Prevalence of asthma among Chinese adolescents living in Canada and in China

Background

Studies of the prevalence of asthma among migrating populations may help in identifying environmental risk factors.

Methods

We analyzed data from Vancouver, Canada, and from Guangzhou, Beijing and Hong Kong, China, collected during phase 3 of the International Study of Asthma and Allergies in Childhood. We subdivided the Vancouver adolescents according to whether they were Chinese immigrants to Canada, Canadian-born Chinese or Canadian-born non-Chinese. We compared the prevalence of asthma and wheezing among Chinese adolescents born in Canada, Chinese adolescents who had immigrated to Canada and Chinese adolescents living in China.

Results

Of 7794 Chinese adolescents who met the inclusion criteria, 3058 were from Guangzhou, 2824 were from Beijing, and 1912 were from Hong Kong. Of 2235 adolescents in Vancouver, Canada, 475 were Chinese immigrants, 617 were Canadian-born Chinese, and 1143 were Canadian-born non-Chinese. The prevalence of current wheezing among boys ranged from 5.9% in Guangzhou to 11.2% in Canadian-born Chinese adolescents. For girls, the range was 4.3% in Guangzhou to 9.8% in Canadian-born Chinese adolescents. The prevalence of ever having had asthma ranged from 6.6% to 16.6% for boys and from 2.9% to 15.0% for girls. Prevalence gradients persisted after adjustment for other environmental variables (odds ratios for ever having had asthma among Canadian-born Chinese compared with native Chinese in Guangzhou: 2.72 [95% confidence interval 1.75–4.23] for boys and 5.50 [95% confidence interval 3.21–9.44] for girls; p < 0.001 for both). Among Chinese adolescents living in Vancouver, the prevalence of ever wheezing increased with duration of residence, from 14.5% among those living in Canada for less than 7 years to 20.9% among those living their entire life in Canada. The same pattern was observed for the prevalence of ever having had asthma, from 7.7% to 15.9%.

Interpretation

Asthma symptoms in Chinese adolescents were lowest among residents of mainland China, were greater for those in Hong Kong and those who had immigrated to Canada, and were highest among those born in Canada. These findings suggest that environmental factors and duration of exposure influence asthma prevalence.The prevalence of asthma symptoms exhibits large geographic variations, even among genetically similar groups,^1,2 which suggests that differences may reflect variation in environmental factors. Epidemiologic studies have demonstrated associations between asthma and exposure to household allergens,³ pets,⁴ environmental tobacco smoke⁵ and environmental pollution,⁶ as well as sex,⁷ obesity,⁸ number of siblings and birth order,⁹ and maternal education.¹⁰ Increasing “westernization” of environmental factors (such as changes in maternal diet, smaller family size, fewer infections during infancy, increased use of antibiotics and vaccination, less exposure to rural environments and improved sanitation) has been associated with an increased risk of childhood asthma.¹¹ Conversely, the hygiene hypothesis proposed by Strachan in 1989 suggested that infections and contact with older siblings may reduce the risk of allergic diseases.¹²Migration studies examining children of the same ethnic background living in different environments for part or all of their lives may help to identify factors relevant to the development of diseases and may explain some of the observed geographic variations in prevalence. In the International Study of Asthma and Allergies in Childhood, prevalence rates for asthma in Canada were among the highest in the world, whereas those in China were among the lowest.² This difference could reflect genetic or environmental factors. China has been and continues to be a major source of international migration.^13,14 Of immigrants in Vancouver, Canada, who landed between 1985 and 2001, half were born in East Asia, mainly Hong Kong and mainland China.¹⁵ Few studies on the prevalence of asthma among immigrants have been undertaken in Canada,¹⁶ and data for Chinese people living in Canada are not available.We hypothesized that the prevalence of asthma would be highest among Canadian-born Chinese adolescents, lower among Chinese adolescents who had immigrated to Canada and lowest among Chinese adolescents living in China. We further hypothesized that, among Chinese immigrants to Canada, prevalence rates of asthma would relate to duration of residence in Canada.     

Effectiveness of a home-based balance-training program in reducing sports-related injuries among healthy adolescents: a cluster randomized controlled trial

Background

Sport is the leading cause of injury requiring medical attention among adolescents. We studied the effectiveness of a home-based balance-training program using a wobble board in improving static and dynamic balance and reducing sports-related injuries among healthy adolescents.

