The prospective evaluation of the TB strain typing service in England: a mixed methods study.

BACKGROUND: In response to rising TB notification rates in England, universal strain typing was introduced in 2010. We evaluated the acceptability, effectiveness and cost-effectiveness of the TB strain typing service (TB-STS). METHODS: We conducted a mixed-methods evaluation using routine laboratory, clinic and public health data. We estimated the effect of the TB-STS on detection of false positive Mycobacterium tuberculosis diagnoses (2010-2012); contact tracing yield (number of infections or active disease per pulmonary TB case); and diagnostic delay. We developed a deterministic age-structured compartmental model to explore the effectiveness of the TB-STS, which informed a cost-effectiveness analysis. RESULTS: Semi-structured interviews explored user experience. Strain typing identified 17 additional false positive diagnoses. The TB-STS had no significant effect on contact tracing yield or diagnostic delay. Mathematical modelling suggested increasing the proportion of infections detected would have little value in reducing TB incidence in the white UK-born population. However, in the non-white UK-born and non-UK-born populations, over 20 years, if detection of latent infection increases from 3% to 13% per year, then TB incidence would decrease by 11%; reducing diagnostic delay by one week could lead to 25% reduction in incidence. The current TB-STS was not predicted to be cost-effective over 20 years (£95 628/quality-adjusted life-years). Interviews found people had mixed experiences, but identified broader benefits, of the TB-STS. CONCLUSIONS: To reduce costs, improve efficiency and increase effectiveness, we recommend changes to the TB-STS, including discontinuing routine cluster investigations and focusing on reducing diagnostic delay across the TB programme. This evaluation of a complex intervention informs the future of strain typing in the era of rapidly advancing technologies.

Effective interprofessional simulation training for medical and midwifery students.

Introduction: Good interprofessional teamworking is essential for high quality, efficient and safe clinical care. Undergraduate interprofessional training has been advocated for many years to improve interprofessional working. However, few successful initiatives have been reported and even fewer have formally assessed their educational impact. Methods: This was a prospective observational study of medical and midwifery students at a tertiary-level maternity unit. An interprofessional training module was developed and delivered by a multiprofessional faculty to medical and midwifery students, including short lectures, team-building exercises and practical simulation-based training for one obstetric (shoulder dystocia) and three generic emergencies (sepsis, haemorrhage, collapse). Outcome measures were interprofessional attitudes, assessed with a validated questionnaire (UWE Interprofessional Questionnaire) and clinical knowledge, measured with validated multiple-choice questions. Results: Seventy-two students participated (34 medical, 38 midwifery). Following training median interprofessional attitude scores improved in all domains (p<0.0001), and more students responded in positive categories for communication and teamwork (69-89%, p=0.004), interprofessional interaction (3-16%, p=0.012) and interprofessional relationships (74-89%, p=0.006). Scores for knowledge improved following training for medical students (65.5% (61.8-70%) to 82.3% (79.1-84.5%) (median (IQR)) p<0.0001) and student midwives (70% (64.1-76.4%) to 81.8% (79.1-86.4%) p<0.0001), and in all subject areas (p<0.0001). Conclusions: This training was associated with meaningful improvements in students' attitudes to teamwork, and knowledge acquisition. Integrating practical tasks and teamwork training, in authentic clinical settings, with matched numbers of medical and non-medical students can facilitate learning of both why and how to work together. This type of training could be adopted widely in undergraduate healthcare education.

How often do hematologists consider celiac disease in iron-deficiency anemia? Results of a national survey.

BACKGROUND: Celiac disease (CD) is underdiagnosed, and iron-deficiency anemia (IDA) is a common presentation of CD. No guidelines exist in the literature for screening for CD among those with IDA in the United States. We surveyed hematologists to deter- mine rates of CD screening in patients with IDA. METHODS: A survey was e-mailed to members of the American Society of Hematology. RESULTS: There were 385 complete responses from 4551 e-mails. Most respondents were practicing clinicians (74%), clinical researchers (10%), or laboratory researchers (6%). Specialists in benign hematology accounted for 45% of respondents, oncologists accounted for 33%, and specialists in malignant hematology accounted for 22%. The most common practice types were university-affiliated hospital (43%), private clinic (29%), community hospital (12%), and Veterans Affairs or military hospital (9%). Only 8.6% believed all patients with IDA should be screened for CD. Respondents who had completed their fellowship within 5 years were more likely than more experienced clinicians to believe that all patients with IDA should receive CD screening (OR, 2.8; CI; 1.1-7.5; P=.04). Having a higher volume of IDA patients per month also increased the likelihood of testing (P=.01). In multivariate analysis, specialists in malignant hematology (OR, 3.2; CI, 1.1-9.5; P=.04) and oncologists (OR, 3.5; CI, 1.3-9.5; P=.02) were more likely than specialists in benign hematology to screen all patients for CD, as were those who saw predominately pediatric patients with IDA vs adult patients (OR, 16.9; CI, 3.0-97.0; P=.002). CONCLUSIONS: Practicing hematologists infrequently screen for CD in IDA. Physicians who have recently finished their fellowship and those who see a high volume of patients with IDA are more likely to screen for CD.

