Human rabies postexposure prophylaxis and rabid terrestrial animals in Ontario, Canada: 2014-2016.

BACKGROUND: The number of rabid terrestrial animals in Ontario has decreased markedly since the 1970s and 1980s. However, the number of recommended rabies postexposure prophylaxis (RPEP) courses has not decreased proportionally. The decision to recommend RPEP for terrestrial animal exposures should be based on a risk assessment that considers the prevalence of rabies in these animals within a jurisdiction, among other factors. OBJECTIVE: To explore trends in RPEP recommendations for exposures to terrestrial animals in Ontario in relation to the recency of terrestrial animal rabies cases by public health unit (PHU) jurisdiction. METHODS: RPEP recommendation data for the 36 Ontario PHUs were obtained from the Ontario integrated Public Health Information System and animal rabies data by PHU were obtained from the Ministry of Natural Resources and Forestry. We calculated the annual RPEP recommendation rates for terrestrial animals by PHU for 2014 to 2016, and plotted the 2016 rates in relation to the year of the most recently identified rabid terrestrial animal in the PHU. RESULTS: Between 2014 and 2016, the annual RPEP recommendation rates for terrestrial animal exposures by PHU ranged from 3.0 to 35.2 per 100,000 persons, with a median of 11.9 RPEP recommendations per 100,000 persons. In 2016, ten PHUs had not identified a rabid terrestrial animal in their jurisdiction for more than15 years. Five of these PHUs had RPEP recommendation rates above the provincial median. CONCLUSION: Along with other factors, consideration of the occurrence of rabies in terrestrial animals in a jurisdiction can assist in the risk assessment of dogs, cats or ferrets that are not available for subsequent observation.

Treatment patterns and clinical outcomes in patients with renal cell carcinoma in the UK: insights from the RECCORD registry.

BACKGROUND: The aim of the RECCORD registry was to gather real-world UK data on the use of targeted therapies in renal cell carcinoma (RCC) and assess clinical outcomes. Here, demographic and outcome data are presented with the treatment patterns and demographic profile of patients on the registry. PATIENTS AND METHODS: Patients were retrospectively identified at seven UK hospitals with large cancer centres in England (5), Scotland (1) and Wales (1). Anonymised data were collected through an online registry covering demographics, treatments and outcomes. Five hundred and fourteen UK adult patients with metastatic RCC were included in the study for analysis. Patients were included if they were treated for metastatic RCC at one of the seven centres, and started systemic anti-cancer treatment from March 2009 to November 2012 inclusive. In addition to demographic factors, the principal outcome measures were overall survival (OS), time to disease progression and toxicity. RESULTS: The majority of first-line treatment was with sunitinib; first-line use of pazopanib increased as the study progressed. 15.8% of patients received second-line treatment, half of whom were prescribed everolimus. Median OS (from initiation of first-line treatment) was 23.9 months (95% confidence interval [CI] 18.6-29.1 months), similar to that reported for clinical trials of targeted RCC therapies [Ljungberg B, Campbell SC, Choi HY et al. The epidemiology of renal cell carcinoma. Eur Urol 2011; 60: 615-621; Abe H, Kamai T. Recent advances in the treatment of metastatic renal cell carcinoma. Int J Urol 2013; 20: 944-955; Motzer RJ, Hutson TE, Tomczak P et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009; 27: 3584-3590]. OS was significantly longer for those who received second-line treatment after disease progression (33.0 months; 95% CI 30.8-35.2 months) than those who did not (20.9 months; 95% CI 16.4-25.3 months; P = 0.008). CONCLUSIONS: RECCORD is a large 'real-world' database assessing metastatic RCC treatment patterns and outcomes. Treatment patterns changed over time as targeted therapies were approved and became widely available; survival data in RECCORD are consistent with those reported for systemic treatments in clinical trials. Kaplan-Meier analysis of results demonstrated that receiving second-line therapy was a major prognostic factor for longer OS.

