Stability of a Novel PEGylation Site on a Putative Haemoglobin-Based Oxygen Carrier.

PEGylation of protein sulfhydryl residues is a common method used to create a stable drug conjugate to enhance vascular retention times. We recently created a putative haemoglobin-based oxygen carrier using maleimide-PEG to selectively modify a single engineered cysteine residue in the α subunit (αAla19Cys). However, maleimide-PEG adducts are subject to deconjugation via retro-Michael reactions, with consequent cross-conjugation to endogenous plasma thiols such as those found on human serum albumin or glutathione. In previous studies mono-sulfone-PEG adducts have been shown to be less susceptible to deconjugation. We therefore compared the stability of our maleimide-PEG Hb adduct with one created using a mono-sulfone PEG. The corresponding mono-sulfone-PEG adduct was significantly more stable when incubated at 37 °C for 7 days in the presence of 1 mM reduced glutathione, 20 mg/mL human serum albumin, or human serum. In all cases haemoglobin treated with mono-sulfone-PEG retained >90% of its conjugation whereas maleimide-PEG showed significant deconjugation, especially in the presence of 1 mM reduced glutathione where <70% of the maleimide-PEG conjugate remained intact. Although maleimide-PEGylation of Hb seems adequate for an oxygen therapeutic intended for acute use, if longer vascular retention is required reagents such as mono-sulfone-PEG may be more appropriate.

From an assessment of multiple chelators, clodronate has potential for use in continuous chelation.

AIM: To identify chelators which when mixed with sodium hypochlorite (NaOCl) are stable, exhibiting minimal loss of free available chlorine (FAC) over 80 min and to further investigate potential mixtures by assessing FAC over 18 h and the capacity to remove smear layer. METHODOLOGY: 0.25 mol L-1 EDTA (10%), 0.25 mol L-1 EGTA (egtazic acid), 0.25 mol L-1 CDTA (cyclohexanediaminetetraacetic acid), 0.25 mol L-1 DTPA (pentetic acid), 0.5 mol L-1 ATMP (aminotri(methylene phosphonic acid)) and 1 mol L-1 HPAA, (hydroxyphosphonoacetic acid), all at alkaline pH, were mixed equally with 5% NaOCl. 0.5 mol L-1 alkaline clodronate and 0.5 mol L-1 Na4 etidronate (15%) were mixed equally with 10% NaOCl. For all mixtures, the pH and temperature were measured over 80 min and additionally for the clodronate mixture over 18 h. Iodometric titration was used to measure the FAC of all mixtures except for HPAA. The following were compared with respect to their ability to remove smear layer: 1 mol L-1 clodronate + 10% NaOCl, 0.5 mol L-1 clodronate + 10% NaOCl, 1 mol L-1 etidronate + 10% NaOCl, 0.5 mol L-1 clodronate + 10% NaOCl and the sequences 5% NaOCl/17% EDTA/5% NaOCl and 5% NaOCl/17% EDTA. The area fraction occupied by open dentinal tubules as a percentage of the total area (% AF) from scanning electron microscopy micrographs was calculated using Image J. The results were statistically analysed with alpha set at 0.05. RESULTS: Compared to its control, the mixture 0.5 mol L-1 clodronate + 10% NaOCl lost no FAC over 18 h (P > 0.05). The FAC of 0.25 mol L-1 CDTA mixed with 5% NaOCl fell to 96%, 92%, 75% and 4.9% at 20, 40, 60 and 80 min, respectively. Temperature rises were observed in all cases except in the etidronate and clodronate mixtures. Only in the clodronate mixture did the pH remain above pH 12 for the whole experiment. Although smear layer was removed, the % AF in 1 mol L-1 clodronate + 10% NaOCl, 0.5 mol L-1 clodronate + 10% NaOCl, 1 mol L-1 etidronate + 10% NaOCl was less than for 0.5 mol L-1 etidronate + 10% NaOCl and 5% NaOCl/17% EDTA/5% NaOCl and 5% NaOCl/17% EDTA. CONCLUSION: Alkaline 0.5 mol L-1 clodronate mixed equally with 10% NaOCl has potential for use in continuous chelation, based on this assessment of stability and smear layer removal. Further research is needed to establish its efficacy and safety.