Anti-erythropoietin antibody-mediated pure red cell aplasia in a living donor liver transplant recipient treated for hepatitis C virus.

After liver transplantation, reinfection of the newly engrafted liver with hepatitis C virus is essentially universal in patients who are viremic at the time of transplantation. Treatment with interferon preparations with or without ribavirin is recommended in patients with marked histologic injury; however, hematologic toxicity associated with therapy has been reported, which is usually treated with growth factor support, including erythropoietin analogues. We present the first reported case of anti-erythropoietin antibody-mediated pure red cell aplasia arising in the setting of hepatitis C virus therapy in a patient who underwent living donor liver transplantation.

The spectrum of myelodysplastic syndromes post-solid organ transplantation: a single institutional experience.

An increased incidence of acute myeloid leukemia (AML) has recently been documented in patients post-solid organ transplantation but the incidence and types of myelodysplastic syndromes (MDS) occurring in this patient population are not known. We identified 5 patients (3M, 2F, age 48-64 years) who developed MDS ranging from 1.8 to 25 years (median 4.2 years) post-solid organ transplantation, only 2 patients had received azathioprine. The cumulative incidence of MDS in heart and lung transplant recipients at 15 years was 0.5% and 1.8%, respectively, which is markedly higher compared to the general population. Low-risk types of MDS predominated, 3 of 5 patients are alive (median 3.9 years) since diagnosis. Deletions of chromosome 20q, which have not been previously reported in post-transplant MDS/AML, were identified in 3 cases. Our findings expand the morphologic and cytogenetic spectrum of MDS occurring post-solid organ transplantation and suggest that mechanisms beside azathioprine toxicity might be important in disease pathogenesis.

Combined fludarabine and rituximab for low grade lymphoma and chronic lymphocytic leukemia.

As both fludarabine and rituximab are active against indolent lymphoproliferative disorders, we have studied the combination of fludarabine and rituximab in patients with low-grade lymphoma and chronic lymphocytic leukemia (CLL) in phase I/II fashion. Of 33 patients enrolled, 21(63.6%) had low-grade lymphoma and 12 (36.4%) had CLL. They received fludarabine 30 mg/m2 on days 1-4 and rituximab 125, 250 or 375 mg/m2 on day 5 at intervals of 28 days to a maximum of 8 cycles. Three patients were removed from the study because of rituximab-associated anaphylaxis and four because of prolonged hematopoietic toxicity. Toxicity and responsiveness did not differ at the different dose levels of rituximab. For 29 evaluable patients, responses were seen in 82.8% and complete responses in 34.5%. Of 7 responding patients not referred for stem cell transplantation, 6 remain in complete remission at a median follow-up of 16 months (range 4-30 months). Of 13 previously untreated patients, all responded and 46.2% had a complete response. Of 16 previously treated patients, 68.5% responded and 25% had a complete response. The combination of fludarabine and rituximab has major activity and acceptable toxicity in patients with low-grade lymphoma and CLL.

Leptomeningeal relapse of multiple myeloma following allogeneic stem cell transplantation.

Progressive multiple myeloma may manifest features of 'de-differentiation', including a plasmablastic appearance, failure to secrete paraprotein, extramedullary involvement, and resistance to treatment. A 44-year-old woman with kappa-light chain myeloma underwent allogeneic stem cell transplantation (SCT). Twenty months later she developed paraspinal plasmablastic myeloma in the absence of paraprotein in urine or myeloma in the marrow. The paraspinal masses responded to chemotherapy. At 30 months she developed myelomatous meningitis, which proved resistant to intrathecal chemotherapy, irradiation, and donor lymphocyte infusion (DLI). The leptomeningeal disease led to death at 38 months. This is the first report of leptomeningeal relapse of myeloma after allografting.

Short report: penile lymphoma following local injections for erectile dysfunction.