An investigation of the radiation doses to the lower legs and feet of staff undertaking interventional procedures.

OBJECTIVE: Occupational radiation doses from fluoroscopic procedures are some of the highest doses of exposure amongst medical staff using radiography. Protective equipment and dose monitoring are used to minimize and control the risk from these occupational doses. Other studies have considered the effectiveness of this protection, but this study further considers whether protection is adequate for the lower leg and foot and the extent to which these doses can be reduced. METHODS: Scatter air kerma profiles at toe level were measured with an ionization chamber. Thermoluminescent dosemeters and lower extremity phantoms were used to estimate the dose variation with the height of patient couch. A 7-week period of in situ toe dose monitoring of four radiologists was also undertaken. RESULTS: The use of protective curtains effectively reduced the exposure to most of the lower extremities. Toe doses were found to be high and increased with increase in couch height. In situ monitoring indicated annual toe doses of 110 mSv for two of the four radiologists monitored. CONCLUSION: Protective curtains should be used, but they might have limitations with respect to toe doses. Annual toe doses approaching the classification threshold of 150 mSv were measured for two radiologists. Caution should be exercised when there is a gap below curtains and, when possible, staff should step back from the couch. Lower legs and toes should be included in local radiation protection programmes. ADVANCES IN KNOWLEDGE: Toe doses in interventional radiology may be higher than expected and may have to be included in radiation protection programmes.

Cochrane corner: ergonomic positioning or equipment for treating carpal tunnel syndrome.

BACKGROUND: Non-surgical treatments, including ergonomic positioning or equipment, are sometimes offered to people experiencing mild to moderate symptoms from carpal tunnel syndrome. The effectiveness and duration from ergonomic positioning or equipment interventions for treating carpal tunnel syndrome are unknown. OBJECTIVES: To assess the effects of ergonomic positioning compared with no treatment, a placebo or another non-surgical intervention in people with carpal tunnel syndrome. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (14 June 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (2011, Issue 2, in The Cochrane Library), MEDLINE (1966 to June 2011), EMBASE (1980 to June 2011), CINAHL Plus (1937 to June 2011), and AMED (1985 to June 2011). We also reviewed the reference lists of randomized or quasi-randomized trials identified from the electronic search. SELECTION CRITERIA: Randomized or quasi-randomized controlled trials comparing ergonomic positioning or equipment with no treatment, placebo or another non-surgical intervention in people with carpal tunnel syndrome. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, extracted data and assessed risk of bias of included studies. They calculated risk ratios and mean differences with 95% confidence intervals for the primary and secondary outcomes. Results of clinically and statistically homogeneous trials were pooled, where possible, to provide estimates of the effect of ergonomic positioning or equipment.

Sustained TL1A expression modulates effector and regulatory T-cell responses and drives intestinal goblet cell hyperplasia.

The tumor necrosis factor (TNF) superfamily protein TNF-like 1A (TL1A) is the ligand for death receptor 3 (DR3). TL1A is induced on activated dendritic cells (DCs) and its expression has been linked to human inflammatory bowel disease. To address how TL1A might influence intestinal inflammation, we generated transgenic mice that constitutively express TL1A on DCs. TL1A transgenic mice developed striking goblet cell hyperplasia in the ileum that was associated with elevated interleukin (IL)-13 levels in the small intestine. IL-13- and IL-17-producing small intestinal lamina propria T cells were increased in TL1A transgenic mice. TL1A also enhanced regulatory T (Treg) cell turnover in vivo and directly stimulated Treg cell proliferation in vitro. The presence of TL1A attenuated the ability of Treg cells to suppress conventional T cells, an effect that required DR3 signaling in either conventional T cells or Treg cells. Our findings identify mechanisms by which chronic DR3 signaling could promote pathogenesis in inflammatory bowel disease.

Comparison of the RSV respi-strip with direct fluorescent-antigen detection for diagnosis of respiratory syncytial virus infection in pediatric patients.