Methods

In this cluster randomized controlled trial, we randomly selected 10 of 15 high schools in Calgary to participate in the fall of 2001. We then recruited students from physical education classes and randomly assigned them, by school, to either the intervention (n = 66) or the control (n = 61) group. Students in the intervention group participated in a daily 6-week and then a weekly 6-month home-based balance-training program using a wobble board. Students at the control schools received testing only. The primary outcome measures were timed static and dynamic balance, 20-m shuttle run and vertical jump, which were measured at baseline and biweekly for 6 weeks. Self-reported injury data were collected over the 6-month follow-up period.

Results

At 6 weeks, improvements in static and dynamic balance were observed in the intervention group but not in the control group (difference in static balance 20.7 seconds, 95% confidence interval [CI] 10.8 to 30.6 seconds; difference in dynamic balance 2.3 seconds, 95% CI 0.7 to 4.0 seconds). There was evidence of a protective effect of balance training in over 6 months (relative risk of injury 0.2, 95% CI 0.05 to 0.88). The number needed to treat to avoid 1 injury over 6 months was 8 (95% CI 4 to 35).

Interpretation

Balance training using a wobble board is effective in improving static and dynamic balance and reducing sports-related injuries among healthy adolescents.Adolescents commonly participate in sports.^1,2 In a survey of adolescents in Alberta, 59% reported that they took part in sports more than 5 hours per week (unpublished data). In North America, sport is the leading cause of injury requiring medical attention and visits to an emergency department among adolescents.^3,4 In Alberta 26% of youths aged 15–19 years in a survey reported sustaining a sports-related injury requiring medical attention.⁵ The impact may be lifelong, as there is evidence that knee and ankle injuries may result in an increased risk of osteoarthritis later in life.^6,7,8 In addition, each year 8% of adolescents drop out of sports activities because of injury.⁹ The reduction in physical activity resulting from sports-related injuries could have significant long-term effects on morbidity and mortality.^10,11Proprioceptive balance training is used in rehabilitation following sports-related injuries and is becoming recognized as an important element in injury prevention in sports.^{12,13,14,15,16,17,18,19} Running, jumping or pivoting on one leg relies on a sense of joint position and muscular control for joint stability. There is evidence that static balance improves following proprioceptive balance training using a wobble board.^20,21,22,23 However, most of these studies did not examine the effect of dynamic proprioceptive balance training, which may improve postural control in athletic situations and prevent some injuries.There is evidence from randomized trials that multifaceted prevention programs, including proprioceptive balance training using a wobble board, are effective in reducing injuries to the lower extremities in specific sports.^{12,13,14,15,16,17,18,19} However, the programs in these trials were multifaceted (i.e., included warm-up, flexibility, jump training, strength training, rehabilitation and sport-specific technical components), and balance was not measured. The effectiveness of balance training alone on balance ability and prevention of injury remains unclear. Moreover, the use of these techniques in adolescents and non-elite athletes has not been studied.The objectives of our study were to determine the effectiveness of a proprioceptive home-based balance-training program in improving static and dynamic balance in adolescents and to examine the effectiveness of this training program on reducing sports-related injury among adolescents.     

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.     

Analysis of Human Immunodeficiency Virus Type 1 Viremia and Provirus in Resting CD4+ T Cells Reveals a Novel Source of Residual Viremia in Patients on Antiretroviral Therapy

