRSA first detected during the neutropenia phase (n=5) and MRSA only post discharge (n=21). MRSA was implicated in a number of deaths, at all time points, in those infected. An intensive eradication policy resulted in new infections dropping to <2%. In conclusion, MRSA is likely to remain endemic in our unit, but robust early screening protocols and aggressive eradication strategies have effectively limited the spread of and morbidity due to this pathogen.

A study to determine the safety profile and maximum tolerated dose of micafungin (FK463) in patients undergoing haematopoietic stem cell transplantation.

This open-label, dose-escalation study assessed the maximum tolerated dose (MTD) of the new antifungal micafungin in patients undergoing haematopoietic stem cell transplantation (HSCT). Participants received 3, 4, 6 or 8 mg/kg/day micafungin intravenously from 7 days to a maximum of 28 days or until neutropaenia resolved. The MTD was defined as the highest dose not causing the same Grade 3 or 4 adverse event in three or more patients. All 36 participants received >/=8 days treatment for a median of 18 days (range: 8-28); 1 patient withdrew consent and a further 11 discontinued to receive another systemic antifungal agent for a suspected infection. No case of confirmed invasive fungal infection occurred. Adverse events were those expected for patients undergoing HSCT and showed no evidence of dose-related toxicity. Criteria for MTD were not met; no patient had a Grade 3 or 4 adverse event considered causally related to micafungin. Thus, the MTD of micafungin can be inferred to be 8 mg/kg/day or higher.

p21Ras activation by the guanine nucleotide exchange factor Sos, requires the Sos/Grb2 interaction and a second ligand-dependent signal involving the Sos N-terminus.

It has been suggested that a key event in growth factor-induced p21Ras activation by the guanine nucleotide exchange factor Sos, is the recruitment of Sos to the plasma membrane by its interaction with the adaptor protein Grb2. However, other evidence argues that the sub cellular localisation of Sos is independent of Grb2, and that the Sos/Grb2 interaction can be dispensed with for p21Ras activation. To clarify the role of the Sos/Grb2 interaction in ligand-stimulated p21Ras activation, we have utilised the observation that overexpression of the Sos C-terminal domain can effectively inhibit p21Ras-dependent signalling in three different mammalian systems. We have shown that concurrent expression of Grb2, but not SH2 or SH3 domain mutants of Grb2, or the alternative adaptor protein Nck, can rescue this inhibitory effect of the C-terminus. This shows that the Grb2/Sos interaction is required to mediate growth factor-dependent activation of p21Ras, and requires the presence of intact SH2 and SH3 domains of Grb2. This approach was also used for a functional analysis of Sos which revealed that growth factor dependent signals are transmitted through both the N-terminal and C-terminal domains.

Donor lymphocyte infusions can result in sustained remissions in patients with residual or relapsed lymphoid malignancy following allogeneic haemopoietic stem cell transplantation.

We treated 17 patients with refractory (n = 7) or relapsed lymphoid malignancy (n = 10) following allogeneic HSCT with donor lymphocyte infusions (DLI). Patients with low-grade disease received DLI alone (n = 7) or following radiotherapy (n = 1). Patients with aggressive disease (n = 9) received prior chemotherapy. Nine out of 15 patients receiving DLI from sibling donors responded after one (n = 6), two (n = 2) and three (n = 1) infusions. Both MUD recipients achieved CR after two and three DLI. In all, 10/17 patients achieved CR including 3/4 patients with chronic lymphatic leukaemia (CLL), 4/4 with mantle cell lymphoma (MCL), 3/4 with follicular NHL but 0/5 with aggressive NHL/Richters. The median CD3 cell dose to achieve CR for siblings was 2 x 10(7)/kg. One patient with CLL had a second transplant following DLI-induced aplasia and is in CR at 14 months giving a final CR rate of 64%. Grade II-IV acute GVHD developed in 45% and chronic GVHD in 8/9 evaluable patients. Of the 11 patients finally achieving CR, one patient with MCL relapsed at 18 months post-DLI but all others remain in remission with a median follow-up of 40 months (range 12-64 months). Low-grade NHL and MCL have a high response rate and sustained remissions following DLI. Aggressive disease responds poorly however, despite pre-DLI chemotherapy.

Early allogeneic transplantation for refractory or relapsed acute leukaemia following remission induction with FLAG.