The RSV Respi-Strip was compared to the SimulFluor respiratory screen for detecting respiratory syncytial virus in nasopharyngeal aspirates from pediatric patients. Of samples tested, 115/239 (49%) were positive by direct fluorescent-antigen detection. The sensitivity and specificity of the RSV Respi-Strip were 92% (95% confidence interval [CI], 86% to 96%) and 98% (95% CI, 94% to 100%), respectively, with a diagnostic efficiency of 95%.

Disturbances in peripheral blood B cell subpopulations in autoimmune patients.

A variety of cell surface markers are being used to identify B cell subpopulations in peripheral blood. Currently at least eight subpopulations have been identified. Analyses of healthy individuals indicate that in general the various B cell subpopulations exist in relatively similar ratios in unrelated individuals. It has been demonstrated that B lymphocyte homeostasis is disturbed during infection and autoimmune disease. In this review we compare the distribution of B cell subpopulations in the peripheral blood of patients with systemic lupus erythematosus, rheumatoid arthritis and primary Sjogren's syndrome with each other, and with healthy individuals. The different autoimmune diseases have distinct changes in the B cell subpopulations. Understanding the nature of these B subpopulation signatures will potentially impact understanding the mechanisms of disease, diagnosis and therapy.

Tryptase-positive mast cells accompany lymphocytic as well as lymphoplasmacytic lymphoma infiltrates in bone marrow trephine biopsies.

AIMS: To investigate the specificity of increased bone marrow mast cell numbers in lymphoplasmacytic lymphoma (LPL) and to evaluate the relationship between mast cell number and the immunoglobulin phenotype of neoplastic lymphoid cells. METHODS AND RESULTS: Retrospective study of bone marrow trephine biopsy specimens from patients with LPL, compared with selected cases representing chronic lymphocytic leukaemia (CLL) and multiple myeloma (MM) of known immunoglobulin light and heavy chain phenotype. Bone marrow mast cells were counted following immunohistochemical staining of sections for mast cell tryptase. We have confirmed previous observations that mast cell numbers are increased in bone marrow infiltrates of LPL. However, we found similarly high mast cell numbers in CLL. High mast cell numbers were associated with neoplastic lymphoid cells expressing an IgM kappa phenotype. Mast cell numbers were low in all cases of MM studied and in controls with no lymphoma present. We observed an apparent bias towards kappa light chain expression in our cases of LPL. CONCLUSIONS: Mast cell number should not be considered a reliable factor in the differential diagnosis of LPL and CLL when assessing bone marrow histology. Possible bias towards kappa light chain expression in LPL requires further study, as do the mechanism and functions of mast cell recruitment by neoplastic lymphoid cells.

DNA fusion vaccine designed to induce cytotoxic T cell responses against defined peptide motifs: implications for cancer vaccines.

DNA vaccination offers a strategy to induce immune attack on cancer cells, but tumor Ags are often weak. Inclusion of a "foreign" protein increases immunogenicity, and we found previously that fusion of the fragment C (FrC) of tetanus toxin to the tumor Ag sequence promotes Ab and CD4(+) responses against B cell tumors. For CTL responses, use of the full two-domain FrC may be less helpful, because known immunogenic MHC class I-binding peptides in the second domain could compete with attached tumor-derived epitopes. Therefore, we removed the second domain, retaining the N-terminal domain, which contains a "universal" helper epitope. We investigated the ability to induce CTL responses of candidate peptides placed at the C terminus of this domain. As test peptides, we repositioned the two known CTL motifs from the second domain to this site. Strong CTL responses to each peptide were induced by the engineered construct, as compared with the native FrC construct. Induced CTLs were able to specifically kill tumor cells transfected with FrC as a surrogate tumor Ag both in vitro and in vivo. Further reduction of the domain to a short helper epitope generated only weak CTL responses against fused peptides, and synthetic peptides mixed with the plasmid containing the first domain were ineffective. The single FrC domain-peptide vaccine design also was able to induce high levels of CTLs against a known epitope from carcinoembryonic Ag. Response to peptide was suppressed if two FrC domains were present, consistent with immunodominance. These principles and designs may have relevance for cancer vaccines delivered via DNA.