Real-world effectiveness of peginterferon α-2b plus ribavirin in a Canadian cohort of treatment-naïve chronic hepatitis C patients with genotypes 2 or 3: results of the PoWer and RediPEN studies.

The purpose of this investigation was to assess the real-life effectiveness of pegylated interferon (peg-IFN) α-2b with ribavirin (RBV) in a cohort of treatment-naïve patients with chronic genotypes 2 (G2) or 3 (G3) hepatitis C virus (HCV) infection. A post-hoc pooled analysis of two Canadian multicenter, observational studies, RediPEN and PoWer, was carried out. A total of 1242 G2- or G3-infected patients were included. The primary outcome was sustained virologic response (SVR). Secondary endpoints included early virologic response (EVR), end-of-treatment (EOT) response, and relapse. Multivariate logistic regression was used to identify independent predictors of treatment response. SVR in G2 and G3 was 74.4 % and 63.6 %, respectively. Relapse occurred in 12.7 % and 19.1 % of G2- and G3-infected patients achieving EOT response, respectively. Overall, G3 was found to independently predict reduced SVR [odds ratio (OR) = 0.20; p = 0.007] and increased relapse (OR = 6.84; p = 0.022). Among G3-infected patients, increasing fibrosis score was the most important factor predicting reduced SVR [F2 vs. F0/F1 (OR = 0.41; p = 0.009); F3 vs. F0/F1 (OR = 0.72; p = 0.338); F4 vs. F0/F1 (OR = 0.27; p = 0.001)]. Male gender (OR = 13.16; p = 0.020) and higher fibrosis score [F2 vs. F0/F1 (OR = 9.72; p = 0.016); F3/F4 vs. F0/F1 (OR = 4.23; p = 0.113)] were associated with increased relapse in G3 patients. These results support the real-life effectiveness of peg-IFN α-2b plus ribavirin in HCV G2- and G3-infected patients. Overall, genotype was identified as the most significant predictor of treatment outcome. Fibrosis score and gender were key outcome predictors in the G3-infected population. In clinical settings, peg-INF/RBV offers an alternative for patients without access to all oral direct-acting antivirals.

The impact of public transport on the health of work commuters: a systematic review.

Although the public transport (PT) commute can form a substantial part of the working day, there is a significant gap in our understanding of how it influences health of those who engage in it. The purpose of this systematic review was to therefore generate evidence from 1972 about the extent to which the PT commute (involving train, bus, subway, tram, or metro) impacts on the mental health, physical health and well-being of the working people. We identified 47 studies in English worldwide involving an empirical quantitative focus which met the inclusion criteria. Of these, 23 studies involved over 500 participants. Although initial multi-modal comparisons showed impact on sickness rate, self-rated health complaints, perceived stress level and reduction in sleep, a more homogeneous analysis of rail commuters showed elevation in salivary cortisol, perceived stress, and affective reactions to crowding. Findings also revealed a bias towards use of endogenous self-report measures. On this basis, we argue that it would be of benefit to test theoretical models to account for more objective measures of job and commuting stress. Recommendations were made for flexible working agendas.

Nonthrombogenic plastic surfaces.

Heparin has been chemically combined with a number of plastic surfaces rendering them nonthrombogenic as judged by Lee-White coagulation tests in vitro with human blood. Addition of quaternary ammonium groups to the plastic permitted formation of insoluble complexes with heparin. These heparinized surfaces were essentially nonthrombogenic and adsorb blood proteins to a significantly smaller degree from dilute solution than do the unmodified plastic surfaces. The affinity of the formed blood elements for these modified surfaces is much less than for the unmodified surfaces.

Guidelines for the diagnosis and management of osteoporosis in postmenopausal women and men from the age of 50 years in the UK.

