Anaphylaxis following quadrivalent human papillomavirus vaccination

Background

In 2007, Australia implemented the National human papillomavirus (HPV) Vaccination Program, which provides quadrivalent HPV vaccine free to all women aged 12–26 years. Following notification of 7 presumptive cases of anaphylaxis in the state of New South Wales, Australia, we verified cases and compared the incidence of anaphylaxis following HPV vaccination to other vaccines in comparable settings.

Methods

We contacted all patients with suspected anaphylaxis and obtained detailed histories from telephone interviews and a review of medical records. A multidisciplinary team determined whether each suspected case met the standardized Brighton definition. Some participants also received skin-prick allergy testing for common antigens and components of the HPV vaccine.

Results

Of 12 suspected cases, 8 were classified as anaphylaxis. Of these, 4 participants had negative skin-prick test results for intradermal Gardasil. From the 269 680 HPV vaccine doses administered in schools, 7 cases of anaphylaxis were identified, which represents an incidence rate of 2.6 per 100 000 doses (95% CI 1.0–5.3 per 100 000). In comparison, the rate of identified anaphylaxis was 0.1 per 100 000 doses (95% CI 0.003–0.7) for conjugated meningococcal C vaccination in a 2003 school-based program.

Interpretation

Based on the number of confirmed cases, the estimated rate of anaphylaxis following quadrivalent HPV vaccine was significantly higher than identified in comparable school-based delivery of other vaccines. However, overall rates were very low and managed appropriately with no serious sequelae.Anaphylaxis to a vaccine, or to a known ingredient, is widely recognized as the only absolute contraindication to vaccination. Vaccine ingredients with the potential to cause anaphylaxis in sensitized people include egg proteins (e.g., influenza vaccine), gelatin (in live viral vaccines) and antibiotics.¹ Although anaphylaxis due to vaccination is rare, with an estimated incidence of 0.1–1 per 100 000 doses,² its occurrence, especially if death occurs, has the potential to severely damage public and provider confidence in vaccination.Identified cases of anaphylaxis following vaccination tend to occur less than 1 hour after vaccination.¹ Measurement of anaphylaxis and comparisons between different settings are made difficult, however, by the lack of a universally agreed definition of anaphylaxis³ and by variable presentation and rate of progression, especially if adrenaline is given. Rates of anaphylaxis reported by vaccine safety surveillance systems may be underreported (apart from anaphylactic shock) and vary depending upon the population vaccinated, the type of vaccines used and the type of surveillance system. As they are newly licensed, the rate of anaphylaxis that may occur following immunization with prophylactic human papillomavirus (HPV) vaccines is currently unknown and awaits results from vaccine safety surveillance systems.In late June 2007, we identified a potential vaccine safety signal (reported information about a previously unknown or incompletely documented but possible causal adverse event following vaccination⁴), when 7 presumptive cases of anaphylaxis were reported following quadrivalent HPV vaccination. We aimed to estimate the rate of anaphylaxis following HPV vaccination.     

Effect of human papillomavirus (HPV) vaccination on clinical indicators of sexual behaviour among adolescent girls: the Ontario Grade 8 HPV Vaccine Cohort Study

Background:

Suboptimal human papillomavirus (HPV) vaccine coverage in some jurisdictions is partly attributed to fears that vaccination may increase risky sexual behaviour. We assessed the effect of HPV vaccination on clinical indicators of sexual behaviour among adolescent girls in Ontario.

Methods:

Using Ontario’s administrative health databases, we identified a population-based cohort of girls in grade 8 in the 2 years before (2005/06 and 2006/07) and after (2007/08 and 2008/09) implementation of Ontario’s grade 8 HPV vaccination program. For each girl, we then obtained data on vaccine receipt in grades 8 and 9 and data on indicators of sexual behaviour (pregnancy and non–HPV-related sexually transmitted infections) in grades 10–12. Using a quasi-experimental method known as regression discontinuity, we estimated, for each outcome, the risk difference (RD) and relative risk (RR) attributable to vaccination and to program eligibility.

Results:

The cohort comprised 260 493 girls, of whom 131 781 were ineligible for the program and 128 712 were eligible. We identified 15 441 (5.9%) cases of pregnancy and sexually transmitted infection and found no evidence that vaccination increased the risk of this composite outcome: RD per 1000 girls −0.61 (95% confidence interval [CI] −10.71 to 9.49) and RR 0.96 (95% CI 0.81 to 1.14). Similarly, we found no discernible effect of program eligibility: RD per 1000 girls −0.25 (95% CI −4.35 to 3.85) and RR 0.99 (95% CI 0.93 to 1.06). The findings were similar when outcomes were assessed separately.

Interpretation:

We present strong evidence that HPV vaccination does not have any significant effect on clinical indicators of sexual behaviour among adolescent girls. These results suggest that concerns over increased promiscuity following HPV vaccination are unwarranted and should not deter from vaccinating at a young age.Infection with the human papillomavirus (HPV) is the most commonly diagnosed sexually transmitted infection in Canada and around the world.¹ Although most of these infections are transient and self-resolving, others persist and can cause important health outcomes, including cervical cancer and anogenital warts.In 2006, Canada was among 49 countries to license Gardasil (Merck, Whitehouse Station, New Jersey), a quadrivalent HPV vaccine designed to protect against 4 types of HPV (6, 11, 16, 18) that cause 70% of cases of cervical cancer and most cases of anogenital warts.^2–4 As one of the first cancer-preventing vaccines, this vaccine received expedited approval in several countries and was the subject of intensive marketing, lobbying and public health campaigns around the world.⁵ By 2012, it had been approved in almost 100 countries, many of which also implemented nationwide HPV vaccination programs aimed primarily at immunizing young girls before the onset of sexual activity.⁶Despite the popularity of large-scale immunization programs, HPV vaccination has faced a great deal of controversy regarding unanswered questions about the real-world effects of this vaccine.^7,8 A major topic of public debate has been the possibility that HPV vaccination might lead to sexual disinhibition,⁹ that is, that receipt of the vaccine might give women and girls a false sense of protection against all sexually transmitted infections and that this false sense of protection might lead them to engage in more risky sexual behaviours than they would otherwise (e.g., be more promiscuous or neglect to use condoms). Increases in these risky behaviours could have important clinical consequences, including increased risk of pregnancy and sexually transmitted infections. Although there is little empirical support for the notion that sexual health interventions promote risky sexual behaviours,^10,11 this possible unintended effect of the HPV vaccine would undermine its value for reducing the burden of sexual health–related diseases. Moreover, parental fears of increased promiscuity following HPV vaccination have been reported as a major determinant of vaccine refusal,¹² which may help to explain suboptimal HPV vaccine coverage in some jurisdictions.^6,13 Evidently, both actual and perceived sexual disinhibition can have a negative effect on the potential health benefits of HPV vaccination. Therefore, we conducted a population-based, retrospective cohort study to assess the effect of HPV vaccination on clinical indicators of sexual behaviour among adolescent girls in Ontario.     

Pneumococcal vaccination and risk of myocardial infarction

Background

Based on promising results from laboratory studies, we hypothesized that pneumococcal vaccination would protect patients from myocardial infarction.

Methods

We conducted a hospital-based case–control study that included patients considered to be at risk of myocardial infarction. We used health databases to obtain hospital diagnoses and vaccination status. We compared patients who had been admitted for treatment of myocardial infarction with patients admitted to a surgical department in the same hospital for a reason other than myocardial infarction between 1997 and 2003.

Results

We found a total of 43 209 patients who were at risk; of these, we matched 999 cases and 3996 controls according to age, sex and year of hospital admission. Cases were less likely than controls to have been vaccinated (adjusted odds ratio [OR] 0.53, 95% confidence interval [CI] 0.40–0.70). This putative protective role of the vaccine was not observed for patients who had received the vaccine up to 1 year before myocardial infarction (adjusted OR 0.85, 95% CI 0.54–1.33). In contrast, if vaccination had occurred 2 years or more before the hospital admission, the association was stronger (adjusted OR 0.33, 95% CI 0.20–0.46).