Highly active antiretroviral therapy (HAART) can reduce human immunodeficiency virus type 1 (HIV-1) viremia to clinically undetectable levels. Despite this dramatic reduction, some virus is present in the blood. In addition, a long-lived latent reservoir for HIV-1 exists in resting memory CD4⁺ T cells. This reservoir is believed to be a source of the residual viremia and is the focus of eradication efforts. Here, we use two measures of population structure—analysis of molecular variance and the Slatkin-Maddison test—to demonstrate that the residual viremia is genetically distinct from proviruses in resting CD4⁺ T cells but that proviruses in resting and activated CD4⁺ T cells belong to a single population. Residual viremia is genetically distinct from proviruses in activated CD4⁺ T cells, monocytes, and unfractionated peripheral blood mononuclear cells. The finding that some of the residual viremia in patients on HAART stems from an unidentified cellular source other than CD4⁺ T cells has implications for eradication efforts.Successful treatment of human immunodeficiency virus type 1 (HIV-1) infection with highly active antiretroviral therapy (HAART) reduces free virus in the blood to levels undetectable by the most sensitive clinical assays (18, 36). However, HIV-1 persists as a latent provirus in resting, memory CD4⁺ T lymphocytes (6, 9, 12, 16, 48) and perhaps in other cell types (45, 52). The latent reservoir in resting CD4⁺ T cells represents a barrier to eradication because of its long half-life (15, 37, 40-42) and because specifically targeting and purging this reservoir is inherently difficult (8, 25, 27).In addition to the latent reservoir in resting CD4⁺ T cells, patients on HAART also have a low amount of free virus in the plasma, typically at levels below the limit of detection of current clinical assays (13, 19, 35, 37). Because free virus has a short half-life (20, 47), residual viremia is indicative of active virus production. The continued presence of free virus in the plasma of patients on HAART indicates either ongoing replication (10, 13, 17, 19), release of virus after reactivation of latently infected CD4⁺ T cells (22, 24, 31, 50), release from other cellular reservoirs (7, 45, 52), or some combination of these mechanisms. Finding the cellular source of residual viremia is important because it will identify the cells that are still capable of producing virus in patients on HAART, cells that must be targeted in any eradication effort.Detailed analysis of this residual viremia has been hindered by technical challenges involved in working with very low concentrations of virus (13, 19, 35). Recently, new insights into the nature of residual viremia have been obtained through intensive patient sampling and enhanced ultrasensitive sequencing methods (1). In a subset of patients, most of the residual viremia consisted of a small number of viral clones (1, 46) produced by a cell type severely underrepresented in the peripheral circulation (1). These unique viral clones, termed predominant plasma clones (PPCs), persist unchanged for extended periods of time (1). The persistence of PPCs indicates that in some patients there may be another major cellular source of residual viremia (1). However, PPCs were observed in a small group of patients who started HAART with very low CD4 counts, and it has been unclear whether the PPC phenomenon extends beyond this group of patients. More importantly, it has been unclear whether the residual viremia generally consists of distinct virus populations produced by different cell types.Since the HIV-1 infection in most patients is initially established by a single viral clone (23, 51), with subsequent diversification (29), the presence of genetically distinct populations of virus in a single individual can reflect entry of viruses into compartments where replication occurs with limited subsequent intercompartmental mixing (32). Sophisticated genetic tests can detect such population structure in a sample of viral sequences (4, 39, 49). Using two complementary tests of population structure (14, 43), we analyzed viral sequences from multiple sources within individual patients in order to determine whether a source other than circulating resting CD4⁺ T cells contributes to residual viremia and viral persistence. Our results have important clinical implications for understanding HIV-1 persistence and treatment failure and for improving eradication strategies, which are currently focusing only on the latent CD4⁺ T-cell reservoir.     

Current and former marijuana use: preliminary findings of a longitudinal study of effects on IQ in young adults

Background

Assessing marijuana''s impact on intelligence quotient (IQ) has been hampered by a lack of evaluation of subjects before they begin to use this substance. Using data from a group of young people whom we have been following since birth, we examined IQ scores before, during and after cessation of regular marijuana use to determine any impact of the drug on this measure of cognitive function.

Methods

We determined marijuana use for seventy 17- to 20-year-olds through self-reporting and urinalysis. IQ difference scores were calculated by subtracting each person''s IQ score at 9–12 years (before initiation of drug use) from his or her score at 17–20 years. We then compared the difference in IQ scores of current heavy users (at least 5 joints per week), current light users (less than 5 joints per week), former users (who had not smoked regularly for at least 3 months) and non-users (who never smoked more than once per week and no smoking in the past two weeks).

Results

Current marijuana use was significantly correlated (p < 0.05) in a dose- related fashion with a decline in IQ over the ages studied. The comparison of the IQ difference scores showed an average decrease of 4.1 points in current heavy users (p < 0.05) compared to gains in IQ points for light current users (5.8), former users (3.5) and non-users (2.6).