Postoperative adhesions: ten-year follow-up of 12,584 patients undergoing lower abdominal surgery.

PURPOSE: Postoperative adhesions are a significant problem after colorectal surgery. However, the basic epidemiology and clinical burden are unknown. The Surgical and Clinical Adhesions Research Study has investigated the scale of the problem in a population of 5 million. METHODS: Validated data from the Scottish National Health Service Medical Record Linkage Database were used to define a cohort of 12,584 patients undergoing open lower abdominal surgery in 1986. Readmissions for potential adhesion-related disease in the subsequent ten years were analyzed. The methodology was conservative in interpreting adhesion-related disease. RESULTS: In the study cohort 32.6 percent of patients were readmitted a mean of 2.2 times in the subsequent ten years for a potential adhesion-related problem. Although 25.4 percent of readmissions were in the first postoperative year, they continued steadily throughout the study period. After open lower abdominal surgery 7.3 percent (643) of readmissions (8,861) were directly related to adhesions. This varied according to operation site: colon (7.1 percent), rectum (8.8 percent), and small intestine (7.6 percent). The readmission rate was assessed to provide an indicator of relative risk of adhesion-related problems after initial surgery. The overall average rate of readmissions was 70.4 per 100 initial operations, with 5.1 directly related to adhesions. This rose to 116.4 and 116.5, respectively, after colonic or rectal surgery-with 8.2 and 10.3 directly related to adhesions. CONCLUSIONS: There is a high relative risk of adhesion-related problems after open lower abdominal surgery and a correspondingly high workload associated with these readmissions. This is influenced by the initial site of surgery, colon and rectum having both the greatest impact on workload and highest relative risk of directly adhesion-related problems. The study provides sound justification for improved adhesion prevention strategies.

The impact of adhesions on hospital readmissions over ten years after 8849 open gynaecological operations: an assessment from the Surgical and Clinical Adhesions Research Study.

OBJECTIVE: To investigate the epidemiology of, and the clinical burden related to, adhesions following gynaecological surgery. POPULATION: The Scottish National Health Service Medical Record Linkage Database was used to define a cohort of 8849 women undergoing open gynaecological surgery in 1986. METHODS: All readmissions for potential adhesion related disease in the subsequent 10 years were reviewed. MAIN OUTCOME MEASURES: Readmissions and the degree of adhesion involvement gave an indication of clinical burden and workload. The rate of readmission following the initial surgery determined the relative risk of disease related to adhesions. RESULTS: Two hundred and forty-five (4.5%) of 5433 readmissions following open gynaecological surgery were directly related to adhesions. 34.5% of patients were readmitted, on average 1.9 times, for a problem potentially related to adhesions or for further intra-abdominal surgery that could be complicated by adhesions. Readmissions related to adhesions continued throughout the 10 year period of the study. The overall rate of readmission was 64.0/100 initial operations. For readmissions directly related to adhesions, the rate was 2.9/100 initial operations. Operations on the ovary had the highest rate directly related to adhesions (7.5/100 initial operations), with an overall rate of readmission of 106.4/100 initial operations. CONCLUSIONS: Despite the conservative approach taken in this study, the clinical burden, workload and relative risk of readmissions related to adhesions following open gynaecological surgery was considerable. Post-operative adhesions have important consequences for patients, surgeons and the healthcare system. These results emphasise the need for more effective strategies to prevent adhesions.

Outcome of lamivudine resistant hepatitis B virus infection in the liver transplant recipient.