We report a case of high grade lymphoma which appeared at the site of prior injections of medications into the shaft of the penis for erectile dysfunction. We discuss the possible mechanisms of causation for this unusual form of lymphoma.

Retrospective study of the association of stress and smoking during pregnancy in rural women.

Women who continue to smoke during pregnancy put themselves and their fetuses at serious risk for complications. Various smoking cessation programs have been designed that specifically target pregnant smokers. Longitudinal studies, however, have shown that there is a group of women who are unable to quit smoking while pregnant. Women from a rural area of the Mid-West (N=299) were interviewed postpartum to determine the stresses these women experienced prenatally and the association of the stress with continuing to smoke during pregnancy. Subjects were divided into three groups: Nonsmokers, Quitters, Smokers. This study not only confirms other reports that these women are more stressed but also documents some of the major stressors. Statistically significant differences were found between groups for financial worries (P=.0002), problems with the family (P<.001), and domestic violence (P<.001). Assessing pregnant women for stress and, especially, domestic violence should be part of the implementation of the Clinical Practice Guidelines for Smoking Cessation.

Sexual health and the practice nurse: a survey of reported practice and attitudes.

BACKGROUND: Practice nurses have an important role in the provision of sexual health services in general practice. AIM: This study set out to determine practice nurses' reported practice and training in sexual health, attitudes towards sexual health, barriers to discussing sexual health with patients, and training needs. METHOD: A confidential self-administered postal questionnaire survey was sent to all 298 practice nurses in one English health district (Leicestershire). RESULTS: Completed questionnaires were returned by 234 practice nurses (response rate 79%). Most nurses routinely offered well-person checks (90%), cervical smears (89%), travel clinics (83%), saw women with genito-urinary symptoms (77%) and offered family planning advice (54%). Only a minority of nurses (13%) offered specific teenage health clinics. Sexual health issues were always discussed in a majority of consultations when giving family planning advice (65%) and in women with genito-urinary symptoms (58%). Most practice nurses (62%) had undertaken at least one course dealing with sexual health issues in the last 5 years. Uptake of training was, however, significantly lower in certain groups of nurses. An analysis of the attitude statements suggested that nurses were more comfortable discussing sexual health issues with female patients and teenagers than with male patients and those of different sexual orientations. Nurses who had received training reported more positive attitudes towards discussing sexual health issues with patients. CONCLUSION: Practice nurses offer a wide range of services in which the need to be able to take a sexual history and offer appropriate advice is important. There is scope to improve the provision of sexual health services by nurses in general practice, particularly in relation to services for teenagers.

Evidence-based guidelines for the management of genital chlamydial infection in general practice. (Leicestershire Chlamydia Guidelines Group).

BACKGROUND: Valid clinical guidelines can be effective in improving patient care. Genital Chlamydia trachomatis infection is the commonest curable sexually transmitted disease (STD) in England and Wales and is an important cause of pelvic inflammatory disease (PID), tubal infertility and ectopic pregnancy. No published guidelines exist on managing genital chlamydial infection in British general practice. OBJECTIVE: We aimed to develop valid guidelines for the management of genital chlamydial infection for use in British general practice. METHODS: A district-wide postal questionnaire survey was used to document current clinical practice. A critical review of the evidence concerning the management of genital chlamydial infection as it relates to British general practice was performed. The information gained from the critical review and survey was used to develop evidence-based guidelines within a multidisciplinary guideline recommendation group. RESULTS: The guidelines covered the diagnosis, investigation, drug treatment and referral of adult male and female patients with genital chlamydial infection in general practice. CONCLUSION: Valid guidelines for the management of genital chlamydial infection have been developed for use in British general practice. Appropriate dissemination and implementation of the guidelines should lead to earlier detection and treatment of men and women with chlamydial infection and thereby reduce the incidence of PID, tubal infertility and ectopic pregnancy in women.

The importance of sleep following ENT surgery.

This study reviewed a group of 48 children following ENT surgery and considered the implications of too little sleep after their operation. All the children had either an adenoidectomy, a tonsillectomy, or an adenotonsillectomy. Their post-operative sleep was timed and their state of nausea was recorded when they awoke. There appeared to be a correlation between the length of undisturbed sleep and the incidence of nausea or vomiting. It is suggested that this result should influence the advice given to parents of the benefits about sleep for their child in the post-operative period.

The morphologic and molecular genetic categories of posttransplantation lymphoproliferative disorders are clinically relevant.