Interpretation

Current marijuana use had a negative effect on global IQ score only in subjects who smoked 5 or more joints per week. A negative effect was not observed among subjects who had previously been heavy users but were no longer using the substance. We conclude that marijuana does not have a long-term negative impact on global intelligence. Whether the absence of a residual marijuana effect would also be evident in more specific cognitive domains such as memory and attention remains to be ascertained.Marijuana produces well-documented, acute cognitive changes that last for several hours after the drug has been ingested.^1,2,3 Whether it produces cognitive dysfunction beyond this period of acute intoxication is much more difficult to establish. Approaches to investigating long-lasting effects include clinical assessment of long-term users,^4,5,6 observations of subcultures in countries where long-term daily use of cannabis has been the cultural norm for decades^7,8,9 and marijuana administration studies in which subjects with a history of use ranging from infrequent to extensive are given the drug in controlled laboratory settings after various periods of abstinence.^10,11,12 As discussed in several reviews of the literature,^1,13,14 the findings have been equivocal.Most studies that examined heavy marijuana users for possible cognitive dysfunction lasting beyond the acute intoxication period assessed subjects after an abstinence period of only a day or two.^10,12,15,16 The fact that cannabinoid metabolites have been detected in the urine of long-term marijuana users after weeks or even months of abstinence^17,18,19 compromises the interpretation of these studies. To account for potential pre-existing differences between users and non-users, studies have typically matched the comparison group with the user group in terms of non-marijuana variables.^6,20 Suggestions for improving study designs^13,14 have emphasized both the need for comparison groups to be as similar as possible to the drug-using group and the need for a prolonged abstinence period. The most desirable procedure would involve a longitudinal, prospective design in which cognitive measures were available for all non-using and using subjects before and after marijuana consumption had been initiated by the users.¹⁵The Ottawa Prenatal Prospective Study (OPPS), underway since 1978, satisfies these criteria. This study permits both within-subject and between-subject comparisons among relatively low-risk non-users and users before, during and after quitting regular marijuana use. The primary objective of the OPPS is the neuropsychologic assessment of children exposed prenatally to marijuana or cigarettes. Women who used and did not use marijuana and cigarettes volunteered to participate during their pregnancy, and their children, now between the ages of 17 and 20 years, have been assessed since birth. Details of the recruitment of the largely middle-class families, the assessment procedures and the findings for the children from birth to adolescence have been summarized elsewhere.^21,22The objectives of the current study were as follows: to determine if current, regular marijuana use is predictive of decline in IQ from pre-usage levels, to determine if a differential effect on IQ occurs with heavy versus light current, regular marijuana use, and to determine if any IQ effects persist after subjects cease using marijuana for at least 3 months.     

Investigation of Clade B New World Arenavirus Tropism by Using Chimeric GP1 Proteins

Clade B of the New World arenaviruses contains both pathogenic and nonpathogenic members, whose surface glycoproteins (GPs) are characterized by different abilities to use the human transferrin receptor type 1 (hTfR1) protein as a receptor. Using closely related pairs of pathogenic and nonpathogenic viruses, we investigated the determinants of the GP1 subunit that confer these different characteristics. We identified a central region (residues 85 to 221) in the Guanarito virus GP1 that was sufficient to interact with hTfR1, with residues 159 to 221 being essential. The recently solved structure of part of the Machupo virus GP1 suggests an explanation for these requirements.Arenaviruses are bisegmented, single-stranded RNA viruses that use an ambisense coding strategy to express four proteins: NP (nucleoprotein), Z (matrix protein), L (polymerase), and GP (glycoprotein). The viral GP is sufficient to direct entry into host cells, and retroviral vectors pseudotyped with GP recapitulate the entry pathway of these viruses (5, 13, 24, 31). GP is a class I fusion protein comprising two subunits, GP1 and GP2, cleaved from the precursor protein GPC (4, 14, 16, 18, 21). GP1 contains the receptor binding domain (19, 28), while GP2 contains structural elements characteristic of viral membrane fusion proteins (8, 18, 20, 38). The N-terminal stable signal peptide (SSP) remains associated with the mature glycoprotein after cleavage (2, 39) and plays a role in transport, maturation, and pH-dependent fusion (17, 35, 36, 37).The New World arenaviruses are divided into clades A, B, and C based on phylogenetic relatedness (7, 9, 11). Clade B contains the human pathogenic viruses Junin (JUNV), Machupo (MACV), Guanarito (GTOV), Sabia, and Chapare, which cause severe hemorrhagic fevers in South America (1, 10, 15, 26, 34). Clade B also contains the nonpathogenic viruses Amapari (AMAV), Cupixi, and Tacaribe (TCRV), although mild disease has been reported for a laboratory worker infected with TCRV (29).Studies with both viruses and GP-pseudotyped retroviral vectors have shown that the pathogenic clade B arenaviruses use the human transferrin receptor type 1 (hTfR1) to gain entry into human cells (19, 30). In contrast, GPs from nonpathogenic viruses, although capable of using TfR1 orthologs from other species (1), cannot use hTfR1 (1, 19) and instead enter human cells through as-yet-uncharacterized hTfR1-independent pathways (19). In addition, human T-cell lines serve as useful tools to distinguish these GPs, since JUNV, GTOV, and MACV pseudotyped vectors readily transduce CEM cells, while TCRV and AMAV GP vectors do not (27; also unpublished data). These properties of the GPs do not necessarily reflect a tropism of the pathogenic viruses for human T cells, since viral tropism is influenced by many factors and T cells are not a target for JUNV replication in vivo (3, 22, 25).     