The prognosis for patients with secondary AML, primary resistant AML or ALL and early (<12 months) relapse of acute leukaemia remains extremely poor with conventional chemotherapy. As part of a strategy to improve the outcome for these patients we have treated 22 consecutive patients (18 AML, four ALL, median age 35 years) with either primary resistant disease (n=3), early relapsed leukaemia (n= 12) or secondary AML (n= 7, four RAEBt, two antecedant ALL and one antecedant Hodgkin's disease) with 'FLAG' induction chemotherapy with the aim of proceeding to early allogeneic transplantation either from sibling or unrelated donors. Eighteen patients achieved CR after one course of FLAG, including five patients who had documented p-glycoprotein-induced multidrug resistance and 10 patients with adverse cytogenetic abnormalities. Eight patients were consolidated with a second course of FLAG prior to transplantation and so far 16 patients have undergone allogeneic transplantation, 10 from unrelated donors and six from sibling donors (one mismatched). By the time of transplant three patients had progressed and were in early relapse and all have relapsed post BMT. Of the remaining 13 patients transplanted in remission, nine remain in CCR at a range of 4-26 months, three have died of transplant-related complications (18%) and one patient has relapsed. We conclude that the use of FLAG induction therapy followed by early allogeneic transplantation from either a sibling or unrelated donor can be an effective strategy for the treatment of this difficult group of young patients with poor risk acute leukaemia and appears to be associated with a low procedure-related risk.

Chlamydia trachomatis IgG3 seropositivity is associated with gastroschisis.

OBJECTIVE: To investigate the association between Chlamydia trachomatis (CT) infection seropositivity and gastroschisis. STUDY DESIGN: In this case-control study we enrolled pregnant women either prenatally diagnosed with gastroschisis (cases, n=33) or with a normal ultrasound (controls, n=66). Both groups attended the University of Utah's Maternal Fetal Medicine Diagnostic Center for their diagnostic ultrasound or because of a community obstetrician referral. Participants completed a structured interview on potential risk factors. Anti-CT immunoglobulin (IgG)1 and IgG3 were measured by a CT elementary body enzyme-linked immunosorbent assay. RESULT: Median age at sexual debut was lower and reported sexual partner number higher in cases compared with controls. Risk factors for gastroschisis included having ⩾ 3 sexual partners (odds ratio (OR)=3.3, 95% CI 1.2, 9.4), change in partner from the previous pregnancy (OR=3.6, 95% CI 0.9, 13.9) and anti-CT IgG3 seropositivity (age-adjusted OR=3.9, 95% CI: 1.1, 13.2). CONCLUSION: Anti-CT IgG3 seropositivity was associated with greater than a threefold risk for gastroschisis.

Caspase-8 polymorphisms result in reduced Alemtuzumab-induced T-cell apoptosis and worse survival after transplantation.

Allo-SCT using unrelated donors is a curative treatment for patients with hematological disorders. The best donor is one matched for 10/10 HLA alleles, however studies have shown an additional survival benefit when considering other genetic factors. It has been shown that a six-nucleotide insertion/deletion polymorphism in the CASP8 gene promoter results in reduced susceptibility of T lymphocytes to undergo apoptosis. In 186 SCT recipients, we found a significantly better OS in those who received a transplant from a WT/WT donor compared with donors with a deletion (3 years: 52 vs 34%; P=0.03; multivariate analysis; RR 0.61; 95% CI 0.38-0.98, P=0.04). This was more marked when both the patient and the donor had a deletion (3 years OS: 62% compared with 36%, P=0.01). As the majority of these patients received Alemtuzumab during conditioning, we went on to analyze the in vitro effect of the polymorphism on Alemtuzumab-induced apoptosis. We showed statistically significantly higher percentages of apoptotic naïve CD4 (P<0.0005) and CD8 (P<0.0005) T cells in WT/WT donors in comparison with donors with a deletion. These data imply an unrecognized role for the CASP8 promoter polymorphism on survival following unrelated SCT particularly in the context of T-cell depletion with Alemtuzumab.

Use of haemopoietic growth factors: commentary on the ASCO/ECOG guidelines. American Society of Clinical Oncology/Eastern Co-operative Oncology Group.