BACKGROUND: In many transplant centres lamivudine is an important component of prophylaxis against, and treatment of, hepatitis B virus (HBV) graft infection. Drug resistant HBV species with specific polymerase mutations may emerge during lamivudine treatment. AIMS: To examine the clinical consequences of graft infection by lamivudine resistant virus. METHODS: The clinical course of four liver transplant patients who developed graft infection with lamivudine resistant virus was reviewed. The response of HBV infection to reduction of immunosuppression and to manipulation of antiviral therapy was assessed. For each patient, serum viral titre was measured and the viral polymerase gene was sequenced at multiple time points. RESULTS: High serum titres were observed following emergence of the lamivudine resistant species. Wild type HBV re-emerged as the dominant serum species after lamivudine withdrawal. All patients developed liver failure, and onset of liver dysfunction was observed when resistant virus was the dominant serum species. In three patients, liver recovery was observed when immunosuppression was stopped and when alternative antivirals were given. Wild type virus appeared to respond to ganciclovir, and to reintroduction of lamivudine. For one patient, introduction of famciclovir was associated with clinical, virological, and histological response. CONCLUSIONS: Failure of lamivudine prophylaxis may identify patients at special risk for the development of severe graft infection. Treatment of graft reinfection should include reduction of immunosuppression, and systematic exposure to alternative antivirals. Viral quantitation and genetic sequencing are essential components of therapeutic monitoring.

Human papillomavirus type 16 and 18 detection in the management of mild dyskaryosis.

OBJECTIVE: To determine if semi-quantitative human papillomavirus (HPV) types 16 and 18 detection by polymerase chain reaction can increase the sensitivity and specificity of repeat cytology alone for underlying high grade cervical intraepithelial neoplasia (CIN). DESIGN: Prospective randomised study of immediate treatment and surveillance. SETTING: A dedicated colposcopy clinic serving a regional population. SAMPLE: Three hundred and four women with smears reported as mild dyskaryosis. METHODS: Repeat cytology, HPV 16 and 18 tests, and colposcopy were performed at study entry. Women were randomised to either immediate treatment or surveillance with repeated tests at 6 and 12 months. Unless all study smears were negative, women were treated at study exit by large loop excision of the transformation zone. MAIN OUTCOME MEASURES: Sensitivity and specificity of HPV testing for types 16 and 18 in conjunction with cytology for high grade CIN. RESULTS: Combining repeat cytology with HPV 16 and 18 testing had a sensitivity of 94% and a specificity of 26%, a positive predictive value of 71%, and a negative predictive value of 71%, for underlying high grade CIN. If used to secondary screen in conjunction with repeat cytology for mild dyskaryosis, 88% of women would have been referred for colposcopy on the basis of either test being positive. CONCLUSION: Combining repeat cytology and HPV 16 and 18 detection would result in the majority of women being referred for immediate colposcopy. Taken with an overall default rate of 17%, immediate referral of all women with mild dyskaryosis for colposcopic assessment still appears to be a more effective clinical strategy.

Adhesion-related hospital readmissions after abdominal and pelvic surgery: a retrospective cohort study.

BACKGROUND: Adhesions after abdominal and pelvic surgery are important complications, although their basic epidemiology is unclear. We investigated the frequency of such complications in the general population to provide a basis for the targeting and assessment of new adhesion-prevention measures. METHODS: We used validated data from the Scottish National Health Service medical record linkage database to identify patients undergoing open abdominal or pelvic surgery in 1986, who had no record of such surgery in the preceding 5 years. Patients were followed up for 10 years and subsequent readmissions were reviewed and outcomes classified by the degree of adhesion. We also assessed the rate of adhesion-related admissions in 1994 for the population of 5 million people. FINDINGS: 1209 (5.7%) of all readmissions (21,347) were classified as being directly related to adhesions, with 1169 (3.8%) managed operatively. Overall, 34.6% of the 29,790 patients who underwent open abdominal or pelvic surgery in 1986 were readmitted a mean of 2.1 times over 10 years for a disorder directly or possibly related to adhesions, or for abdominal or pelvic surgery that could be potentially complicated by adhesions. 22.1% of all outcome readmissions occurred in the first year after initial surgery, but readmissions continued steadily throughout the 10-year period. In 1994, 4199 admissions were directly related to adhesions. INTERPRETATION: Postoperative adhesions have important consequences to patients, surgeons, and the health system. Surgical procedures with a high risk of adhesion-related complications need to be identified and adhesion prevention carefully assessed.