Interpretation

Pneumococcal vaccination was associated with a decrease of more than 50% in the rate myocardial infarction 2 years after exposure. If confirmed, this association should generate interest in exploring the putative mechanisms and may offer another reason to promote pneumococcal vaccination.Despite important advances in primary prevention, atherosclerosis remains the leading cause of death in developed societies.¹ In addition to risk factors such as hypertension, diabetes mellitus, tobacco use and dyslipidemia, less traditional risk factors have also been sought. Many markers, including C-reactive protein and interleukins, highlight inflammation as a key mediator in both the progression and activation of atherosclerotic lesions.^2–4 Some medications that are used to prevent cardiovascular diseases, such as statins, also appear to reduce inflammation.⁵Animal experiments have shown that pneumococcal vaccination reduces the extent of atherosclerotic lesions.⁶ We hypothesized that antibodies directed against Streptococcus pneumoniae also recognize oxidized low-density lipoprotein (LDL) and impede the formation of foam cells. Interestingly, a retrospective cohort study involving World War II veterans who had undergone splenectomy documented excess mortality rates from both pneumonia and ischemic heart disease.⁷ More recent data have suggested that acute pneumococcal infections, but not vaccinations, increase the risk of vascular events;⁸ however, the duration of vaccination exposure considered in that study was limited.Our primary objective was to evaluate the association between pneumococcal vaccination and the risk of myocardial infarction. We also explored whether any effect of vaccination on the risk of infarction waned over time.     

Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy

Background

Whether to continue oral anticoagulant therapy beyond 6 months after an “unprovoked” venous thromboembolism is controversial. We sought to determine clinical predictors to identify patients who are at low risk of recurrent venous thromboembolism who could safely discontinue oral anticoagulants.

Methods

In a multicentre prospective cohort study, 646 participants with a first, unprovoked major venous thromboembolism were enrolled over a 4-year period. Of these, 600 participants completed a mean 18-month follow-up in September 2006. We collected data for 69 potential predictors of recurrent venous thromboembolism while patients were taking oral anticoagulation therapy (5–7 months after initiation). During follow-up after discontinuing oral anticoagulation therapy, all episodes of suspected recurrent venous thromboembolism were independently adjudicated. We performed a multivariable analysis of predictor variables (p < 0.10) with high interobserver reliability to derive a clinical decision rule.

Results

We identified 91 confirmed episodes of recurrent venous thromboembolism during follow-up after discontinuing oral anticoagulation therapy (annual risk 9.3%, 95% CI 7.7%–11.3%). Men had a 13.7% (95% CI 10.8%–17.0%) annual risk. There was no combination of clinical predictors that satisfied our criteria for identifying a low-risk subgroup of men. Fifty-two percent of women had 0 or 1 of the following characteristics: hyperpigmentation, edema or redness of either leg; D-dimer ≥ 250 μg/L while taking warfarin; body mass index ≥ 30 kg/m²; or age ≥ 65 years. These women had an annual risk of 1.6% (95% CI 0.3%–4.6%). Women who had 2 or more of these findings had an annual risk of 14.1% (95% CI 10.9%–17.3%).

Interpretation

Women with 0 or 1 risk factor may safely discontinue oral anticoagulant therapy after 6 months of therapy following a first unprovoked venous thromboembolism. This criterion does not apply to men. (http://Clinicaltrials.gov trial register number {"type":"clinical-trial","attrs":{"text":"NCT00261014","term_id":"NCT00261014"}}NCT00261014)Venous thromboembolism is a common, potentially fatal, yet treatable, condition. The risk of a recurrent venous thromboembolic event after 3–6 months of oral anticoagulant therapy varies. Some groups of patients (e.g., those who had a venous thromboembolism after surgery) have a very low annual risk of recurrence (< 1%),¹ and they can safely discontinue anticoagulant therapy.² However, among patients with an unprovoked thromboembolism who discontine anticoagulation therapy after 3–6 months, the risk of a recurrence in the first year is 5%–27%.^3–6 In the second year, the risk is estimated to be 5%,³ and it is estimated to be 2%–3.8% for each subsequent year.^5,7 The case-fatality rate for recurrent venous thromboembolism is between 5% and 13%.^8,9 Oral anticoagulation therapy is very effective for reducing the risk of recurrence during therapy (> 90% relative risk [RR] reduction);^3,4,10,11 however, this benefit is lost after therapy is discontinued.^3,10,11 The risk of major bleeding with ongoing oral anticoagulation therapy among venous thromboembolism patients is 0.9–3.0% per year,^3,4,6,12 with an estimated case-fatality rate of 13%.¹³Given that the long-term risk of fatal hemorrhage appears to balance the risk of fatal recurrent pulmonary embolism among patients with an unprovoked venous thromboembolism, clinicians are unsure if continuing oral anticoagulation therapy beyond 6 months is necessary.^2,14 Identifying subgroups of patients with an annual risk of less than 3% will help clinicians decide which patients can safely discontinue anticoagulant therapy.We sought to determine the clinical predictors or combinations of predictors that identify patients with an annual risk of venous thromboembolism of less than 3% after taking an oral anticoagulant for 5–7 months after a first unprovoked event.     

Characteristics of women undergoing repeat induced abortion

Background

Although repeat induced abortion is common, data concerning characteristics of women undergoing this procedure are lacking. We conducted this study to identify the characteristics, including history of physical abuse by a male partner and history of sexual abuse, of women who present for repeat induced abortion.

Methods

We surveyed a consecutive series of women presenting for initial or repeat pregnancy termination to a regional provider of abortion services for a wide geographic area in southwestern Ontario between August 1998 and May 1999. Self-reported demographic characteristics, attitudes and practices regarding contraception, history of relationship violence, history of sexual abuse or coercion, and related variables were assessed as potential correlates of repeat induced abortion. We used χ² tests for linear trend to examine characteristics of women undergoing a first, second, or third or subsequent abortion. We analyzed significant correlates of repeat abortion using stepwise multivariate multinomial logistic regression to identify factors uniquely associated with repeat abortion.

Results

Of the 1221 women approached, 1145 (93.8%) consented to participate. Data regarding first versus repeat abortion were available for 1127 women. A total of 68.2%, 23.1% and 8.7% of the women were seeking a first, second, or third or subsequent abortion respectively. Adjusted odds ratios for undergoing repeat versus a first abortion increased significantly with increased age (second abortion: 1.08, 95% confidence interval [CI] 1.04–1.09; third or subsequent abortion: 1.11, 95% CI 1.07–1.15), oral contraceptive use at the time of conception (second abortion: 2.17, 95% CI 1.52–3.09; third or subsequent abortion: 2.60, 95% CI 1.51–4.46), history of physical abuse by a male partner (second abortion: 2.04, 95% CI 1.39–3.01; third or subsequent abortion: 2.78, 95% CI 1.62–4.79), history of sexual abuse or violence (second abortion: 1.58, 95% CI 1.11–2.25; third or subsequent abortion: 2.53, 95% CI 1.50–4.28), history of sexually transmitted disease (second abortion: 1.50, 95% CI 0.98–2.29; third or subsequent abortion: 2.26, 95% CI 1.28–4.02) and being born outside Canada (second abortion: 1.83, 95% CI 1.19–2.79; third or subsequent abortion: 1.75, 95% CI 0.90–3.41).

Interpretation

Among other factors, a history of physical or sexual abuse was associated with repeat induced abortion. Presentation for repeat abortion may be an important indication to screen for a current or past history of relationship violence and sexual abuse.Repeat pregnancy termination procedures are common in Canada (where 35.5% of all induced abortions are repeat procedures)^1,2 and the United States (where 48% of induced abortions are repeat procedures).^3,4,5,6,7 Rates of repeat induced abortion increased in both countries for an initial period after abortion was legalized, as a result of an increase in the number of women who had access to a first, and consequently to repeat, legal induced abortion.^1,6,8,9 At present, rates of initial and repeat abortion in Canada and the United States appear to be stabilizing.^2,7Research concerning characteristics of women who undergo repeat induced abortions has been limited in scope. In a literature search we identified fewer than 20 studies in this area published over the past 3 decades. However, available research has shown several consistent findings. Women undergoing repeat abortions are more likely than those undergoing a first abortion to report using a method of contraception at the time of conception.^7,8,10,11 In addition, women seeking repeat abortions report more challenging family situations than women seeking initial abortions: they are more likely to be separated, divorced, widowed or living in a common-law marriage, and to report difficulties with their male partner.^1,5,8,11,12 They also are older,^7,13 have more children^1,5,13 and are more often non-white^7,11,13 than women seeking initial abortions.There is little evidence to suggest that women seeking repeat abortion are using pregnancy termination as a method of birth control.^1,5,6,8,11 Evidence also does not indicate that women seeking repeat abortion are psychologically maladjusted.^8,13Our literature review showed that many studies of repeat abortion are 20 to 30 years old and are based on data collected when abortion was a newly legalized procedure.^5,11 Furthermore, in studies of correlates of repeat abortion the investigators did not examine a range of personality characteristics that are known to influence women''s reproductive health outcomes,^14,15 including attitudes about sexuality,¹⁴ health locus of control,^16,17 degree of social integration,¹⁶ attitudes about contraception^18,19 and history of sexual or physical abuse.^20,21,22 The objective of the current study was to identify characteristics of women who undergo repeat induced abortion.     

