Poor outcomes after whole brain radiotherapy in patients with brain metastases: results from an international multicentre cohort study.

AIMS: To describe the characteristics and outcomes of cancer patients receiving Whole Brain Radiotherapy (WBRT) and delineate poor outcome groups after WBRT. MATERIALS AND METHODS: From 1991 to 2007, 3459 patients receiving WBRT for brain metastases at three centres (in Australia and the Netherlands) were retrospectively reviewed. The effect of clinicodemographic factors, including age, gender, primary cancer, time to WBRT from primary cancer diagnosis and WBRT timing relative to other radiotherapy courses on overall survival, survival from WBRT commencement (WBRT-SV) and death within 6 weeks were analysed. RESULTS: WBRT was the first radiotherapy course in 2161/3459 (63%) and the last in 2932/3459 (85%). The most common primary cancer sites with brain metastases were lung (n = 1800; 52%), breast (n = 568; 16%), melanoma (n = 350; 10%) and colorectal (n = 209; 6%). The median time to WBRT from primary cancer diagnosis was 34 weeks, overall survival 1.42 years (0.04-28.70) and WBRT-SV 0.33 years (0-8.60). Older age, male gender and a shorter time from the primary cancer diagnosis to WBRT predicted worse overall survival and WBRT-SV. Seventeen per cent survived less than 6 weeks. Older patients with a shorter time from the primary cancer diagnosis to WBRT and a lower WBRT episode number were more likely to die less than 6 weeks after WBRT. CONCLUSIONS: Cancer patients with brain metastases have poor overall outcomes. High mortality within 6 weeks of starting WBRT suggests patient selection remains challenging.

The oral health status, practices and knowledge of pregnant women in south-western Sydney.

BACKGROUND: Current evidence highlights the importance of oral health during pregnancy. However, little is known about the oral health of pregnant women in Australia. The aim of this study was to report the oral health status, knowledge and practices of pregnant women in south-western Sydney. METHODS: A cross-sectional survey of 241 pregnant women attending a large hospital in south-western Sydney. RESULTS: More than half (59.3%) reported dental problems during pregnancy, less than a third (30.5%) saw a dentist in the last six months, only 10% had received any information about perinatal oral health and many (>50%) were unaware of the potential impact of poor maternal oral health on pregnancy and infant outcomes. Analysis revealed a significant difference (<0.05) in the uptake of dental services among pregnant women who had higher household incomes, private health insurance, received information about perinatal oral health and knowledge about maternal oral health. CONCLUSIONS: The participants reported significant barriers to obtaining dental care including limited access to affordable dental services and lack of awareness about the importance of maternal oral health. The findings suggest the need for preventive strategies involving dentists and antenatal providers to improve maternal oral health in Australia.

Mesh fixation with fibrin sealant during endoscopic totally extraperitoneal inguinal hernia approach: a review of 640 repairs.

PURPOSE: Endoscopic repair of inguinal hernia can decrease the incidence of chronic groin pain. Staple mesh fixation is the surgical technique preferentially used but may also cause residual pain. Although a substantial number of specialists advocate no mesh fixations, concerns are that this could lead to an increase in recurrence rates. This study aimed to assess the safety and the effectiveness of fibrin sealant, as an alternative technique to staple mesh fixation after totally extraperitoneal (TEP) inguinal hernia repair. METHODS: A total of 472 patients underwent elective TEP inguinal hernia repair between February 2005 and July 2011. Mesh fixation was achieved using fibrin sealant. Patients were reviewed postoperatively at Week 2, Week 6, and Month 6. Patient satisfaction was assessed in a subgroup of 116 patients using a comprehensive scoring system designed for hernia repairs, and pain was assessed using a standard Visual Analog pain Scale. RESULTS: No conversion to open surgery was observed. There were two cases of major morbidities and no mortality. Three months after surgery, only three patients (0.6 %) experienced chronic groin or testicular discomfort. At Week 6, 98.9 % of the patients were either satisfied or very satisfied with their outcome, and 96.8 % denied any residual pain. Finally, only six hernia recurrences (0.9 %) were reported, of which five occurred during the first months of the study. CONCLUSIONS: Fibrin sealant is safe and reliable for mesh fixation of inguinal hernia during TEP repair with a very high satisfaction index and limited risk of developing chronic pain.

Towards an ontology for data quality in integrated chronic disease management: a realist review of the literature.