Prevalence and incidence of hypertension from 1995 to 2005: a population-based study

Background

Researchers have predicted that there will be a relative increase of 24% in the prevalence of hypertension in developed countries from 2000 to 2025. Hypertension is a leading risk factor for death, stroke, cardiovascular disease and renal disease. Thus, accurate estimates of the prevalence of hypertension in a population have important implications for public policy. We sought to assess whether the estimated increase in the prevalence of hypertension has been underestimated.

Methods

We performed a population-based cohort study using linked administrative data for adults aged 20 years and older in Ontario, Canada''s most populous province with more than 12 million residents. Using a validated case-definition algorithm for hypertension, we examined trends in prevalence from 1995 to 2005 and in incidence from 1997 to 2004.

Results

The number of adults with hypertension more than doubled from 1995 to 2005. The age-and sex-adjusted prevalence increased from 153.1 per 1000 adults in 1995 to 244.8 per 1000 in 2005, which was a relative increase of 60.0% (p < 0.001). The age-and sex-adjusted incidence of hypertension increased from 25.5 per 1000 adults in 1997 to 32.1 per 1000 in 2004, which was a relative increase of 25.7% (p < 0.001).

Interpretation

Our findings indicate that the rise in hypertension prevalence will likely far exceed the predicted prevalence for 2025. Public health strategies to prevent and manage hypertension and its sequelae are urgently needed.Hypertension is an important risk factor for death, stroke and cardiovascular disease and a major cause of end-stage renal disease. Kearney and colleagues¹ estimated that the prevalence of hypertension in 2000 was 26% of the adult population globally and that in 2025 the prevalence would increase by 24% in developed countries and 80% in developing countries. Results of a recent population-based study performed in Canada indicated that the prevalence of diabetes mellitus increased substantially from 1995 to 2005, and that the 2005 prevalence had already exceeded the World Health Organization''s projected global rate for 2030.² This rapid rise in diabetes prevalence has been attributed to an unprecedented increase in obesity and lifestyle changes in developed countries.^3,4 Obesity and sedentary lifestyles are also major risk factors for hypertension.⁵ Therefore, the prevalence of hypertension is also likely rising at a faster rate than predicted.Prior population estimates for the prevalence of hypertension in Canada have been based largely on physical-measures surveys⁶ and patient self-report surveys.⁷ Although these methods are costly and time-consuming, they are not subject to bias associated with changes in physician practice patterns and diagnosis. The last physical-measures survey for hypertension in Canada was conducted between 1986 and 1992.⁶ Although the next physical-measures survey is expected to begin in 2008, these surveys are limited by their inability to follow patients or assess trends over time because they are conducted only at a single point and involve a relatively small sample of patients. In Canada, self-report surveys are conducted every 2 to 3 years; however, similar to physical-measures surveys, they are limited in their scope and ability to follow patients over time. In addition, it is possible that participants may under-report hypertension.⁸ Thus, population estimates based on self-report surveys may underestimate the true prevalence of hypertension.⁹Prompted by the substantial underestimation of the projection for diabetes prevalence, we sought to determine whether projections for hypertension have also been underestimated. We examined trends in the prevalence and incidence of hypertension in Canada from 1995 to 2005.     

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.     