The effect of patients' sex on physicians' recommendations for total knee arthroplasty

Background

The underuse of total joint arthroplasty in appropriate candidates is more than 3 times greater among women than among men. When surveyed, physicians report that the patient''s sex has no effect on their decision-making; however, what occurs in clinical practice may be different. The purpose of our study was to determine whether patients'' sex affects physicians'' decisions to refer a patient for, or to perform, total knee arthroplasty.

Methods

Seventy-one physicians (38 family physicians and 33 orthopedic surgeons) in Ontario performed blinded assessments of 2 standardized patients (1 man and 1 woman) with moderate knee osteoarthritis who differed only by sex. The standardized patients recorded the physicians'' final recommendations about total knee arthroplasty. Four surgeons did not consent to the inclusion of their data. After detecting an overall main effect, we tested for an interaction with physician type (family physician v. orthopedic surgeon). We used a binary logistic regression analysis with a generalized estimating equation approach to assess the effect of patients'' sex on physicians'' recommendations for total knee arthroplasty.

Results

In total, 42% of physicians recommended total knee arthroplasty to the male but not the female standardized patient, and 8% of physicians recommended total knee arthroplasty to the female but not the male standardized patient (odds ratio [OR] 4.2, 95% confidence interval [CI] 2.4–7.3, p < 0.001; risk ratio [RR] 2.1, 95% CI 1.5–2.8, p < 0.001). The odds of an orthopedic surgeon recommending total knee arthroplasty to a male patient was 22 times (95% CI 6.4–76.0, p < 0.001) that for a female patient. The odds of a family physician recommending total knee arthroplasty to a male patient was 2 times (95% CI 1.04–4.71, p = 0.04) that for a female patient.

Interpretation

Physicians were more likely to recommend total knee arthroplasty to a male patient than to a female patient, suggesting that gender bias may contribute to the sex-based disparity in the rates of use of total knee arthroplasty.Disparity in the use of medical or surgical interventions based on patient characteristics, such as sex, ethnic background or socioeconomic status, is an important health care issue.¹ Women are less likely than men to receive lipid-lowering medication after a myocardial infarction,² receive kidney dialysis,³ be admitted to an intensive care unit,⁴ or undergo cardiac catheterization,⁵ renal transplantation⁶ or total joint arthroplasty.⁷ Although women''s preferences for surgery or the information needed to make an informed decision may differ from men and explain sex-based differences in care,^8,9 subtle or overt gender bias may inappropriately influence physicians'' clinical decision-making.^2,5,7 A more pronounced gender bias might be expected when the clinical decision involves an elective surgical procedure such as total joint arthroplasty.Total hip and knee arthroplasty is the definitive treatment for relieving pain and restoring function in people with moderate to severe osteoarthritis for whom medical therapy has failed.¹⁰ Although age-adjusted rates of total joint arthroplasty are higher among women than among men,¹¹ based on a population-based epidemiologic survey, underuse of arthroplasty is 3 times greater in women.⁷ In prior opinion surveys, more than 93% of referring physicians and orthopedic surgeons have reported that patients'' sex has no effect on their decision to refer a patient for, or perform, total knee arthroplasty.^12,13 However, there may be a difference between what is reported in a survey and what occurs in clinical practice. The purpose of our study was to determine whether physicians would provide the same recommendation about total knee arthroplasty to a male and a female standardized patient presenting to their offices with identical clinical scenarios that differed only by sex.     

Efficacy of pneumococcal vaccination in adults: a meta-analysis

Background

Clinical trials and meta-analyses have produced conflicting results of the efficacy of unconjugated pneumococcal polysaccharide vaccine in adults. We sought to evaluate the vaccine''s efficacy on clinical outcomes as well as the methodologic quality of the trials.

Methods

We searched several databases and all bibliographies of reviews and meta-analyses for clinical trials that compared pneumococcal polysaccharide vaccine with a control. We examined rates of pneumonia and death, taking the methodologic quality of the trials into consideration.

Results

We included 22 trials involving 101 507 participants: 11 trials reported on presumptive pneumococcal pneumonia, 19 on all-cause pneumonia and 12 on all-cause mortality. The current 23-valent vaccine was used in 8 trials. The relative risk (RR) was 0.64 (95% confidence interval [CI] 0.43–0.96) for presumptive pneumococcal pneumonia and 0.73 (95% CI 0.56–0.94) for all-cause pneumonia. There was significant heterogeneity between the trials reporting on presumptive pneumonia (I² = 74%, p < 0.001) and between those reporting on all-cause pneumonia (I² = 90%, p < 0.001). The RR for all-cause mortality was 0.97 (95% CI 0.87–1.09), with moderate heterogeneity between trials (I² = 44%, p = 0.053). Trial quality, especially regarding double blinding, explained a substantial proportion of the heterogeneity in the trials reporting on presumptive pneumonia and all-cause pneumonia. There was little evidence of vaccine protection in trials of higher methodologic quality (RR 1.20, 95% CI 0.75–1.92, for presumptive pneumonia; and 1.19, 95% CI 0.95–1.49, for all-cause pneumonia in double-blind trials; p for heterogeneity > 0.05). The results for all-cause mortality in double-blind trials were similar to those in all trials combined. There was little evidence of vaccine protection among elderly patients or adults with chronic illness in analyses of all trials (RR 1.04, 95% CI 0.78–1.38, for presumptive pneumococcal pneumonia; 0.89, 95% CI 0.69–1.14, for all-cause pneumonia; and 1.00, 95% CI 0.87–1.14, for all-cause mortality).

Interpretation

Pneumococcal vaccination does not appear to be effective in preventing pneumonia, even in populations for whom the vaccine is currently recommended.The burden of disease due to Streptococcus pneumoniae falls mainly on children, elderly people and people with underlying conditions such as HIV infection.¹ Pneumococcal polysaccharide vaccines were developed more than 50 years ago and have progressed from 2-valent vaccines to the current 23-valent vaccine, which has been available since the early 1980s. The 23-valent vaccine includes serotypes accounting for 72%² to 95%³ of invasive pneumococcal disease, depending on the geographic area. In many industrialized countries, pneumococcal vaccination is currently recommended for people aged 65 years and older and for individuals aged 2–64 who are at increased risk of pneumococcal disease.^4–6Meta-analyses of controlled clinical trials have produced conflicting results of the efficacy of unconjugated pneumococcal polysaccharide vaccine.^7–22 The lack of consistency between results reported from observational studies and controlled trials is another reason why the efficacy of the vaccine remains controversial. Empirical studies have shown that inadequate quality of clinical trials can lead to biases that distort their results.²³ For example, inadequate allocation concealment or failure to blind patients, caregivers or those assessing outcomes may exaggerate treatment effects.²³ Despite this, none of the previous reviews formally compared effect sizes in trials of high methodologic quality with effect sizes in trials of lower quality. We conducted a systematic review and meta-analysis of clinical trials examining the efficacy of pneumococcal polysaccharide vaccination on clinical outcomes, taking the quality of trials into account.     

Death and renal transplantation among Aboriginal people undergoing dialysis

Background

Despite the increase in the number of Aboriginal people with end-stage renal disease around the world, little is known about their health outcomes when undergoing renal replacement therapy. We evaluated differences in survival and rate of renal transplantation among Aboriginal and white patients after initiation of dialysis.

Methods

Adult patients who were Aboriginal or white and who commenced dialysis in Alberta, Saskatchewan or Manitoba between Jan. 1, 1990, and Dec. 31, 2000, were recruited for the study and were followed until death, transplantation, loss to follow-up or the end of the study (Dec. 31, 2001). We used Cox proportional hazards models to examine the effect of race on patient survival and likelihood of transplant, with adjustment for potential confounders.