BACKGROUND: Posttransplantation lymphoproliferative disorders (PT-LPDs) are a well-known complication of immunosuppression associated with solid organ transplantation. The clinical course of PT-LPDs is unpredictable; some patients experience regression of all lesions with a reduction in immunosuppression, whereas other patients, despite chemotherapy, radiation therapy, or surgery, rapidly die of their disease. In this study, the authors attempted to establish whether the previously described morphologic and molecular genetic categories of PT-LPD--plasmacytic hyperplasia (PH), polymorphic PT-LPD (polymorphic), and malignant lymphoma/multiple myeloma (ML/MM)--are clinically relevant and helpful in predicting the clinical outcome of patients who develop these lesions. METHODS: To determine the clinical significance of the morphologic and molecular genetic categories of PT-LPDs, the clinical characteristics of 32 solid organ transplant recipients (26 heart, 5 kidney, and 1 lung), including age, time from transplantation to development of PT-LPD, stage of disease, and clinical outcome, were compared with the morphologic and molecular genetic features of the 41 PT-LPDs that they developed (15 PH in 12 patients, 19 polymorphic in 16 patients, and 7 ML/MM in 6 patients). Clinical outcome was defined by the following categories: 1) regression (after a reduction in immunosuppression) and surgical resolution (by surgical excision, with or without a reduction in immunosuppression); 2) medical resolution (by chemotherapy and/or radiation therapy); and 3) no response. RESULTS: Although there was no difference in the time from transplantation to PT-LPD development among patients belonging to the three morphologic and molecular genetic categories, there was a significant difference in patient age at the time of PT-LPD development (P < 0.0098). Younger patients developed PH (mean age of 19 years), whereas older patients developed polymorphic PT-LPD (mean age of 35 years) and ML/MM (mean age of 56 years). Patients with PH presented with lower stages of disease (Stages I-II) than patients with ML/MM (P < 0.0004). Furthermore, there was a statistically significant trend between morphologic and molecular genetic category and clinical outcome, with decreased likelihood that lesions categorized as PH, polymorphic, or ML/MM would regress with a reduction in immunosuppression or be resolved by surgery, whereas those classified as ML/MM were more likely to exhibit no response to aggressive clinical intervention (P < 0.00006). Furthermore, no patients with PH died, whereas 20% with polymorphic PT-LPD and 67% with ML/MM died as a direct result of their PT-LPDs. CONCLUSIONS: This study strongly suggests that classification of PT-LPDs into the morphologic and molecular genetic categories PH, polymorphic, PT-LPD and ML/MM is clinically relevant.

Continuous infusion of prostacyclin normalizes plasma markers of endothelial cell injury and platelet aggregation in primary pulmonary hypertension.

BACKGROUND: Primary pulmonary hypertension (PPH) is characterized by vascular injury of pulmonary arterioles, in which endothelial dysfunction may play a major role. Although continuous infusion of prostacyclin (prostaglandin I2, a potent vasodilator released by vascular endothelial cells) improves the clinical status and survival in PPH, its mechanism or mechanisms of action remain unclear. METHODS AND RESULTS: We measured endothelium-derived clotting factors and assayed platelet aggregation in 64 patients (26 adults and 38 children) with PPH before long-term PGI2 therapy. Repeat studies were performed in 42 patients (18 adults, 24 children) after one year of PGI2 therapy. At baseline, 87% of adults and 79% of children had abnormal platelet aggregation. In addition, factor VIII, von Willebrand (vW) antigen, and ristocetin cofactor levels were abnormally high in 92%, 72%, and 52%, respectively, of the adults versus 29%, 16%, and 16%, respectively, of the children (P<.005 adults versus children). With long-term PGI2, platelet aggregation normalized in 83% of the adults and 80% of the children who had platelet aggregation abnormalities at baseline (P<.01). Factor VIII, vW antigen, and ristocetin cofactor also decreased with long-term PGI2 in both groups (P<.02). The ratio of ristocetin cofactor to vW antigen, which may reflect biological activity of vW factor, increased with long-term PGI2 in adults from an abnormally low level (0.6+/-0.2) to normal level (1.10+/-0.4), and in children the ratio increased from 0.8+/-0.3 to 1.3+/-0.4 (normal, 0.8 to 1.4). CONCLUSIONS: Alterations in the coagulation system may contribute to the pathogenesis of PPH; the normalization of these endothelial markers concomitant with improvement in hemodynamic parameters with long-term PGI2 suggests that long-term PGI2 remodels the pulmonary vascular bed with subsequent decreases in endothelial cell injury and hypercoagulability.

Proton pump inhibitors: new drugs and indications.