PURPOSE: Effective use of routine data to support integrated chronic disease management (CDM) and population health is dependent on underlying data quality (DQ) and, for cross system use of data, semantic interoperability. An ontological approach to DQ is a potential solution but research in this area is limited and fragmented. OBJECTIVE: Identify mechanisms, including ontologies, to manage DQ in integrated CDM and whether improved DQ will better measure health outcomes. METHODS: A realist review of English language studies (January 2001-March 2011) which addressed data quality, used ontology-based approaches and is relevant to CDM. RESULTS: We screened 245 papers, excluded 26 duplicates, 135 on abstract review and 31 on full-text review; leaving 61 papers for critical appraisal. Of the 33 papers that examined ontologies in chronic disease management, 13 defined data quality and 15 used ontologies for DQ. Most saw DQ as a multidimensional construct, the most used dimensions being completeness, accuracy, correctness, consistency and timeliness. The majority of studies reported tool design and development (80%), implementation (23%), and descriptive evaluations (15%). Ontological approaches were used to address semantic interoperability, decision support, flexibility of information management and integration/linkage, and complexity of information models. CONCLUSION: DQ lacks a consensus conceptual framework and definition. DQ and ontological research is relatively immature with little rigorous evaluation studies published. Ontology-based applications could support automated processes to address DQ and semantic interoperability in repositories of routinely collected data to deliver integrated CDM. We advocate moving to ontology-based design of information systems to enable more reliable use of routine data to measure health mechanisms and impacts.

Measuring perinatal mental health risk.

The purpose of this review was to critically analyse existing tools to measure perinatal mental health risk and report on the psychometric properties of the various approaches using defined criteria. An initial literature search revealed 379 papers, from which 21 papers relating to ten instruments were included in the final review. A further four papers were identified from experts (one excluded) in the field. The psychometric properties of six multidimensional tools and/or criteria were assessed. None of the instruments met all of the requirements of the psychometric properties defined. Some had used large sample sizes but reported low positive predictive values (Antenatal Risk Questionnaire (ANRQ)) or insufficient information regarding their clinical performance (Antenatal Routine Psychosocial Assessment (ARPA)), while others had insufficient sample sizes (Antenatal Psychosocial Health Assessment Tool, Camberwell Assessment of Need-Mothers and Contextual Assessment of Maternity Experience). The ANRQ has fulfilled the requirements of this analysis more comprehensively than any other instrument examined based on the defined rating criteria. While it is desirable to recommend a tool for clinical practice, it is important that clinicians are made aware of their limitations. The ANRQ and ARPA represent multidimensional instruments commonly used within Australia, developed within large samples with either cutoff scores or numbers of risk factors related to service outcomes. Clinicians can use these tools, within the limitations presented here, to determine the need for further intervention or to refer women to mental health services. However, the effectiveness of routine perinatal psychosocial assessment continues to be debated, with further research required.

Assessing the influences on therapeutic intensification in type 2 diabetes mellitus according to career stage.

AIM: This study was designed to document the factors influencing therapeutic decisions in the management of diabetes in relation to stage of medical career. METHODS: An anonymous survey was distributed among medical students, resident medical officers (RMOs) and general practitioners (GPs) presenting a hypothetical case of a 58 year old patient with sub-optimally controlled diabetes on metfomin and gliclazide. Participants were then asked for their next step in management and about factors that would influence their decision-making. RESULTS: GPs (n=72) were most likely to add pioglitazone (33.3%). RMOs (n=42) were more likely to add insulin (47.6%, p<0.01 vs. GPs). Medical students (n=40) were more likely to review diet and observe (42.5%, p<0.01 vs. GPs). Significant differences were observed between the 3 groups in what influenced their choice of therapy. GPs were most likely to take into account patient related factors such as patient's motivation to improve glycaemic control. CONCLUSION: GPs were less likely to initiate insulin therapy, and our results suggest that this may be due to their greater awareness of patient related barriers to commencing insulin. These results justify support for continuing medical education of GPs that focuses on evidence based guidelines.

Association between SEN virus infection and hepatitis C in Japan.