Results

Of the 4333 adults who commenced dialysis during the study period, 15.8% were Aboriginal and 72.4% were white. Unadjusted rates of death per 1000 patient-years during the study period were 158 (95% confidence interval [CI] 144–176) for Aboriginal patients and 146 (95% CI 139–153) for white patients. When follow-up was censored at the time of transplantation, the age-adjusted risk of death after initiation of dialysis was significantly higher among Aboriginal patients than among white patients (hazard ratio [HR] 1.15, 95% CI 1.02–1.30). The greater risk of death associated with Aboriginal race was no longer observed after adjustment for diabetes mellitus and other comorbid conditions (adjusted HR 0.89, 95% CI 0.77–1.02) and did not appear to be associated with socioeconomic status. During the study period, unadjusted transplantation rates per 1000 patient-years were 62 (95% CI 52–75) for Aboriginal patients and 133 (95% CI 125–142) for white patients. Aboriginal patients were significantly less likely to receive a renal transplant after commencing dialysis, even after adjustment for potential confounders (HR 0.43, 95% CI 0.35–0.53). In an additional analysis that included follow-up after transplantation for those who received renal allografts, the age-adjusted risk of death associated with Aboriginal race (HR 1.36, 95% CI 1.21–1.52) was higher than when follow-up after transplantation was not considered, perhaps because of the lower rate of transplantation among Aboriginals.

Interpretation

Survival among dialysis patients was similar for Aboriginal and white patients after adjustment for comorbidity. However, despite universal access to health care, Aboriginal people had a significantly lower rate of renal transplantation, which might have adversely affected their survival when receiving renal replacement therapy.In North America and the Antipodes, the incidence of diabetes among adolescent and adult Aboriginals has risen dramatically,^1,2,3,4 with corresponding increases in the prevalence of diabetic nephropathy.^5,6,7 Aboriginal people in Canada have experienced disproportionately high incidence rates of end-stage renal disease (ESRD), with an 8-fold increase in the number of prevalent dialysis patients between 1980 and 2000.⁸ Although the incidence of ESRD appears to have decreased in recent years, the prevalence of diabetes mellitus and its complications are rising, especially among young people.^9,10,11Most work evaluating health outcomes among Aboriginal people considers either the general population¹²or diseases for which interventions are implemented over a short period, such as alcohol abuse,¹³ injury¹⁴ or critical illness.¹⁵ Death and markers of poor health are significantly more common among Aboriginal people than among North Americans of European ancestry, perhaps because of the greater prevalence of diabetes mellitus, adverse health effects due to lower socioeconomic status¹⁶ and reduced access to primary care.¹⁷ Aboriginal patients may also face unique barriers to care, including mistrust of non-Aboriginal providers, institutional discrimination or preference for traditional remedies.¹⁸ These factors may be most relevant when contact with physicians is infrequent, which obstructs development of a therapeutic relationship. In contrast, ESRD is a chronic illness that requires ongoing care from a relatively small, stable multidisciplinary team.Although recent evidence highlights racial inequalities in morbidity and mortality among North Americans with ESRD, most studies have focused on black or Hispanic populations.¹⁹We conducted this study to evaluate rates of death and renal transplantation among Aboriginal people after initiation of dialysis in Alberta, Saskatchewan and Manitoba.     

Rate of elective cholecystectomy and the incidence of severe gallstone disease

Background

The use of elective cholecystectomy has increased dramatically following the widespread adoption of laparoscopic cholecystectomy. We sought to determine whether this increase has resulted in a reduction in the incidence of severe complications of gallstone disease.

Methods

We examined longitudinal trends in the population-based rates of severe gallstone disease from 1988 to 2000, using a quasi-experimental longitudinal design to assess the effects of the large increase in elective cholecystectomy rates after 1991 among people aged 18 years and older residing in Ontario. We also measured the rate of hospital admission because of acute diverticulitis, to control for secular trends in the use of hospital care for acute abdominal diseases.

Results

The adjusted annual rate of elective cholecystectomy per 100 000 population increased from 201.3 (95% confidence interval [CI] 197.0–205.8) in 1988–1990 to 260.8 (95% CI 257.1– 264.5) in 1992–2000 (rate ratio [RR] 1.35, 95% CI 1.32– 1.38, p 0.001). An anomalously high number of elective cholecystectomies were performed in 1991. Overall, the annual rate of severe gallstone diseases (acute cholecystitis, acute biliary pancreatitis and acute cholangitis) declined by 10% (RR 0.90, 95% CI 0.88– 0.91) for 1992–2000 as compared with 1988–1991. This decline was entirely due to an 18% reduction in the rate of acute cholecystitis (RR 0.82, 95% CI 0.80–0.84).

Interpretation

The increase in the rate of elective cholecystectomy that occurred following the introduction of laparoscopic cholecystectomy in 1991 was associated with an overall reduction in the incidence of severe gallstone disease that was entirely attributable to a reduction in the incidence of acute cholecystitis.After the widespread introduction of laparoscopic cholecystectomy in 1991, the rate of cholecystectomy in North America increased by 30% to 60%,^1,2,3 primarily because of higher rates of elective operations.¹ Although cholecystectomy is not ordinarily indicated in people with asymptomatic gallstones,^4,5 the decision to perform the procedure is highly discretionary.⁶ It is unclear whether the increased rate of elective cholecystectomy is due to overuse of surgery among people with asymptomatic or minimally symptomatic gallstones, or whether more patients with clinically important gallbladder disease are willing to undergo cholecystectomy with the availability of laparoscopic surgery.^7,8Most cholecystectomies are done in people with uncomplicated biliary colic, the most common presentation of symptomatic gallstones.⁸ Severe complications of gallbladder disease, such as acute cholecystitis, acute biliary pancreatitis and acute cholangitis, are potentially life-threatening conditions that require hospital care. Greater use of elective cholecystectomy in people at risk of severe gallstone complications should result in a lower incidence of such complications. We sought to determine whether the increase in the rate of elective cholecystectomy was associated with a reduction in the incidence of severe complications of gallbladder disease.     

Fluoroquinolones compared with β-lactam antibiotics for the treatment of acute bacterial sinusitis: a meta-analysis of randomized controlled trials

Background

The presumed superiority of newer fluoroquinolones for the treatment of acute bacterial sinusitis is based on laboratory data but has not yet been established on clinical grounds.

Methods

We performed a meta-analysis of randomized controlled trials comparing the effectiveness and safety of fluoroquinolones and β-lactams in acute bacterial sinusitis.

Results

We identified 8 randomized controlled trials investigating the newer “respiratory” fluoroquinolones moxifloxacin, levofloxacin and gatifloxacin. In the primary effectiveness analysis involving 2133 intention-to-treat patients from 5 randomized controlled trials, the extent of clinical cure and improvement did not differ between fluoroquinolones and β-lactams (odds ratio [OR] 1.09, 95% confidence interval [CI] 0.85–1.39) at the test-of-cure assessment, which varied from 10 to 31 days after the start of treatment. Fluoroquinolones were associated with an increased chance of clinical success among the clinically evaluable patients in all of the randomized controlled trials (OR 1.29, 95% CI 1.03–1.63) and in 4 blinded randomized controlled trials (OR 1.45, 95% CI 1.05–2.00). There was no statistically significant difference between fluoroquinolones and amoxicillin–clavulanate (OR 1.24, 95% CI 0.93–1.65). Eradication or presumed eradication of the pathogens isolated before treatment was more likely with fluoroquinolone treatment than with β-lactam treatment (OR 2.11, 95% CI 1.09–4.08). In the primary safety analysis, adverse events did not differ between treatments (OR 1.17, 95% CI 0.86–1.59). However, more adverse events occurred with fluoroquinolone use than with β-lactam use in 2 blinded randomized controlled trials. The associations described here were generally consistent when we included 3 additional studies involving other fluoroquinolones (ciprofloxacin and sparfloxacin) in the analysis.