In 1999 and 2000 the Royal College of Physicians published guidelines for the prevention and treatment of osteoporosis [Royal College of Physicians. Osteoporosis: clinical guidelines for the prevention and treatment. London: Royal College of Physicians; 1999; Royal College of Physicians and Bone and Tooth Society of Great Britain. Update on pharmacological interventions and an algorithm for management. London, UK: Royal College of Physicians; 2000.; Royal College of Physicians. Glucocorticoid-induced osteoporosis. Guidelines on prevention and treatment; Bone and Tooth Society of Great Britain, National Osteoporosis Society and Royal College of Physicians. London, UK: Royal College of Physicians; 2002]. Since then, there have been significant advances in the field of osteoporosis including the development of new techniques for measuring bone mineral density, improved methods of assessing fracture risk and new treatments that have been shown to significantly reduce the risk of fractures. Against this background, the National Osteoporosis Guideline Group (NOGG), in collaboration with many Societies in the UK, have updated the original guidelines [Royal College of Physicians, National Osteoporosis Guideline Group on behalf of the Bone Research Society, British Geriatrics Society, British Orthopaedic Association, British Society of Rheumatology, National Osteoporosis Society, Osteoporosis 2000, Osteoporosis Dorset, Primary Care Rheumatology Society, Society for Endocrinology. Osteoporosis. Clinical guideline for prevention and treatment, Executive Summary. University of Sheffield Press; 2008], a practical summary of which is detailed below. The management algorithms are underpinned by a health economic analysis applied to the epidemiology of fracture in the UK.

Re-treatment with peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have relapsed or not responded to a first course of pegylated interferon-based therapy.

BACKGROUND: Pegylated interferon (pegIFN) and ribavirin combination therapy remains the first-line treatment for chronic hepatitis C virus (HCV) infection. In contrast to the wealth of studies in treatment-naive patients, the effectiveness of retreatment in patients who have previously failed pegIFN-based therapy is largely unreported. AIM: To assess the effectiveness of the retreatment of patients who have previously failed an initial course of pegIFN-based therapy with pegIFNalpha-2a and ribavirin. METHODS: A post-hoc analysis of a multicentre open-label study was performed. Patients received pegIFNalpha-2a and ribavirin at a dose of 800 mg/day and later 1000 mg/day to 1200 mg/day for 24 to 48 weeks at the discretion of the investigator. Outcomes at week 12 (early virological response [EVR]) and week 24 (sustained virological response [SVR]) were analyzed. RESULTS: Eighty-seven patients who had relapsed after previous pegIFN-based therapy (n=28; 78% genotype 1) or were nonresponders (n=59; 71% genotype 1) were analyzed. Of the relapsers, 86% achieved an EVR and 68% achieved an SVR. In relapsers to pegIFN monotherapy (n=15) or pegIFN plus ribavirin (n=13), 60% and 77% achieved an SVR, respectively. Fibrosis and genotype did not affect the likelihood of SVR in relapsers although this may be the result of the relatively small number of patients. In previous nonresponders, an EVR was achieved in 53% but an SVR occurred in only 17%. In nonresponders to pegIFN monotherapy (n=9) and pegIFN plus ribavirin (n=50), 33% and 14% achieved an SVR, respectively. Genotype did not affect SVR in nonresponders. Only 10% with a METAVIR score of F3 or F4 on liver biopsy achieved an SVR. CONCLUSIONS: Relapse after previous pegIFN-based therapy is associated with a strong probability of treatment success whereas retreatment of those with previous nonresponse does not.

The Impact of Trained Volunteer Mealtime Assistants on the Dietary Intake of Older Female In-Patients: The Southampton Mealtime Assistance Study.