There is a strong association between 2 SEN virus (SENV) variants (SENV-D and SENV-H) and transfusion-associated non-A-E hepatitis. In total, 200 subjects from a Japanese region where hepatitis C virus (HCV) is highly endemic and 194 persons from a contiguous area where HCV is not endemic were tested for SENV-D and SENV-H DNA by polymerase chain reaction. SENV DNA was detected equally in subjects from each area (56% prevalence in the area of high endemicity vs. 61% in the nonendemic area). Age-specific prevalence of SENV was similar to that of TT virus, with equal distribution at all ages in both areas; HCV was predominant in the elderly population. Alanine aminotransferase levels were significantly associated with HCV viremia but not with SENV viremia. SENV is a common infection that appears to have transmission routes and age-related prevalence that are distinct from those of HCV. No evidence was found that SENV caused hepatitis or worsened the course of hepatitis C.

Stability of HCV-RNA level and its lack of correlation with disease severity in asymptomatic chronic hepatitis C virus carriers.

This study examines the relationship between HCV-RNA levels and disease severity in 60 individuals with chronic hepatitis C virus infection. HCV-RNA levels were quantified by the branched DNA (bDNA) assay in 445 samples (median: eight samples per patient) obtained over a median of 40.4 months (95% confidence interval (CI): 37.0-42.5). The median log HCV-RNA level was 6.77 (95% CI: 6.62-6.92) molecular equivalents/mL (MEQ/mL). The median log range of HCV-RNA levels in individual patients over the course of the study was 0.89 (95% CI: 0.69-1.16). HCV-RNA level varied over time by less than one log in 62% of patients, by 1-1.5 logs in 22% and by greater than 1.5 logs in only 17%. Univariate analysis, revealed an inverse association between HCV-RNA levels and ALT levels (P=0.037). Univariate and logistic regression analysis showed no significant association between HCV-RNA levels and either the degree of inflammation or fibrosis. In contrast, there was a significant positive association between alanine aminotransferase (ALT) levels and histological activity especially in individuals with ALTs> 100 IU/L. Hence, HCV-RNA levels: (i) almost always fell within the dynamic range of the bDNA assay; (ii) were stable in asymptomatic chronically infected patients, with only a small proportion of patients exceeding a range of 1.5 logs; (iii) did not correlate with either the extent of inflammation or degree of fibrosis. In contrast, there was a strong association between ALT level and the histological severity of liver disease.

SEN virus infection and its relationship to transfusion-associated hepatitis.

SEN virus (SEN-V) is a recently identified single-stranded, circular DNA virus. Two SEN-V variants (SENV-D and SENV-H) were assayed by polymerase chain reaction (PCR) to investigate their role in the causation of transfusion-associated non-A to E hepatitis. The incidence of SEN-V infection after transfusion was 30% (86 of 286) compared with 3% (3 of 97) among nontransfused controls (P < .001). Transfusion risk increased with the number of units transfused (P < .0001) and donor-recipient linkage for SEN-V was shown by sequence homology. The prevalence of SEN-V in 436 volunteer donors was 1.8%. Among patients with transfusion-associated non-A to E hepatitis, 11 of 12 (92%) were infected with SEN-V at the time of transfusion compared with 55 of 225 (24%) identically followed recipients who did not develop hepatitis (P < .001). No effect of SEN-V on the severity or persistence of coexistent hepatitis C virus (HCV) infection was observed. In 31 infected recipients, SEN-V persisted for greater than 1 year in 45% and for up to 12 years in 13%. SEN-V-specific RNA (a possible replicative intermediate) was recovered from liver tissue. In summary, SENV-D and -H were present in nearly 2% of US donors, and were unequivocally transmitted by transfusion and frequently persisted. The strong association of SEN-V with transfusion-associated non-A to E hepatitis compared with controls raises the possibility, but does not establish that SEN-V might be a causative agent of posttransfusion hepatitis. The vast majority of SEN-V-infected recipients did not develop hepatitis.

Genomic and molecular evolutionary analysis of a newly identified infectious agent (SEN virus) and its relationship to the TT virus family.

A new group of transmissible single-stranded (ss) DNA viruses (SENV) distantly related to the large TT virus (TTV) family was recently identified. Eight different SENV isolates have been found, some with an association with posttransfusion hepatitis. A phylogenetic analysis of near-complete open-reading frame 1, including conserved motifs and excluding recombinant regions, was performed. The analysis used TTV-like minivirus as an outgroup, to determine a root of the phylogenetic tree, and compared 8 SENV isolates, 6 prototype TTV isolates, and 7 TTV variants (including SANBAN, TUS01, PMV, and YONBAN). Four distinct clusters separated by a bootstrap value of 100% were observed. YONBAN isolates formed a distinct outer group, representing the earliest recognized phylogenetic divergence (group 1). Prototype TTV formed group 2, PMV formed group 3, and SENV, SANBAN, and TUS01 isolates formed group 4, the most recently evolved group. This taxonomic classification suggests that these circular ssDNA viruses probably evolved from a common ancestor virus.