An approach to the management of unintentional weight loss in elderly people

UNINTENTIONAL WEIGHT LOSS, or the involuntary decline in total body weight over time, is common among elderly people who live at home. Weight loss in elderly people can have a deleterious effect on the ability to function and on quality of life and is associated with an increase in mortality over a 12-month period. A variety of physical, psychological and social conditions, along with age-related changes, can lead to weight loss, but there may be no identifiable cause in up to one-quarter of patients. We review the incidence and prevalence of weight loss in elderly patients, its impact on morbidity and mortality, the common causes of unintentional weight loss and a clinical approach to diagnosis. Screening tools to detect malnutrition are highlighted, and nonpharmacologic and pharmacologic strategies to minimize or reverse weight loss in older adults are discussed.Unintentional weight loss is the involuntary decline in total body weight over time. In clinical practice, it is encountered in up to 8% of all adult outpatients¹ and 27% of frail people 65 years and older.² Weight loss is an important risk factor in elderly patients. It is associated with increased mortality, which can range from 9% to as high as 38% within 1 to 2.5 years after weight loss has occurred.^1,3,4 Frail elderly people,⁵ people with low baseline body weight,^5,6,7 and elderly patients recently admitted to hospital are particularly susceptible to increased mortality.^8,9 Weight loss is also associated with an increased risk of in-hospital complications,^10,11 a decline in activities of daily living or physical function,^12,13 higher rates of admission to an institution^2,8 and poorer quality of life.¹⁴     

Malaria “epidemic” in Quebec: diagnosis and response to imported malaria

Background

Imported malaria is an increasing problem. The arrival of 224 African refugees presented the opportunity to investigate the diagnosis and management of imported malaria within the Quebec health care system.

Methods

The refugees were visited at home 3–4 months after arrival in Quebec. For 221, a questionnaire was completed and permission obtained for access to health records; a blood sample for malaria testing was obtained from 210.

Results

Most of the 221 refugees (161 [73%]) had had at least 1 episode of malaria while in the refugee camps. Since arrival in Canada, 87 (39%) had had symptoms compatible with malaria for which medical care was sought. Complete or partial records were obtained for 66 of these refugees and for 2 asymptomatic adults whose children were found to have malaria: malaria had been appropriately investigated in 55 (81%); no malaria smear was requested for the other 13. Smears were reported as positive for 20 but confirmed for only 15 of the 55; appropriate therapy was verified for 10 of the 15. Of the 5 patients with a false-positive diagnosis of malaria, at least 3 received unnecessary therapy. Polymerase chain reaction testing of the blood sample obtained at the home visit revealed malaria parasites in 48 of the 210 refugees (23%; 95% confidence interval [CI] 17%– 29%). The rate of parasite detection was more than twice as high among the 19 refugees whose smears were reported as negative but not sent for confirmation (47%; 95% CI 25%– 71%).

Interpretation

This study has demonstrated errors of both omission and commission in the response to refugees presenting with possible malaria. Smears were not consistently requested for patients whose presenting complaints were not “typical” of malaria, and a large proportion of smears read locally as “negative” were not sent for confirmation. Further effort is required to ensure optimal malaria diagnosis and care in such high-risk populations.In many industrialized countries, the incidence of imported malaria is rising because of changing immigration patterns and refugee policies as well as increased travel to malaria-endemic regions.^{1,2,3,4,5,6,7,8,9,10} Imported malaria is not rare in Canada (300–1000 cases per year),³ the United States^2,3,4 or other industrialized countries.^5,6,7,8,9,10 Malaria can be a serious challenge in these countries because of its potentially rapid and lethal course.^11,12,13,14 The task of front-line health care providers is made particularly difficult by the protean clinical presentations of malaria. Classic periodic fevers (tertian or quartan) are seen infrequently.^{9,15,16,17,18,19} Atypical and subtle presentations are especially common in individuals who have partial immunity (e.g., immigrants and refugees from disease-endemic areas) or are taking malaria prophylaxis (e.g., travellers).^9,16,17 Even when malaria is considered, an accurate diagnosis can remain elusive or can be delayed as a result of inadequate or distant specialized laboratory support.^19,20In Quebec, the McGill University Centre for Tropical Diseases collaborates with the Laboratoire de santé publique du Québec to raise awareness of imported malaria, to offer training and quality-assurance testing, and to provide reference diagnostic services. A preliminary diagnosis is typically made by the local laboratory, and smears (with or without staining) are sent to the McGill centre, where they are reviewed within 2–48 hours, depending on the urgency of the request. Initial medical decisions are usually based on local findings and interpretations. Although malaria is a reportable disease, there is no requirement to use the reference service.On Aug. 9, 2000, 224 refugees from Tanzanian camps landed in Montréal aboard an airplane chartered by Canadian immigration authorities. Over the ensuing 5 weeks, the McGill University Centre for Tropical Diseases noted an increase in demand for malaria reference services and an apparent small “epidemic” of imported malaria. This “epidemic” prompted us to investigate the performance of the health care system in the diagnosis and management of imported malaria.     