OBJECTIVE: Malnutrition among older hospital inpatients is common and is associated with poor clinical outcomes. Time-pressured staff may struggle to provide mealtime assistance. This study aimed to evaluate the impact of trained volunteer mealtime assistants on the dietary intake of older inpatients. DESIGN: Quasi-experimental two year pre and post- test study of the introduction of volunteer mealtime assistants to one acute medical female ward, with contemporaneous comparison with a control ward. SETTING: Two acute medical female wards in a university hospital in England. PARTICIPANTS: Female acute medical inpatients aged 70 years and over who were not tube fed, nil by mouth, terminally ill or being nursed in a side room. INTERVENTION: The introduction of volunteer mealtime assistants to one ward to help patients during weekday lunchtimes in the intervention year. MEASUREMENTS: Patients' background and clinical characteristics were assessed; 24-hour records were completed for individual patients to document dietary intake in both years on the two wards. RESULTS: A total of 407 patients, mean (SD) age 87.5 (5.4) years, were studied over the two-year period; the majority (57%) needed mealtime assistance and up to 50% were confused. Patients' clinical characteristics did not differ between wards in the observational or intervention years. Throughout the intervention year volunteers provided mealtime assistance on weekday lunchtimes on the intervention ward only. Daily energy (median 1039 kcal; IQR 709, 1414) and protein (median 38.9 g: IQR 26.6, 54.0) intakes were very low (n=407). No differences in dietary intake were found between the wards in the observational or intervention years, or in a pre-post-test comparison of patients on the intervention ward. Data were therefore combined for further analysis to explore influences on dietary intake. In a multivariate model, the only independent predictor of energy intake was the feeding assistance required by patients; greater need for help was associated with lower energy intake (P<0.001). Independent predictors of protein intake were the feeding assistance given (P<0.001) and use of sip feeds; sip feed users had slightly higher protein intakes (P=0.014). CONCLUSIONS: Trained volunteers were able to deliver mealtime assistance on a large scale in an effective and sustainable manner, with the potential to release time for nursing staff to complete other clinical tasks. The study participants had a low median intake of energy and protein highlighting the importance of patient factors associated with acute illness; a stratified approach including oral and parenteral nutritional supplementation may be required for some acutely unwell patients. The level of mealtime assistance required was the factor most strongly associated with patients' poor intake of energy and protein and may be a useful simple indicator of patients at risk of poor nutrition.

Oral EBV and KSHV infection in HIV.

The gamma herpesviruses, Kaposi's-sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), are tightly associated with the development of AIDS-associated oral disease and malignancy during immune suppression. The objective of this investigation was to characterize oral infection and pathogenesis in healthy and immune-suppressed individuals. To characterize oral EBV and KSHV infection, we examined throat washings and oral epithelial cells from HIV-positive and HIV-negative individuals. Quantitative/real-time polymerase-chain-reaction (PCR) assays, transmission electronmicroscopy, immunostaining, and sequence analysis were used to identify viral infection. Virus was isolated from throat-wash samples and was used to infect epithelial and lymphoid cell lines. We detected EBV and KSHV in the oral cavity in healthy and immune-suppressed individuals. Viral strain analysis of KSHV K1 in multiple clones from the oral cavities of healthy persons and immunosuppressed patients detected several strains previously detected in KS lesions, with minor strain variation within individuals. Immunoelectron microscopy for multiple viral antigens detected consistent expression of viral proteins and oral epithelial specimens. In oral epithelial cells infected with wild-type KSHV in vitro, the K8.1 glycoprotein associated with lytic KSHV infection was detected in both primary and telomerase immortalized oral epithelial cultures by 24 hours post-infection. Virions were detected, subsequent to infection, by scanning electron microscopy. Oral epithelial cells were also infected in vitro with wild-type EBV originating from throat washes. Analysis of these data suggests that, like EBV, KSHV infection is present in the oropharynx of healthy individuals, is transmissible in vitro, and may be transmitted by saliva.

Relationship between personality and satisfaction with the dentition in tooth wear patients.

This study was undertaken to identify whether personality traits had any relationship with patients' satisfaction with their dentition in tooth wear cases. One hundred tooth wear patients and one hundred controls were recruited into the study. A Dental Impact on Daily Living questionnaire was used to assess impact of tooth wear on day to day life and satisfaction with the dentition. An ordinal scale was used to assess tooth wear severity in tooth wear patients. The NEO Five Factor inventory was used to assess personal profiles. Tooth wear patients were less satisfied with their dentition, had higher Neuroticism, lower Extraversion, and higher Openness than the controls.