Effect of hepatitis G virus infection on progression of HIV infection in patients with hemophilia. Multicenter Hemophilia Cohort Study.

BACKGROUND: Infection with hepatitis G virus (HGV), also known as GB virus C, is prevalent but is not known to be associated with any chronic disease. Infection with HGV may affect the risk for AIDS in HIV-infected persons. OBJECTIVE: To compare AIDS-free survival in patients with and those without HGV infection during 16 years of follow-up after HIV seroconversion. DESIGN: Subanalysis of a prospective cohort study. SETTING: Comprehensive hemophilia treatment centers in the United States and Europe. PATIENTS: 131 patients with hemophilia who became HIV-positive between 1978 and 1985. MEASUREMENTS: Age, CCR5 genotype, HIV and HCV viral loads, CD4+ and CD8+ lymphocyte counts, and 12-year AIDS-free survival by HGV positivity (viremia [RNA] or anti-E2 antibodies). RESULTS: Compared with HGV-negative patients, the 60 HGV-positive patients (46%), including 22 who were positive for HGV RNA, had higher CD4+ lymphocyte counts (difference, 211 cells/mm3 [95% Cl, 88 to 333 cells/mm3]) and 12-year AIDS-free survival rates (68% compared with 40%; rate difference, 1.9 per 100 person-years [Cl, -0.3 to 4.2 per 100 person-years]), despite similar ages and HIV viral loads. In multivariate proportional hazards models, risk for AIDS was 40% lower for HGV-positive patients independent of age, HIV and HCV viral loads, CD4+ and CD8+ lymphocyte counts, and CCR5 genotype. CONCLUSIONS: Patients with past or current HGV infection have higher CD4+ lymphocyte counts and better AIDS-free survival rates. The mechanism of this association is unknown.

Prevalence of hepatitis G virus in patients with hemophilia and their steady female sexual partners.

BACKGROUND: Hepatitis G virus (HGV), also known as GB virus C, is a newly discovered Flavivirus that is transmissible by blood transfusion and other possible routes. OBJECTIVE: To study the risk of sexual transmission of HGV in female sexual partners of men with hemophilia (n = 161 couples). METHODS: Blood samples obtained from 11 medical centers were analyzed for (1) HGV RNA by polymerase chain reaction; (2) antibodies to HGV by enzyme immunoassay; and (3) other viruses and T-cell counts by routine laboratory tests. Subjects completed a questionnaire that assessed sexual intercourse frequency, number of sexual partners, condom usage, sexually transmitted diseases, illicit drug usage, and needlestick or broken-glass injuries. RESULTS: The HGV infection (RNA +/- antibody positive) prevalence was 48% among men and 21% among women. Prevalence of hepatitis C virus, hepatitis B virus, and HIV among men was 99%, 94%, and 86%, compared with 3%, 11%, and 12% among women, respectively. The odds ratio for HGV infection for women with an HGV-positive male sexual partner was 2.14 (P = 0.06) without adjustment, and 2.77 (P = 0.03) with adjustment for other variables, none of which were independently significant. CONCLUSION: These results suggest a low level of HGV sexual transmission.

Transfusion-associated TT virus infection and its relationship to liver disease.

TT virus (TTV) has been proposed as the causative agent of non-A to E hepatitis. We studied the association between TTV viremia and biochemical evidence of hepatitis in blood donors and prospectively-followed patients. TTV was found in 7.5% of 402 donors and in 11.0% of 347 patients before transfusion. The rate of new TTV infections was 4.7% in 127 nontransfused, and 26.4% in 182 transfused patients (P <.0001). The risk of infection increased with the number of units transfused (P <.0001). The rate of new TTV infections in 13 patients with non-A to E hepatitis (23.2%) was almost identical to the rate in 124 patients who were transfused, but did not develop hepatitis (21.8%). Of 45 patients with acute hepatitis C, 40.0% were simultaneously infected with TTV. TTV did not worsen the biochemical severity (mean ALT: 537 in TTV+; 550 in TTV-) or persistence of hepatitis C. In non-A to E cases, the mean ALT was 182 in those TTV-positive and 302 in TTV-negatives. No consistent relationship between alanine transaminase level and TTV DNA level was observed in 4 patients with long-term, sequential samples. Of 21 viremic subjects, 67% cleared TTV within 5 years (38% in 1 year); 33% were viremic throughout follow-up extending to 22 years. We conclude that TTV is a very common, often persistent infection that is transmitted by transfusion and by undefined nosocomial routes. We found no association between TTV and non-A to E hepatitis and no effect of TTV on the severity or duration of coexistent hepatitis C. TTV may not be a primary hepatitis virus.