High pre-treatment serum hepatitis B virus titre predicts failure of lamivudine prophylaxis and graft re-infection after liver transplantation.

BACKGROUND/AIMS: Orthotopic liver transplantation has an established role for the treatment of patients with chronic liver failure secondary to hepatitis B virus (HBV) infection. Unfortunately, recurrent infection of the graft can be associated with aggressive disease, and with diminished graft and patient survival. Currently, the role of nucleoside analogues for prevention of graft re-infection is being evaluated. Preliminary results are encouraging, but treatment failure has been associated with emergence of drug-resistant virus. METHODS: We have studied ten consecutive patients who received lamivudine prophylaxis for prevention of HBV graft reinfection. Sequential sera, collected prelamivudine then during treatment before and after liver transplantation, were examined. Conventional serological markers were measured, as were serum viral DNA levels with a sensitive quantitative polymerase chain reaction assay. RESULTS: Lamivudine treatment effected a reduction in serum HBV levels, but six patients still had measurable viral DNA at the time of transplantation. Five patients developed graft re-infection with lamivudine-resistant virus. Resistant virus emerged 8 to 15 months post-transplant. The likelihood of emergence of resistant virus was related to the pre-treatment serum HBV titre. Persistent serum viral DNA positivity and evidence of graft re-infection during the early post-transplant period did not predict the subsequent emergence of resistant virus. CONCLUSIONS: Our observations suggest that the resistant species may be present in the viral quasispecies in the serum and liver of patients with high-level replication prior to lamivudine exposure. The resistant species can persist during lamivudine treatment prior to transplantation, and emerge following transplantation. These observations suggest strategies which might prevent the emergence of drug-resistant species, and imply that graft re-infection may be a preventable phenomenon.

Platelet adherence and detachment: a flow study with a series of hydroxyethyl methacrylate-ethyl methacrylate copolymers using video microscopy.

The adhesion and detachment of platelets were studied on glass coatings of a series of copolymers of hydroxyethyl methacrylate (HEMA) and ethyl methacrylate (EMA). Observations of the interactions of mepacrine labelled washed platelets with these surfaces from a flowing (500 s-1 wall shear rate) suspension in Tyrode's solution containing albumin and red cells were made with epifluorescent video microscopy (EVM). Total platelet adhesion, including platelets which adhere on first contact and platelets which attach temporarily before adhesion, and the number of detaching platelets were minimal for the 0 and 20% EMA copolymers, reached a maximum for the 50% EMA copolymer and showed reduced values for the 80% and 100% EMA copolymers. For the 50, 80, and 100% EMA copolymers, the adhesion values expressed, as a percentage of total contacting platelets, were not different. Albumin adsorption to these copolymers shows a continuous increase from the 0% to the 100% EMA copolymer. It is likely that the peak in platelet adhesion at the 50% EMA composition is related to: low protein adsorption on the 0 and 20% EMA copolymers, too little albumin adsorption to block adhesion on the 50% EMA copolymer, and full-scale blocking on the 80 and 100% EMA copolymers due to greater albumin adsorption.

Aluminium leaching and fluoride.

Aluminium leaching from cooking utensils is a source of dietary aluminium and there are differing reports in the literature concerning the effects of fluoride ions on aluminium leaching. This paper reports that aluminium leaching may be increased by around 5% when fluoride ion at 1 mg/litre is present. More dramatic increases in aluminium leaching occur if the fluoride ion concentration is increased to 20 mg/litre, but this would rarely, if ever, be found in a culinary situation. At fluoride ion concentrations likely to be encountered in cooking, the increased leaching due to fluoride is very small in relation to the effects of pH on aluminium leaching.