Proton pump inhibitors irreversibly inhibit the enzyme hydrogen-potassium adenosine triphosphatase (H(+)-K(+)-ATPase), which suppresses acid production in the parietal cell of the stomach. Omeprazole, the prototype proton pump inhibitor, has proved to be very effective. However, newer agents are being designed to provide even more potent acid suppression and longer-acting proton pump inhibition, with the goal of further controlling gastric hypersecretion. Lansoprazole is the second proton pump inhibitor available on the market. Pantoprazole is not yet available for general use in the United States. However, each of these drugs is slightly different from omeprazole, thus offering some possible clinical advantages. Compared with omeprazole, lansoprazole has a longer duration of action and improved activity against Helicobacter pylori, while pantoprazole has less interaction with the cytochrome P-450 system and more predictable bioavailability. All three agents have similarly high healing rates for acid peptic diseases and appear to be superior to histamine2-receptor antagonists.

Reduced preovulatory granulosa cell steroidogenesis in women with endometriosis.

To examine the cause of altered follicular fluid steroid levels and lower in vitro fertilization rate observed in infertile women with minor endometriosis, we have compared the production of estradiol (aromatase activity) and progesterone of freshly isolated granulosa cells (3h. incubation) from such women and a control group with tubal or unexplained infertility, having IVF during unstimulated or gonadotropin-stimulated cycles. As previously observed, mature oocytes from women with endometriosis had a reduced fertilization and cleavage rate in vitro in unstimulated cycles (19/37[51%] vs. 69/94[73%], p < 0.05) and stimulated cycles (20/37[57%] vs. 32/39[82%], p < 0.01). Median [95%CI] basal aromatase activity was lower in endometriosis compared with control in unstimulated cycles (2.84[2.03-3.49] pmol E2/10(3) cells/3h, n = 31 vs. 3.63[2.72-3.49], n = 55, p = 0.057) and stimulated cycles (0.31[0.16-0.50], n = 14 vs. 0.99[0.70-1.52], n = 20, p < 0.001). Progesterone production followed a similar pattern in unstimulated (0.56[0.50-0.89] pmol/10(3) cells/3h, n = 29 vs. 1.23[0.69-1.54], n = 52,) and stimulated (0.37[0.20-0.73], n = 16 vs. 0.95[0.72-1.17], n = 21) cycles (p < 0.05). Addition of FSH, LH or hCG (30ng/mL) to the incubation medium enhanced progesterone production 2 to 3-fold, but had no effect on aromatase activity. Our results indicate a defect in granulosa cell steroidogenesis associated with endometriosis, which could affect oocyte function and explain the reduction in fertilizing capacity and subsequent competence of the corpus luteum, and the associated subfertility.

ABL oncogene expression during erythroleukemia cell differentiation.

The translocation between chromosome 9 and chromosome 22 which creates the Philadelphia chromosome moves the ABL oncogene from its normal location on chromosome 9 and fuses it with a portion of the BCR gene on chromosome 22. This new BCR/ABL fusion gene generates a unique 8.7 kilobase (kb) RNA which codes for a new 210 kilodalton (kd, p210) protein which has a protein tyrosine kinase activity that is greatly increased in comparison to the normal ABL protein. The human K562 cell line was derived from a patient with CML, and serves as one model for the regulation of expression of the ABL and BCR/ABL genes. This study examines the expression of the BCR/ABL fusion gene and the normal ABL gene in relation to differentiation and changes in proliferative state. The expression of both the normal ABL transcripts and the BCR/ABL fusion transcript decrease approximately ten-fold when the cells are induced to differentiate with hemin. In contrast, expression of the MYC oncogene is unaffected by hemin-induced differentiation. The results suggest that both ABL and BCR/ABL expression vary in proportion to the differentiation of the cells, but minimally if at all as a function of the cells' proliferative state.

Chromatin alterations surrounding the BCR/ABL fusion gene in K562 cells.

Chronic myelogenous leukemia (CML) is characterized by the presence of a novel fusion gene comprised of portions of the BCR gene from chromosome (ch) 22 and the ABL gene from ch 9. The present study was designed to identify regulatory DNA regions as determined by DNAase I hypersensitivity to address the question of whether altered chromatin contributes to changes in ABL expression. We identify five hypersensitive (HS) sites within the abnormal BCR/ABL allele in K562 cells in a pattern different from the normal BCR. The pattern of hypersensitivity is modified when the cells undergo hemin induced differentiation. These results indicate that the normal BCR has a chromatin configuration consistent with active transcription and that the BCR/ABL fusion gene chromatin is different. This may be important in the pathogenesis of CML.