Interpretation

In the treatment of acute bacterial sinusitis, newer fluoroquinolones conferred no benefit over β-lactam antibiotics. The use of fluoroquinolones as first-line therapy cannot be endorsed.Acute bacterial sinusitis (more accurately known as rhinosinusitis, given that the nasal mucosa is commonly involved¹) is one of the most frequent health disorders;² it has an adverse impact on patients'' quality of life³ and accounts for nearly 3 million ambulatory care visits in the United States annually⁴ and substantial health care costs.⁵Acute bacterial sinusitis typically follows an episode of viral upper respiratory tract illness.² The diagnosis of bacterial disease in routine clinical practice is usually based on the presence of a constellation of clinical manifestations.¹ The bacterial pathogens most commonly involved are Streptococcus pneumoniae, Haemophilus influenzae and, to a lesser degree, Moraxella catarrhalis.^6,7 Over the years, these pathogens have acquired various degrees of resistance to many traditional antibiotics.⁸The benefit of older antibiotics over placebo in the treatment of acute bacterial sinusitis appears limited, mostly because of the high success rate achieved with placebo.^9,10 However, newer, third-and fourth-generation fluoroquinolones possess excellent in vitro activity against the most common respiratory pathogens,¹¹ and for this reason these drugs are often designated as “respiratory.” Based on analysis of the available laboratory data, current guidelines give the newer fluoroquinolones the highest ranking, in terms of expected clinical effectiveness, among the antimicrobials used to treat acute bacterial sinusitis (although admittedly the difference is marginal).⁷The presumed clinical advantage of the respiratory fluoroquinolones over other classes of antimicrobials has not been clearly demonstrated in comparative clinical trials or meta-analyses.^9,10 We aimed to comprehensively reassess the role of fluoroquinolones in the treatment of acute bacterial sinusitis, in terms of effectiveness and safety, by performing a meta-analysis of relevant randomized controlled trials.     

Access to health care among status Aboriginal people with chronic kidney disease

Background

Ethnic disparities in access to health care and health outcomes are well documented. It is unclear whether similar differences exist between Aboriginal and non-Aboriginal people with chronic kidney disease in Canada. We determined whether access to care differed between status Aboriginal people (Aboriginal people registered under the federal Indian Act) and non-Aboriginal people with chronic kidney disease.

Methods

We identified 106 511 non-Aboriginal and 1182 Aboriginal patients with chronic kidney disease (estimated glomerular filtration rate less than 60 mL/min/1.73 m²). We compared outcomes, including hospital admissions, that may have been preventable with appropriate outpatient care (ambulatory-care–sensitive conditions) as well as use of specialist services, including visits to nephrologists and general internists.

Results

Aboriginal people were almost twice as likely as non-Aboriginal people to be admitted to hospital for an ambulatory-care–sensitive condition (rate ratio 1.77, 95% confidence interval [CI] 1.46–2.13). Aboriginal people with severe chronic kidney disease (estimated glomerular filtration rate < 30 mL/min/1.73 m²) were 43% less likely than non-Aboriginal people with severe chronic kidney disease to visit a nephrologist (hazard ratio 0.57, 95% CI 0.39–0.83). There was no difference in the likelihood of visiting a general internist (hazard ratio 1.00, 95% CI 0.83–1.21).

Interpretation

Increased rates of hospital admissions for ambulatory-care–sensitive conditions and a reduced likelihood of nephrology visits suggest potential inequities in care among status Aboriginal people with chronic kidney disease. The extent to which this may contribute to the higher rate of kidney failure in this population requires further exploration.Ethnic disparities in access to health care are well documented;^1,2 however, the majority of studies include black and Hispanic populations in the United States. The poorer health status and increased mortality among Aboriginal populations than among non-Aboriginal populations,^3,4 particularly among those with chronic medical conditions,^5,6 raise the question as to whether there is differential access to health care and management of chronic medical conditions in this population.The prevalence of end-stage renal disease, which commonly results from chronic kidney disease, is about twice as common among Aboriginal people as it is among non-Aboriginal people.^7,8 Given that the progression of chronic kidney disease can be delayed by appropriate therapeutic interventions^9,10 and that delayed referral to specialist care is associated with increased mortality,^11,12 issues such as access to health care may be particularly important in the Aboriginal population. Although previous studies have suggested that there is decreased access to primary and specialist care in the Aboriginal population,^13–15 these studies are limited by the inclusion of patients from a single geographically isolated region,¹³ the use of survey data,¹⁴ and the inability to differentiate between different types of specialists and reasons for the visit.¹⁵In addition to physician visits, admission to hospital for ambulatory-care–sensitive conditions (conditions that, if managed effectively in an outpatient setting, do not typically result in admission to hospital) has been used as a measure of access to appropriate outpatient care.^16,17 Thus, admission to hospital for an ambulatory-care–sensitive condition reflects a potentially preventable complication resulting from inadequate access to care. Our objective was to determine whether access to health care differs between status Aboriginal (Aboriginal people registered under the federal Indian Act) and non-Aboriginal people with chronic kidney disease. We assess differences in care by 2 measures: admission to hospital for an ambulatory-care–sensitive condition related to chronic kidney disease; and receipt of nephrology care for severe chronic kidney disease as recommended by clinical practice guidelines.¹⁸     

Respiratory fluoroquinolones for the treatment of community-acquired pneumonia: a meta-analysis of randomized controlled trials

Background

We investigated whether the use of respiratory fluoroquinolones was associated with better clinical outcomes compared with the use of macrolides and β-lactams among adults with pneumonia.

Methods

We searched PubMed, Current Contents, Scopus, EMBASE, ClinicalTrials.gov and Cochrane with no language restrictions. Two reviewers independently extracted data from published trials that compared fluoroquinolones (levofloxacin, moxifloxacin, gemifloxacin) with macrolides or β-lactams or both. A meta-analysis was performed with the clinical outcomes of mortality, treatment success and adverse outcomes.

Results

We included 23 trials in our meta-analysis. There was no difference in mortality among patients who received fluoroquinolones or the comparator antibiotics (OR 0.85, 95% CI 0.65–1.12). Pneumonia resolved in more patients who received fluoroquinolones compared with the comparator antibiotics for the included outcomes in the intention-to-treat population (OR 1.17, 95% CI 1.00–1.36), clinically evaluable population (OR 1.26, 95% CI 1.06–1.50) and the microbiologically assessed population (OR 1.67, 95% CI 1.28–2.20). Fluoroquinolones were more effective than a combination of β-lactam and macrolide (OR 1.39, 95% CI 1.02–1.90). They were also more effective for patients with severe pneumonia (OR 1.84, 95% CI 1.02–3.29), those who required admission to hospital (OR = 1.30, 95% CI 1.04–1.61) and those who required intravenous therapy (OR = 1.44, 15% CI 1.13–1.85). Fluoroquinolones were more effective than β-lactam and macrolide in open-label trials (OR = 1.35, 95% CI 1.08–1.69) but not in blinded randomized controlled trials (OR = 1.13, 95% CI 0.85–1.50).

Interpretation

Fluoroquinolones were associated with higher success of treatment for severe forms of pneumonia; however, a benefit in mortality was not evident. A randomized controlled trial that includes patients with severe pneumonia with or without bacteremia is needed.Community-acquired pneumonia is among the leading reasons for hospital admission¹ and resource consumption.^2,3 It is the most frequent cause of community-acquired infections among patients admitted to intensive care units.⁴ In addition, it is among the leading causes of death worldwide.Physicians must choose an optimal therapeutic regimen that eliminates the infection effectively, minimizes the risk of developing drug resistance and does not compromise the safety of the patient. The combination of β-lactam and macrolide covers the most common possible pathogens involved in the pathogenesis of pneumonia.⁵ More recently, fluoroquinolones with enhanced activity against Streptococcus pneumoniae were introduced in clinical practice. The favourable pharmacokinetic profile of fluoroquinolones allows for once daily administration, often eliminating the need for parenteral treatment. Furthermore, initial treatment with fluoroquinolones was among the predictors of lower treatment failure among patients with pneumonia.⁶In 2007, the Infectious Diseases Society of America and the American Thoracic Society released new guidelines for the management of care for adult patients with community-acquired pneumonia.⁷ In these guidelines, levofloxacin, gemifloxacin and moxifloxacin were reported to be equally effective as the combination of β-lactam and macrolide, and were proposed to be the preferred treatment option for patients who require admission to hospital, as well as for patients with comorbidity who receive treatment as outpatients. In addition to being safe, these fluoroquinolones are more effective against the most common types of bacteria responsible for the development of community-acquired pneumonia.⁷ For example, S. pneumoniae strains are not fully susceptible to ciprofloxacin. On the other hand, trovafloxacin, clinafloxacin, gatifloxacin and other quinolones are not used because of safety concerns or because they are not widely available. The trials that compared fluoroquinolones with other antibiotics regimens for the treatment of pneumonia were designed on the basis of noninferiority (i.e., an antibiotic is equally effective to a comparator), and several were conducted in order to receive approval from the relevant agencies.We sought to examine whether the use of fluoroquinolones was associated with more advantages or disadvantages than the use of macrolides or β-lactams in terms of mortality, resolution of pneumonia and adverse effects.     