Indirect inhibition by antibiotics of nucleotide and deoxynucleotide biosynthesis in Plasmodium falciparum.

The effects of the antibiotics, doxycycline, azithromycin, ciprofloxacin and chloramphenicol, upon levels of nucleoside-5'-triphosphates (NTPs) and 2'-deoxynucleoside-5'-triphosphates (dNTPs) have been compared in the malarial parasite, Plasmodium falciparum, and in human CCRF-CEM leukemia cells. All 4 antibiotics had more severe effects upon levels of NTPs and dNTPs in P. falciparum compared with leukemia cells providing an explanation for their selective toxicity against malaria and their utility as antimalarial drugs. In bacteria, the first 3 drugs inhibit protein synthesis while ciprofloxacin inhibits topoisomerase II. The observed depletions of NTPs and dNTPs would be a secondary effect of the drug but may result in death of the parasite.

Antimalaria activity of the triple combination of proguanil, atovaquone and dapsone.

The combination of proguanil and atovaquone has been shown to be more effective in curing drug-resistant infections of falciparum malaria than atovaquone or proguanil alone. Our current study sought to determine whether the antimalaria activity could be increased by adding dapsone. Plasma samples, obtained from individuals 4-72 h after proguanil-atovaquone administration, were 2-3 times more active against Plasmodium falciparum in vitro when dapsone was added to them. The enhanced activity of the combination of proguanil, atovaquone and dapsone is probably due to the combined activity of two synergistic combinations: proguanil-atovaquone and cycloguanil (metabolite of proguanil)-dapsone. These findings suggest that further studies are needed to evaluate the clinical value of the triple drug combination of proguanil, atovaquone and dapsone in the treatment of multi-drug resistant malaria.

Ex vivo antimalarial activity of proguanil combined with dapsone against cycloguanil-resistant Plasmodium falciparum isolates.

The ex vivo antimalarial activity of plasma samples obtained from 20 healthy Caucasian volunteers following daily proguanil (200 mg) plus dapsone (8 mg) for malaria chemoprophylaxis inhibited five cycloguanil-resistant Thai isolates of Plasmodium falciparum. All volunteers were phenotyped as extensive metabolisers (EMs) of proguanil. Three of the five isolates were obtained from Thai soldiers who had failed malaria prophylaxis on daily proguanil (200 mg) plus dapsone (4.0 or 12.5 mg). The Thai soldiers were also classified as EMs, but had relatively lower plasma cycloguanil concentrations compared to values reported in the literature for Caucasians and black Kenyans. Although the high level of parasite resistance to cycloguanil was the most likely explanation for the Thai soldiers failing prophylaxis on proguanil plus dapsone, their low cycloguanil concentrations may have also contributed to their lack of protection. However, in areas where parasites are more susceptible to cycloguanil, such as in certain regions of Africa, proguanil plus dapsone may still be an effective chemoprophylactic drug combination.

Direct comparison of antimalarial activity among PS-15 combination therapies by bioassay of serum samples from treated Saimiri sciureus.

Sixteen Saimiri sciureus monkeys were administered PS-15-atovaquone, PS-15-sulfamethoxazole, PS-15-dapsone, PS-15 alone, and atovaquone alone. The in vitro antimalarial activity of serum against Plasmodium falciparum obtained from these monkeys at 3, 6, and 12 hr after the administration of drug(s) were measured by bioassay and analyzed by Duncan's and Newman-Keul's tests. PS-15-atovaquone was found to be the most effective antimalarial combination, followed by PS-15-sulfamethoxazole, PS-15-dapsone, PS-15 alone, and atovaquone alone. These dual PS-15 combinations are effective combinations and, in-particular, PS-15-atovaquone is worthy of further evaluation.