Maternal and early life factors of tooth emergence patterns and number of teeth at 1 and 2 years of age.

Various environmental factors have been associated with the timing of eruption of primary dentition, but the evidence to date comes from small studies with limited information on potential risk factors. We aimed to investigate associations between tooth emergence patterns and pre-conception, pregnancy and postnatal influences. Dentition patterns were recorded at ages 1 and 2 years in 2915 children born to women in the Southampton Women's Survey from whom information had been collected on maternal factors before conception and during pregnancy. In mutually adjusted regression models we found that: children were more dentally advanced at ages 1 and 2 years if their mothers had smoked during pregnancy or they were longer at birth; mothers of children whose dental development was advanced at age 2 years tended to have poorer socioeconomic circumstances, and to have reported a slower walking speed pre-pregnancy; and children of mothers of Asian ethnicity had later tooth development than those of white mothers. The findings add to the evidence of environmental impacts on the timing of the eruption of primary dentition in indicating that maternal smoking during pregnancy, socio-economic status and physical activity (assessed by reported walking speed) may influence the child's primary dentition. Early life factors, including size at birth are also associated with dentition patterns, as is maternal ethnicity.

The association between water fluoridation and hip fracture among white women and men aged 65 years and older. A national ecologic study.

For the past 45 years, there has been a great deal of debate regarding the health issues surrounding the fluoridation of public water supplies. In order to assess the association between fluoridation and hip fracture, we identified 129 counties across the United States considered to be exposed to public water fluoridation and 194 counties without exposure. Data from the Health Care Financing Administration and the Department of Veterans Affairs were used to calculate the incidence of hip fracture among white persons, aged 65 years or older, in fluoridated and nonfluoridated counties. There was a small statistically significant positive association between fracture rates and fluoridation. The relative risk (95% confidence interval) of fracture in fluoridated counties compared to nonfluoridated counties was 1.08 (1.06 to 1.10) for women and 1.17 (1.13 to 1.22) for men. As comparisons were made at the grouped level, it may be inappropriate at this time to draw inferences at the individual level. The relationship observed at the county level needs to be duplicated at the individual level with more precise measures of fluoride exposure.

Health characteristics by occupation and industry of longest employment.

Includes estimates on length of longest job held, limitation of activity, disability days, incidence of acute conditions, persons injured, hospitalizations, and utilization of medical and dental services of persons aged 17 years and over in the civilian noninstitutionalized population. These estimates are presented by occupation and industry of longest employment for those who had ever worked. Estimates are based on data collected in the National Health Interview Survey of 1980.

Secondary prevention of osteoporosis: when should a non-vertebral fracture be a trigger for action?

The burden of non-vertebral fractures is enormous. Hip fractures account for nearly 10% of all fractures (and a much greater proportion in the elderly), while wrist fractures may account for up to 23% of all limb fractures. The best available predictors of non-vertebral fracture risk are low BMD and a tendency to fall. Hip, forearm, proximal humerus and rib fractures have all been associated with low BMD, though ankle fracture is not strongly related to osteoporosis. Although clinical risk factors identify only about one-third of postmenopausal women at increased risk of osteoporotic fracture, the occurrence of one fracture commonly predicts a second fracture. Guidelines are presented for identifying and treating patients at risk of non-vertebral osteoporotic fractures, especially those with a previous fracture, based on the algorithm recently published by the Royal College of Physicians and the Bone and Tooth Society. Prevention of falls and use of external hip protectors may reduce the occurrence of hip fracture. Treatment options for patients presenting with hip fracture include HRT, bisphosphonates, and calcium plus vitamin D, and for Colles' fracture include general measures, HRT, bisphosphonates, or calcitonin plus calcium.

Dissolution of mercury from amalgam into saline solution.