Interventions led by nurse continence advisers in the management of urinary incontinence: a randomized controlled trial

Background

The short-term efficacy of combined lifestyle and behavioural interventions led by nurses in the management of urinary incontinence has not been rigorously evaluated by randomized controlled trial. We conducted a 6-month randomized controlled trial to determine whether a model of service delivery that included lifestyle and behavioural interventions led by “nurse continence advisers” in collaboration with a physician with expertise in continence management could reduce urinary incontinence and pad use in an outpatient population. We also aimed to evaluate the impact of this approach on subjects'' knowledge about incontinence and their quality of life.

Methods

We used advertising in the mainstream media, newsletters to family physicians and community information sessions in 1991 to invite volunteers who were 26 years of age or older and suffered from incontinence to participate in a randomized controlled trial. Men and women who met the eligibility criteria were randomly allocated to receive either counselling from specialized nurses to manage incontinence using behavioural and lifestyle modification sessions every 4 weeks for 25 weeks or usual care. Symptoms of incontinence and the use of incontinence pads were the primary outcome measures.

Results

Using sealed envelopes, 421 patients were randomly allocated to the treatment or control groups. On average, patients in the treatment group experienced 2.1 “incontinent events” per 24 hours before treatment and 1.0 incontinent event per 24 hours at the end of the study. Control patients had an average of 2.4 incontinent events per 24 hours before the study and 2.2 incontinent events per 24 hours at the end of the study. The mean decrease in events in the treatment group was 1.2 and in the control group 0.2 (p = 0.001). Pad use declined from a mean of 2.2 per 24 hours before randomization in the treatment group to 1.2 per 24 hours at the end of the study, compared with 2.6 pads per 24 hours in the control group at the start of the study and 2.4 per 24 hours at the end. Pad use per 24 hours decreased on average by 0.9 pads in the treatment group and 0.1 in the control group (p = 0.021).

Interpretation

Behavioural and lifestyle counselling provided by specialized nurses with training in managing incontinence reduces incontinent events and incontinence pad use.Urinary incontinence primarily affects young-to-middle-aged women and elderly men and women. The prevalence of urinary incontinence in people aged 65 years and older living in the community ranges from 8% to 30%.^1,2,3,4,5,6 Urinary incontinence is underrecognized and those affected are often embarrassed and ashamed, thus, the problem frequently remains hidden.^1,2North American and Canadian practice guidelines for the effective management of adult urinary incontinence have advocated thorough initial assessment, then staged multidisciplinary approaches beginning with the least invasive and reversible (lifestyle and behavioural) interventions, before drug therapy (reversible) and surgery (invasive and irreversible).^1,2,3 The role of continence advisers in the management of urinary incontinence has evolved from its early beginnings in the United Kingdom^7,8,9,10,11 and is now increasingly recognized in North America.^12,13,14 There has been some evaluation of the short-term efficacy of multidisciplinary incontinence management by nurse practitioners or “nurse continence advisers” in community and outpatient settings.^{15,16,17,18,19,20} However, the short-term efficacy of combined lifestyle and behavioural interventions led by nurse continence advisers has not been rigorously evaluated using randomized controlled trials.Urinary incontinence has many causes, particularly in elderly people,²¹ and the potential for overall clinical improvement is greater when multiple interventions target several factors. Each intervention effects a small positive change, and these small changes cumulatively have a large positive outcome.²¹ Individual components of lifestyle and behavioural interventions are increasingly being shown to be effective. For example, behavioural training, including pelvic muscle exercises, has reduced urinary incontinence significantly,^22,23,24 in some cases up to 57%.²⁵ A combined approach consisting of both bladder training and pelvic muscle exercises, provided by trained registered nurses, has resulted in significantly fewer incontinent episodes than either approach alone.²⁶ Pelvic floor exercises have been shown to be equally effective in women with stress, urge and mixed urinary incontinence.²⁷ Adherence to pelvic floor muscle exercises has been shown to be sustained for up to 5 years in 70% of women who have intensive exercise training.²⁸ Decreasing caffeine intake has also been shown to reduce episodes of incontinence.²⁹ Reducing fluid intake in people with detrusor instability, but not those with genuine stress incontinence, reduces the number of “incontinent events.” Increasing fluid intake makes the urinary incontinence worse.³⁰Our 6-month randomized controlled trial was conducted to determine whether a model of service delivery that included lifestyle and behavioural interventions led by nurse continence advisers in collaboration with a physician with expertise in continence management could reduce urinary incontinence and pad use. Our secondary aim was to investigate the impact of incontinence management led by nurse continence advisers on subjects'' knowledge about incontinence and their quality of life.     