Does delivery volume of family physicians predict maternal and newborn outcome?

Background

The number of births attended by individual family physicians who practice intrapartum care varies. We wanted to determine if the practice–volume relations that have been shown in other fields of medical practice also exist in maternity care practice by family doctors.

Methods

For the period April 1997 to August 1998, we analyzed all singleton births at a major maternity teaching hospital for which the family physician was the responsible physician. Physicians were grouped into 3 categories on the basis of the number of births they attended each year: fewer than 12, 12 to 24, and 25 or more. Physicians with a low volume of deliveries (72 physicians, 549 births), those with a medium volume of deliveries (34 physicians, 871 births) and those with a high volume of deliveries (46 physicians, 3024 births) were compared in terms of maternal and newborn outcomes. The main outcome measures were maternal morbidity, 5-minute Apgar score and admission of the baby to the neonatal intensive care unit or special care unit. Secondary outcomes were obstetric procedures and consultation patterns.

Results

There was no difference among the 3 volume cohorts in terms of rates of maternal complications of delivery, 5-minute Apgar scores of less than 7 or admissions to the neonatal intensive care unit or the special care unit, either before or after adjustment for parity, pregnancy-induced hypertension, diabetes, ethnicity, lone parent status, maternal age, gestational age, newborn birth weight and newborn head circumference at birth. High- and medium-volume family physicians consulted with obstetricians less often than low-volume family physicians (adjusted odds ratio [OR] 0.586 [95% confidence interval, CI, 0.479–0.718] and 0.739 [95% CI 0.583–0.935] respectively). High- and medium-volume family physicians transferred the delivery to an obstetrician less often than low-volume family physicians (adjusted OR 0.668 [95% CI 0.542–0.823] and 0.776 [95% CI 0.607–0.992] respectively). Inductions were performed by medium-volume family physicians more often than by low-volume family physicians (adjusted OR 1.437 [95% CI 1.036–1.992].

Interpretation

Family physicians'' delivery volumes were not associated with adverse outcomes for mothers or newborns. Low-volume family physicians referred patients and transferred deliveries to obstetricians more frequently than high- or medium-volume family physicians. Further research is needed to validate these findings in smaller facilities, both urban and rural.More than 20 years ago, Luft and associates¹ conducted one of the earliest volume–outcome studies. Since then, many studies addressing the relation between volume of procedures and patient outcomes have been published.^2,3 In some of these studies, either the hospital size or the physician procedural volume was used as a surrogate for physician expertise. Among studies analyzing hospital volumes and outcomes, better outcomes have been associated with higher patient volumes in some instances^4,5,6,7 but not others.^3,8,9 Some studies of individual provider volume have shown a positive relation between volume and outcomes,^10,11 whereas others have shown no relation or inconsistent results.^3,12 Finally, a few studies analyzing both hospital volume and provider volume have reported a positive volume–outcome relation.^13,14Criticism levelled at the methods used in volume–outcome studies have addressed the lack of adjustment for case mix, different cutoff points for volume categories and retrospective design.³ Other factors that have an effect on patient outcomes but that have not been included in previous volume analyses include health maintenance organization status, physician certification and years since graduation, and patient socioeconomic status, age and ethnicity. Furthermore, most of the studies on volume have covered surgical or oncology specialities.The few studies that have been done on volume and outcome in maternity care have shown variable effects. Rural health care is often associated with lower volumes of obstetric procedures. However, no differences in maternal or newborn outcomes have been shown in some comparisons of births in urban and rural locations.^15,16,17,18 Other studies have shown poorer maternal and newborn outcomes in low-volume hospitals, neonatal intensive care units (NICUs) and rural locations.^19,20,21,22 Conversely, higher volume (hospitals with more than 1000 deliveries per year) has been associated with more maternal lacerations or complications.²³When the health care provider has been the unit of analysis, a relation between volume and maternal or newborn outcome has been demonstrated in at least one study²⁴ but not in others.^25,26 Low volume has been defined as 20 to 24 deliveries per year.^24,26 Hass and colleagues²⁴ reported an adjusted odds ratio (OR) of 1.4 for low birth weight for infants delivered by low-volume non-board-certified physicians relative to high-volume non-board-certified physicians; the adjusted OR was 1.56 for low-volume board-certified physicians relative to high-volume board-certified physicians (98.7% of whom were obstetricians).Possible explanations for the differences among studies include differences in health care delivery systems, insurance coverage, experience and training of providers, maternal risk factors, triage or transfer of high-risk cases, choice of outcome measures, and changes over time in access to care, quality assurance and standard of living. Relations have been reported between maternal or newborn outcomes and smoking, maternal history of low birth weight (for previous pregnancies), pregnancy–induced hypertension, diabetes, prepregnancy weight, gestational weight gain, maternal height and age, multiple gestation, previous vaginal birth after cesarean section, history of previous delivery problems, parity, large-for-date fetus, ethnicity and fetal sex.^25,27,28,29 Few studies of the relation between volume of births and obstetric outcome have been able to control for these potentially confounding variables and adjust for maternal risk factors.Our database of detailed accounts of births in one hospital setting allowed us to examine this issue more rigorously. We posed 2 research questions: Is there a relation between the volume of deliveries attended by individual family physicians and maternal and newborn outcomes? If there are differences in outcomes, are they related to different physician practice styles and consultation patterns?     

Physical violence against intimate partners and related exposures to violence among South African men

Background

Despite high rates of intimate partner violence in South Africa, there have been no national studies of men''s perpetration of violence against female partners.

Methods

We analyzed data from the South Africa Stress and Health Study, a cross-sectional, nationally representative study, specifically examining data for men who had ever been married or had ever cohabited with a female partner. We calculated the prevalence of physical violence against intimate female partners and used logistic regression to examine associations with physical abuse during childhood and exposure to parental and community violence.

Results

A total of 834 male participants in the South Africa Stress and Health Study met the study criteria. Of these, 27.5% reported using physical violence against their current or most recent female partner during their current or most recent marriage or cohabiting relationship. Crude odds ratios (ORs) and 95% confidence intervals (CIs) indicated significant associations between perpetration of violence against an intimate partner and witnessing parental violence (OR 3.91, 95% CI 2.66–5.73) or experiencing physical abuse during childhood (OR 3.24, 95% CI 2.27–4.63), but not exposure to community violence (OR 1.29, 95% CI 0.88–1.88). The 2 significant associations persisted in adjusted analyses: OR 3.22 (95% CI 1.94–5.33) for witnessing parental violence and OR 1.73 (95% CI 1.07–2.79) for experiencing physical abuse during childhood.

Interpretation

We found a high prevalence of physical violence perpetrated by men against their intimate partners. Men who experienced physical abuse during childhood or were exposed to parental violence were at the greatest risk.Most research about men''s perpetration of violence against female intimate partners has concentrated on elucidating the factors that put women at risk for experiencing such violence and identifying the related service needs. Less work has been done to investigate the factors affecting men''s risk of perpetrating violence against women. Such work is needed to inform development of empirically based public health programs to reduce men''s use of such violence. Intimate partner violence is of pandemic proportions, with global estimates indicating that 15% to 75% of women have experienced such abuse.^1,2 Such violence may confer grave health consequences, including transmission of HIV/AIDS.³The overwhelming majority of research on violence against intimate partners perpetrated by men has been conducted in Western countries, with the focus on men at high risk for such activity (e.g., prisoners, people enrolled in intervention programs for batterers).^4,5 This work has highlighted the importance of exposure to violence early in life (e.g., witnessing parental violence, experiencing child abuse) in predicting perpetration of violence against a partner during adulthood.⁶ Recently, the potential relations between community violence and men''s perpetration of violence against intimate partners have also been examined.⁷Fewer studies have been done in developing nations, but several notable investigations have recently assessed men''s perpetration of violence against intimate partners in South Africa, specifically in Eastern Cape and Cape Town. Two of these studies have indicated high rates of violence against intimate partners: 31.8% in Eastern Cape⁸ and 42.3% in Cape Town.⁹ The extent to which these findings reflect national rates is unknown. Furthermore, work with both men and women in South Africa has demonstrated strong relations between violence (men''s perpetration and women''s victimization) and higher rates of sexually risky behaviours.^3,8 Associations between women''s experience as victims of intimate partner violence and HIV infection have also been documented.³ These data strongly suggest that men''s perpetration of violence against intimate partners is common in South Africa and that it may play an important role in this nation''s HIV epidemic,^3,8 which currently ranks highest in the world with respect to the number of people living with HIV.¹⁰In the study reported here, we sought to build upon prior work by using a national sample of South African men to examine the prevalence of physical violence perpetrated by men against their female intimate partners and potential violence-related risk factors (i.e., exposure to parental violence, experience of abuse in childhood and exposure to community violence).     