In the past two to three years, a number of clinical guidelines have been issued that have attempted to recommend specific indications for the use of haemopoietic colony-stimulating factors. Some of which have recently been updated. These guidelines are, for the most part, a welcome initiative to guide clinicians as to the most appropriate use of these powerful and expensive drugs. Here, we have attempted to offer a perspective on these guidelines based upon both a review of the literature and our own clinical experience, concentrating primarily on their use following conventional and high-dose therapy and for the purpose of peripheral blood stem cell mobilization. For the latter, it is worth remembering that a product licence for this indication was only obtained in Europe in 1995 and that this only covers autologous mobilization and not the mobilization of normal donors. Both the American Society of Clinical Oncology and the Eastern Co-operative Oncology Group guidelines rightly confine their comments to best practice. However, certainly in the United Kingdom and probably elsewhere, it is impossible to divorce this entirely from the economic realities involved in the widespread use of colony-stimulating factors, hence the increasing number of research papers in which the authors emphasize not only the clinical but also the financial implications of their findings. Here, we have taken note of both clinical and economic considerations in framing our comments.

Allogeneic transplantation using peripheral blood stem cells.

Over the past 9 years there has been a remarkable increase in the use of peripheral blood stem cells (PBSC) for allogeneic transplantation, primarily for matched sibling transplants but also increasingly for unrelated donor transplantation. In 1999 over 50% of all sibling transplants and over 25% of unrelated donor transplants reported to the European Group for Blood and Marrow Transplantation (EBMT) used PBSC. The major reason for this increasing use of PBSC relates to the rapid haemopoietic recovery seen which mirrors the advantages of using PBSC in autologous transplantation. This improvement in engraftment is a consequence of the larger number of stem cells that can be collected from G-CSF-mobilized peripheral blood compared to bone marrow. Evidence from randomized trials now shows a survival advantage for the use of PBSC in patients with advanced leukaemia. The reason for this improved survival appears primarily to relate to a reduced risk of transplant-related mortality and, possibly, a reduced risk of relapse, However, these randomized studies have also confirmed that there is an increased risk of chronic graft-versus-host disease associated with PBSC transplantation and further follow-up is required to determine the long-term impact on outcome.

del(20p) with manifestations of arteriohepatic dysplasia.

A small-for-gestational age white female infant was noted to have multiple minor anomalies and severe jejunal stenosis. Mild peripheral pulmonic stenosis, skeletal anomalies, and cholestasis with paucity of intrahepatic bile ducts were observed, and she was diagnosed as having arteriohepatic dysplasia. Chromosome analysis of peripheral blood leukocytes showed a 46,XX,del(20)(p11.2) chromosome constitution.

Allogeneic transplantation for multiple myeloma: late relapse may occur as localised lytic lesion/plasmacytoma despite ongoing molecular remission.

Allogeneic SCT for myeloma may be curative for young patients, but its role remains controversial because of a reported high TRM in some series. Since 1991, we have performed 25 allografts for myeloma using fully matched sibling donors. Of the 18 evaluable patients, 13 achieved CR at a median time of 2.5 months post-transplant. The five patients who were not in CR when assessed at 3 months received a short course of alpha-interferon and four subsequently achieved CR with this approach at a median of 82 days. One patient who failed to respond to IFN went on to achieve CR after four doses of DLI therapy, thus giving an overall CR rate of 72%. Seven patients have relapsed at a median of 4.7 years post-transplant (range 1.38-7.7 years) including two patients who had received IFN therapy. In five of these cases, relapse has been as a localised area of bone disease or isolated plasmacytoma with no evidence of marrow involvement by trephine biopsy or molecular analysis. All patients with localised relapse were treated with local radiotherapy +/-DLI and four are currently disease free despite two patients having had further treatment for a second localised lesion. Six patients died of TRM (24%) and the OS at 8 years is currently 69% with an EFS of 26%. These results suggest that allogeneic SCT for myeloma can be carried out with an acceptable TRM and a high CR rate. However, late relapses as localised disease may be a frequent finding and may represent foci of myeloma not eradicated by the conditioning. The use of pretransplant MRI scanning and top-up radiotherapy to involved areas may be useful in preventing this type of relapse.

Autologous GVHD following PBSCT, with evidence for a graft-versus-myeloma effect.