Dissolution of mercury from amalgams and some intermetallic compounds found in the amalgam structure, such as gamma 1, gamma 2, and beta 1, was examined during one week of aging in 0.9% NaCl solution at 37 degrees C. The amount of mercury released from gamma 1 (30.2 micrograms/cm2) was at least 13 times that released from amalgam (0.5-2.2 micrograms/cm2) and five times that released from beta 1(5.7 micrograms/cm2). Gamma 2 released the least amount of mercury (0.46 micrograms/cm2). The study revealed that as high as 55% of the mercury ions liberated from the amalgams and the amalgam phases was adsorbed onto the walls of the vials in which the specimens were aged.

Time-dependent dissolution of amalgams into saline solution.

The dissolution of mercury, silver, and copper from polished and unpolished surfaces of low- and high-copper amalgams into saline was investigated with respect to time via atomic absorption spectrophotometry. Greater amounts of mercury and silver were released from unpolished than from polished surfaces. Ion release was greatest during the first three hours after trituration of all amalgams. The rate of dissolution of ions from amalgams into saline is considered to be very low once the amalgam has set, and is probably inhibited by the formation of a surface film formed during immersion.

Water fluoride concentration and fracture of the proximal femur.

STUDY OBJECTIVE: The aim of the study was to examine the relationship between water fluoride concentration and the incidence of hip fracture, since evidence on this is at present inconsistent. DESIGN: Numbers of hospital admissions for fractures of proximal femur were obtained from hospital activity analysis data for the years 1978-1982. The fracture rates were compared with water fluoride concentrations in 39 county districts of England and Wales (fluoride concentrations had been measured in these districts between 1969 and 1973 as part of the British Regional Heart Study). PATIENTS: During the study period, 4121 men and 16,272 women aged 45 years and over were discharged from hospital after hip fracture. RESULTS: Poor correlations were found between discharge rates and both total (r = 0.16, p = 0.34) and natural (r = 0.01, p = 0.95) water fluoride concentrations. CONCLUSIONS: Water fluoridation to levels of around 1 mg/litre is unlikely to reduce hip fracture incidence markedly in this country.

Water fluoridation and osteoporotic fracture.

Osteoporotic fractures constitute a major public health problem. These fractures typically occur at the hip, spine and distal forearm. Their pathogenesis is heterogeneous, with contributions from both bone strength and trauma. Water fluoridation has been widely proposed for its dental health benefits, but concerns have been raised about the balance of skeletal risks and benefits of this measure. Fluoride has potent effects on bone cell function, bone structure and bone strength. These effects are mediated by the incorporation of fluoride ions in bone crystals to form fluoroapatite, and through an increase in osteoblast activity. It is believed that a minimum serum fluoride level of 100 ng/ml must be achieved before osteoblasts will be stimulated. Serum levels associated with drinking water fluoridated to 1 ppm are usually several times lower than this value, but may reach this threshold at concentrations of 4 ppm in the drinking water. Animal studies suggest no effect of low-level (0-3 ppm) fluoride intake on bone strength, but a possible decrease at higher levels. Sodium fluoride has been used to treat established osteoporosis for nearly 30 years. Recent trials of this agent, prescribed at high doses, have suggested that despite a marked increase in bone mineral density, there is no concomitant reduction in vertebral fracture incidence. Furthermore, the increase in bone density at the lumbar spine may be achieved at the expense of bone mineral in the peripheral cortical skeleton. As a consequence, high dose sodium fluoride (80 mg daily) is not currently used to treat osteoporosis. At lower doses, recent trials have suggested a beneficial effect on both bone density and fracture. The majority of epidemiological evidence regarding the effect of fluoridated drinking water on hip fracture incidence is based on ecological comparisons. Although one Finnish study suggested that hip fracture rates in a town with fluoridated water were lower than those in a matching town without fluoride, a later study failed to show differences. Ecological studies from the United States and Great Britain have, if anything, revealed a weak positive association between water fluoride concentration and hip fracture incidence. Two studies examining hip fracture rates before and after fluoridation yielded discordant results, and are complicated by underlying time trends in hip fracture incidence. Only two studies have attempted to examine the relation between water fluoride concentration and fracture risk at an individual level. In one of these, women in a high fluoride community had double the fracture risk of women in a low fluoride community. In the other, there was no relationship between years of fluoride exposure and incidence of spine or non-spine fractures. In conclusion, the epidemiological evidence relating water fluoridation to hip fracture is based upon ecological comparisons and is inconclusive. However, several studies suggest the possibility of a weak adverse effect, which warrants further exploration. Data on the relationship between fluoride intake and hip fracture risk at the individual level, and data relating fluoridation to bone mineral density are required. Until these become available, the burden of evidence suggesting that fluoridation might be a risk factor for hip fracture is weak and not sufficient to retard the progress of the water fluoridation programme.