A Chimeric Alphavirus Replicon Particle Vaccine Expressing the Hemagglutinin and Fusion Proteins Protects Juvenile and Infant Rhesus Macaques from Measles

Measles remains a major cause of child mortality, in part due to an inability to vaccinate young infants with the current live attenuated virus vaccine (LAV). To explore new approaches to infant vaccination, chimeric Venezuelan equine encephalitis/Sindbis virus (VEE/SIN) replicon particles were used to express the hemagglutinin (H) and fusion (F) proteins of measles virus (MV). Juvenile rhesus macaques vaccinated intradermally with a single dose of VEE/SIN expressing H or H and F proteins (VEE/SIN-H or VEE/SIN-H+F, respectively) developed high titers of MV-specific neutralizing antibody and gamma-interferon (IFN-γ)-producing T cells. Infant macaques vaccinated with two doses of VEE/SIN-H+F also developed neutralizing antibody and IFN-γ-producing T cells. Control animals were vaccinated with LAV or with a formalin-inactivated measles vaccine (FIMV). Neutralizing antibody remained above the protective level for more than 1 year after vaccination with VEE/SIN-H, VEE/SIN-H+F, or LAV. When challenged with wild-type MV 12 to 17 months after vaccination, all vaccinated juvenile and infant monkeys vaccinated with VEE/SIN-H, VEE/SIN-H+F, and LAV were protected from rash and viremia, while FIMV-vaccinated monkeys were not. Antibody was boosted by challenge in all groups. T-cell responses to challenge were biphasic, with peaks at 7 to 25 days and at 90 to 110 days in all groups, except for the LAV group. Recrudescent T-cell activity coincided with the presence of MV RNA in peripheral blood mononuclear cells. We conclude that VEE/SIN expressing H or H and F induces durable immune responses that protect from measles and offers a promising new approach for measles vaccination. The viral and immunological factors associated with long-term control of MV replication require further investigation.Measles remains a major cause of child mortality despite the availability of a safe and effective live attenuated virus vaccine (LAV). Recent efforts to improve routine vaccination and implement national immunization days have moved measles control toward the World Health Organization''s goal of a 90% reduction in mortality by 2010 compared to 2000 (7). One persistent impediment to measles control in many countries remains the inability to successfully immunize young infants due to the immaturity of the immune system and interference of maternal antibodies with immune responses to LAV (1, 15, 65).Because the decrease in maternal antibody varies from one infant to another, many children in areas with high measles virus (MV) transmission rates are at risk of acquiring measles prior to vaccination (3, 5, 12). Immaturity also affects the quality and quantity of antibody produced in response to the current vaccine, with lower levels of neutralizing antibody and deficient avidity and isotype maturation in younger than in older infants (15, 16, 37, 59). As a result, the recommended age for vaccination is generally 9 months in developing countries to balance the risk of infection with the likelihood of response to the vaccine (24).A vaccine that could be given to children under the age of 6 months would improve measles control by allowing delivery with other infant vaccines and by closing the window of susceptibility prior to delivery of the current vaccine. Increasing the dose of LAV improved the antibody responses in young infants but resulted in an unexpected increase in mortality for girls, so this is not an acceptable approach to lowering the age of vaccination (18, 26, 29). Experience with a formalin-inactivated measles vaccine (FIMV) in the 1960s also led to unexpected complications. FIMV provided only short-term protection, and vaccinated individuals were at risk for more severe disease (atypical measles) upon infection with wild-type MV (14, 36, 54). Therefore, other strategies are necessary for development of a vaccine for young infants.One particularly promising approach for delivery of vaccine antigens is the use of alphavirus replicon particles (55). Alphaviruses are small positive-strand RNA viruses with the nonstructural replicase proteins encoded in the 5′ two-thirds of the genome and the structural proteins in the 3′ one-third. A subgenomic promoter is used to synthesize an abundant, smaller RNA from which the structural proteins are translated (61). Replicons contain the nonstructural protein genes, the 5′ and 3′ end cis-active replication sequences, and the subgenomic promoter that directs expression of a heterologous gene rather than the viral structural proteins. The replicon RNA can be packaged into virus-like particles by providing the structural proteins in trans using transient transfection (6, 33) or with stable packaging cell lines (51) and can be engineered for efficient delivery to antigen-presenting cells (17). Advantages include high-level expression of the vaccine antigen (68), stimulation of innate immunity (25, 31, 32, 64), and general lack of preexisting immunity in the human population.MV encodes six structural proteins of which two, hemagglutinin (H) and fusion (F), are surface glycoproteins involved in attachment and entry. Antibodies that inhibit MV infection in neutralization assays are directed primarily against the H protein, which also contains important CD8⁺ T-cell epitopes (39, 41). Nonhuman primates, particularly rhesus macaques, develop a disease similar to that of humans and offer the opportunity for assessing both protection from wild-type MV challenge and priming for enhanced disease after immunization with new experimental vaccines (2, 48, 50, 66). Because protection from measles correlates best with the quality and quantity of neutralizing antibodies at the time of exposure (9, 50), most experimental vaccines have used H alone or H and F for induction of MV protective immunity (44, 50, 65, 70).Alphaviruses that have been used for construction of replicon particle vaccines include Sindbis virus (SINV) (6, 68), Semliki Forest virus (33), and Venezuelan equine encephalitis virus (VEEV) (53). Each of the alphavirus vectors studied has its own advantages and disadvantages. For instance, VEEV replicon particles have high levels of gene expression (47), but vaccine production is disadvantaged by the requirement for biosafety level 3 manufacturing. SINV replicon particles avoid the safety concerns of VEEV, but expression levels are lower. Previous studies of a SINV-based replicon particle vaccine expressing MV H (SIN-H) in macaques showed good induction of neutralizing antibody and T-cell responses and protection from rash (44). However, vaccinated monkeys developed viremias after challenge, indicating that they were not protected from infection. In this study, we sought to improve the alphavirus replicon particle approach to vaccination for measles by using a chimeric VEE/SIN vaccine (47) expressing both the MV H and F proteins.     