The development of GVHD following allogeneic BMT is known to be closely associated with significant antileukaemic activity. Immunological graft-versus-leukaemia (GVL) effects are now well established and are commonly exploited in the treatment of leukaemic relapse following allogeneic transplantation by the use of donor lymphocyte infusions. More recently a graft-versus-myeloma (GVM) effect following allogeneic transplantation has been documented, suggesting that eradication of haematological malignancies following allogeneic transplantation is achieved at least in part by immunological mechanisms. It is now also established that spontaneous GVHD can occur following autologous transplantation and can be induced by cyclosporin A administration. However, there is only limited evidence that the development of autologous GVHD has an antitumour effect. We report for the first time the development of autologous GVHD following PBSC transplantation for myeloma apparently resulting in a GVM effect.

Adjuvant alpha-interferon improves complete remission rates following allogeneic transplantation for multiple myeloma.

Allogeneic transplantation may be curative in a proportion of patients with multiple myeloma (MM), but relapse is a major cause of treatment failure. We sought to improve complete remission (CR) rates by the use of alpha-interferon (alpha-IFN) in patients not in CR when evaluated 4 months post-transplant. We report five of 13 evaluable patients undergoing allogeneic sibling BM or PBSC transplantation for MM between 1990 and 1997 who met the criteria for adjuvant alpha-IFN therapy. A starting dose of 3 MU x 3/week was commenced at median time of day +126 (range day +112-224) post-transplant and was well-tolerated. In contrast to other reports we observed no increased toxicity in terms of GVHD compared to those patients not receiving alpha-IFN therapy and only one patient treated with alpha-IFN has developed chronic GVHD. Durable CRs were achieved in two patients within 8 weeks of starting therapy whilst two other patients required a longer course of alpha-IFN to achieve CR (36 weeks and 30 weeks, respectively). One patient whose paraprotein was rapidly rising at the time of alpha-IFN therapy clinically relapsed despite 6 months of treatment. None of the patients who achieved CR following alpha-IFN therapy have relapsed and we conclude that alpha-IFN is a safe and effective adjuvant treatment for some patients in the achievement of CR following allogeneic transplantation for myeloma.

Stem cell mobilisation in lymphoproliferative diseases.

A number of different regimens have evolved for the mobilisation of peripheral blood stem cells for autologous transplantation in patients with lymphoma or myeloma. A successful regimen could be defined as one which consistently resulted in the collection of an optimal number of CD34+ cells with a minimum number of apheresis procedures with minimal toxicity. Initial protocols, which used chemotherapy alone as a mobilising agent, have now been replaced by regimens involving the use of haematopoietic growth factors either alone or in combination with variable doses of cyclophosphamide. Although there is good evidence that high-dose cyclophosphamide (6-7 g/m2) is an effective mobilising agent it is associated with significant toxicity and many groups have now utilised lower doses of cyclophosphamide with reduced toxicity which have still proven to be effective in the majority of patients. More recently a number of 'second generation' combined salvage chemotherapy and mobilisation regimens have been reported for use in the lymphomas which have the advantage of avoiding a specific stem cell mobilisation step and at the same time appear more consistently effective at mobilising stem cells than cyclophosphamide and G-CSF. These regimens are associated with fewer 'poor-mobilisers' and indeed some patients who have failed previous mobilisation with cyclophosphamide and G-CSF have been successfully re-mobilised. It is clear that in both lymphoma and myeloma patients the success of PBSC mobilisation is affected by the amount and type of previous chemotherapy and radiotherapy and probably other pre-treatment factors as exemplified by variability seen in normal donors mobilised with G-CSF alone. In myeloma most groups have utilised cyclophosphamide in variable doses in combination with G-CSF or GM-CSF. However, recent randomised studies have confirmed that G-CSF alone is an effective and nontoxic alternative although it appears that the efficacy of G-CSF as a single agent is related to the dosage used with daily doses of 16 microg/kg/day or greater being most effective. Thus, disease-specific mobilisation strategies appear to be emerging and these will undoubtedly be modified further as more is understood concerning the biology of blood stem cell mobilisation.

Successful engraftment of a second transplant using non-myeloablative conditioning as treatment for graft failure following unrelated donor BMT.

A 32-year-old man with CML in second chronic phase developed primary graft failure following matched unrelated donor transplantation using cryopreserved marrow cells. He was successfully regrafted within 60 days from a second fully matched donor using a non-myeloablative conditioning regimen, with minimal toxicity. He remains in complete haematological, cytogenetic and molecular remission 2 years after second transplant. We believe that reduced intensity or 'mini-transplants' may be preferable for patients requiring second allografts which are usually associated with a high transplant-related mortality.