New stressors for GDPs in the past ten years: a qualitative study.

OBJECTIVE: To identify new stressors that general dental practitioners have experienced from those reported in the UK national surveys of 1986 and 1996. DESIGN: Series of interviews. SETTING: General dental practices from suburban and inner city areas in two health authorities of the North West of England. SUBJECTS: A random sample of ten general dental practitioners participated; there were no refusals. METHOD: In-depth interviews employing a research psychologist were conducted to invite comment on the areas of work pressure they had experienced during the past ten years. Interviews were audio-taped, transcribed and content analysed. RESULTS: More than 130 statements categorised into 29 topics referred to pressures related to work. There was good agreement (93%) between authors and an independent assessor when a sort of the statements into the defined categories was completed. The most referred area of stress was the system changes of running a practice and the possibility of further changes. Patient expectations were considered to be rising. Aggression exhibited by some patients in the practice, the risk of cross-infection, litigation and the dentist working as a team member were newly identified stressors not included in original classifications of dental work pressure. CONCLUSIONS: Dental practitioners from this small study identified uncertainty in the future of the organisation of dental care provision as the most important new pressure of work.

Direct-acting antiviral therapies for hepatitis C genotype 1 infection: a multiple treatment comparison meta-analysis.

BACKGROUND: New direct-acting antiviral agents for hepatitis C genotype 1 infection, boceprevir and telaprevir, offer enhanced sustained virologic response (SVR) among both treatment-naïve and treatment-experienced patients. AIM: To determine the relative efficacy of the new direct-acting antiviral agents by applying a multiple treatment comparison meta-analysis. DESIGN: We included published Phase II and III randomized controlled trials evaluating head-to-head comparisons between boceprevir, telaprevir, peg-interferon alpha-2a with ribavirin and peg-interferon alpha-2b with ribavirin in hepatitis C genotype 1 patients. We applied Bayesian multiple treatment comparison meta-analysis. RESULTS: We included data from four boceprevir, three telaprevir and six peg-interferon alpha-2a plus ribavirin vs. peg-interferon alpha-2b plus ribavirin randomized controlled trials. Both boceprevir and telaprevir offer statistically superior outcomes for SVR, relapse and discontinuation due to adverse events than either peg-interferons among both treatment-naïve and treatment-experienced patients. Among treatment-naïve patients, clinical outcomes were similar for boceprevir and telaprevir, for SVR [odds ratio (OR) 0.90, 95% credible interval (95% CrI) 0.41-1.91] and for relapse (OR 1.09, 95% CrI 0.19-4.84). Similarly, among treatment-experienced patients, clinical outcomes were similar for boceprevir and telaprevir and for SVR (OR 1.45, 95% CrI 0.70-3.08) and for relapse (OR 0.35, 95% CrI 0.13-1.02). For treatment-naïve patients receiving standard-duration therapy, telaprevir yielded lower rates of anemia and neutropenia, but higher rates of rash and pruritus. For treatment-experience patients, all adverse event rates were higher with telaprevir. DISCUSSION: Boceprevir and telaprevir exhibit similar effects among hepatitis C genotype 1 treatment-naïve and treatment-experienced patients.