Dendritic Cells Loaded with Tumor B Cells Elicit Broad Immunity against Murine Gammaherpesvirus 68 but Fail To Prevent Long-Term Latency

It is still unknown whether a noninfectious gammaherpesvirus vaccine is able to prevent or reduce virus persistence. This led us to use dendritic cells loaded with tumor B cells as a vaccine approach for the murine gammaherpesvirus 68 (γHV68) model of infection. Dendritic cells loaded with UV-irradiated latently infected tumor B cells induce broad, strong, and long-lasting immunity against γHV68. Dendritic cell vaccination prevents the enlargement of lymph nodes and severely limits acute infection and early latency but does not prevent γHV68 from establishing long-term latency. Our findings support the concept that attenuated viruses may be the best vaccine option for preventing gammaherpesvirus persistence.Gammaherpesviruses have very high prevalence, infecting 95% of the world population. Natural infection does not induce sterilizing immunity (21, 30). Murine gammaherpesvirus 68 (γHV68) has important biological similarities to its human counterparts and is a good model for characterizing the immune response and for testing vaccine strategies (11, 33). Gammaherpesvirus vaccines designed to induce neutralizing antibodies reduce the incidence and symptoms of infectious mononucleosis (26) but are only minimally protective (1, 7, 22, 28). Peptide- or epitope-based vaccines that induce T-cell responses affect the early phase of infection but do not alter long-term latency (9, 17, 19, 29, 32). Infection with latency-attenuated viruses induces protection against a challenge with wild-type γHV68, although the vaccine virus persists in the host (6, 25, 30) except in the case of γHV68 AC-RTA (16). These findings with live-attenuated viruses reflect the ability of latency-defective viruses to elicit a wide range of humoral and cell-mediated immune responses and suggest that optimal broad immunity may achieve protection. Dendritic cells (DC) are at the core of the immune response, and they are also the main target of adjuvants. Ex vivo-loaded dendritic cells can induce humoral immunity and strong T-cell immunity (3) and accelerated generation of memory T cells (2). Dendritic cells loaded with multiple antigens could circumvent the narrow antigen specificity of peptide- or epitope-based vaccines and lack the safety concerns associated with live-attenuated herpesviruses. Thus, dendritic cell vaccination can be attractive where other approaches have failed or as a tool for elucidating mechanisms of immune protection. Here, we wanted to test whether dendritic cells loaded ex vivo with a broad range of viral antigens would ameliorate disease and confer protection to gammaherpesvirus infection by inducing strong and broad cellular and humoral immunity.     

Weekly work hours and clinical activities of Canadian family physicians: results of the 1997/98 National Family Physician Survey of the College of Family Physicians of Canada

BackgroundHealth systems planning is a challenging task, exacerbated by a lack of detailed information on the role played by family physicians, as indicated by practice variations across regions and demographic characteristics. Outcome measures used in past studies of family physician practice patterns were not uniform. Furthermore, past research has generally been limited to narrowly defined geographic regions. A national study of family physician practice patterns was undertaken to allow regional-level comparisons of clinical workload and range of medical services offered.MethodsThe 1997/98 National Family Physician Survey was mailed to a sample of 5198 Canadian family physicians and general practitioners (FP/GPs); the overall response rate was 58.4% (3036 questionnaires returned, of which 3004 were analyzable). Sampling strata were based on College of Family Physicians of Canada (CFPC) membership status and regions of Canada.ResultsClinical workload varied considerably across the demographic categories studied. Male physicians reported 8.9 more total weekly work hours than female physicians, but the mean number of medical and clinical services offered did not differ between the sexes. Solo practitioners reported 53.8 (95% confidence interval [CI] 52.7–55.0) total weekly work hours, whereas those practising in multidisciplinary clinics reported 45.0 (95% CI 43.2–46.8) hours. FP/GPs in the Atlantic and Prairie provinces reported 5.6 and 5.1 more weekly work hours, respectively, than the national average of 51.4 (95% CI 50.8–52.0) hours. Finally, FP/GPs who served inner-city populations reported 48.6 (95% CI 46.8–50.5) total weekly work hours, whereas those serving rural populations reported 57.0 (95% CI 54.7–59.2) hours. Mean weekly work hours were similar for all age cohorts less than 65 years. FP/GPs practising in less populated provinces and in rural areas reported the highest numbers of work hours, medical services offered and clinical procedures performed. InterpretationThese data suggest significant variations in FP/GP clinical workload in relation to key demographic variables. Physician resource planning in Canada is a challenging and inexact science. Past attempts have resulted in variable estimates of the ultimate need for physician services. There is a clear recognition that we need more information than simple head counts of physicians. We need to know, for example, what physicians do and how they work with other physicians, and we need to identify regional variations and differences in practice patterns.Past studies of family physician practice patterns have measured workload in terms of hours worked,^1,2,3 number of patient visits,^2,3 billings to health insurance plans^4,5 and range of clinical procedures performed.^5,6,7 These outcomes have been analyzed in relation to practice setting,^1,2,6,7 geographic physician density,^4,5 sex,^{1,2,3,4,5,6,7} age,^1,2,4,5,7 years in practice^3,6 and type of practice.^1,2,3,6,7Although past studies have proven useful in describing the significant relations that exist between physician workloads and demographic characteristics, they have not addressed the broader issue of access to family physicians'' services throughout Canada. By gathering uniform information from family doctors across the country, the College of Family Physicians of Canada (CFPC) National Family Physician Survey (NFPS) addresses this information gap. In this report we present the results of the 1997/98 NFPS, describing physician workload measures in relation to a comprehensive set of demographic variables.     

Effect of a topical diclofenac solution for relieving symptoms of primary osteoarthritis of the knee: a randomized controlled trial

Background

Treatment of osteoarthritis with oral NSAID therapy provides pain relief but carries a substantial risk of adverse effects. Topical NSAID therapy offers an alternative to oral treatment, with the potential for a reduced risk of side effects. The objective of this trial was to assess the safety and efficacy of a topical diclofenac solution in relieving the symptoms of primary osteoarthritis of the knee.

Methods

We identified 248 men and women from southern Ontario with primary osteoarthritis of the knee and at least moderate pain. The patients were randomly assigned to apply 1 of 3 solutions to their painful knee for 4 weeks: a topical diclofenac solution (1.5% wt/wt diclofenac sodium in a carrier containing dimethyl sulfoxide [DMSO]); a vehicle-control solution (the carrier containing DMSO but no diclofenac); and a placebo solution (a modified carrier with a token amount of DMSO for blinding purposes but no diclofenac). The primary efficacy end point was pain relief, measured by the Western Ontario and McMaster Universities (WOMAC) LK3.0 Osteoarthritis Index pain subscale. Secondary end points were improved physical function and reduced stiffness (measured by the WOMAC subscales), reduced pain on walking and patient global assessment (PGA). Safety was evaluated with clinical and laboratory assessments.

Results

In the intent-to-treat group the mean change (and 95% confidence interval [CI]) in pain score from baseline to final assessment was significantly greater for the patients who applied the topical diclofenac solution (–3.9 [– 4.8 to –2.9]) than for those who applied the vehicle-control solution (–2.5 [– 3.3 to –1.7]; p = 0.023) or the placebo solution (–2.5 [–3.3 to –1.7]; p = 0.016). For the secondary variables the topical diclofenac solution also revealed superiority to the vehicle-control and placebo solutions, leading to mean changes (and 95% CIs) of –11.6 (–14.7 to –8.4; p = 0.002 and 0.014, respectively) in physical function, –1.5 (–1.9 to –1.1; p = 0.015 and 0.002, respectively) in stiffness and –0.8 (–1.1 to –0.6; p = 0.003 and 0.015, respectively) in pain on walking. The PGA scores were significantly better for the patients who applied the topical diclofenac solution than for those who applied the other 2 solutions (p = 0.039 and 0.025, respectively). The topical diclofenac solution caused some skin irritation, mostly minor local skin dryness, in 30 (36%) of the 84 patients, but this led to discontinuation of treatment in only 5 (6%) of the cases. The incidence of gastrointestinal events did not differ between the treatment groups. No serious gastrointestinal or renal adverse events were reported or detected by means of laboratory testing.

Interpretation

This topical diclofenac solution can provide safe, site-specific treatment for osteoarthritic pain, with only minor local skin irritation and minimal systemic side effects.Osteoarthritis is a degenerative joint disease affecting articular cartilage and underlying bone, commonly of the knee.¹ Current treatment includes the oral use of NSAIDs, either nonselective or cyclooxygenase-2 (COX-2)-selective. These agents carry a substantial risk of clinically significant adverse effects, particularly on the gastrointestinal^2,3 and renal systems.⁴ Although the incidence of gastrointestinal complications has been reported to be lower with COX-2-selective NSAIDs than with nonselective NSAIDs,^5,6,7 the former have been linked to adverse renal effects⁸ and an increased risk of cardiovascular complications.⁹The need for safer treatment of osteoarthritis has led to research into the topical use of NSAIDs.^10,11,12 Recent reviews of the few published placebo-controlled studies suggest that topical NSAID therapy can relieve pain^13,14,15 with few gastrointestinal side effects.¹⁶ Current practice guidelines advocate the use of topical therapy, including NSAIDs, in the management of osteoarthritis.^17,18,19 A diclofenac solution containing the absorption enhancer dimethyl sulfoxide (DMSO) was developed for site-specific topical application. The objective of this study was to demonstrate that applying this solution to a painful knee with primary osteoarthritis could provide symptom relief with minimal systemic side effects.