Coinfecting Prion Strains Compete for a Limiting Cellular Resource

Prion strain interference can influence the emergence of a dominant strain from a mixture; however, the mechanisms underlying prion strain interference are poorly understood. In our model of strain interference, inoculation of the sciatic nerve with the drowsy (DY) strain of the transmissible mink encephalopathy (TME) agent prior to superinfection with the hyper (HY) strain of TME can completely block HY TME from causing disease. We show here that the deposition of PrP^Sc, in the absence of neuronal loss or spongiform change, in the central nervous system corresponds with the ability of DY TME to block HY TME infection. This suggests that DY TME agent-induced damage is not responsible for strain interference but rather prions compete for a cellular resource. We show that protein misfolding cyclic amplification (PMCA) of DY and HY TME maintains the strain-specific properties of PrP^Sc and replicates infectious agent and that DY TME can interfere, or completely block, the emergence of HY TME. DY PrP^Sc does not convert all of the available PrP^C to PrP^Sc in PMCA, suggesting the mechanism of prion strain interference is due to the sequestering of PrP^C and/or other cellular components required for prion conversion. The emergence of HY TME in PMCA was controlled by the initial ratio of the TME agents. A higher ratio of DY to HY TME agent is required for complete blockage of HY TME in PMCA compared to several previous in vivo studies, suggesting that HY TME persists in animals coinfected with the two strains. This was confirmed by PMCA detection of HY PrP^Sc in animals where DY TME had completely blocked HY TME from causing disease.Prions are infectious agents of animals, including humans, which are comprised of PrP^Sc, a misfolded isoform of the noninfectious host encoded protein PrP^C (17, 24, 50, 63). Prion diseases of humans are unique neurodegenerative disorders in that they can have either a sporadic, familial, or infectious etiology. Prions cause disease in economically important domestic and wild animal species such as bovine spongiform encephalopathy in cattle and chronic wasting disease in wild and captive cervids (20, 62). Prion diseases can be zoonotic as illustrated by the transmission of bovine spongiform encephalopathy to humans that resulted in the emergence of variant Creutzfeldt-Jacob disease (14, 19, 22, 23, 46, 61, 68). Prion diseases are inevitably fatal and there are currently no effective treatments (21).Prion strains are defined by a characteristic set of features that breed true upon experimental passage (33, 34). Strain-specific differences have been identified in incubation period, clinical signs, agent distribution, overdominance, host range, neuropathology, and biochemical properties of PrP^Sc (5, 10, 11, 13, 28, 34, 42, 44). Strain-specific conformations of PrP^Sc are hypothesized to encode prion strain diversity; however, it is not understood how these differences result in the distinct strain properties (11, 19, 40, 47, 59, 66).Prion strain interference may be involved in the emergence of a dominant strain from a mixture as could occur during prion adaptation to a new host species or during prion evolution (4, 36, 43, 48, 56). In the natural prion diseases, there are examples where an individual host may be infected with more than one prion strain (15, 25, 55, 57, 58). Experimentally, coinfection or superinfection of prion strains can result in interference where a blocking, long incubation period strain extends the incubation period or completely blocks a superinfecting, short incubation period strain from causing disease (26, 27). Prion interference has been described in experimental studies of mice and hamsters infected with a wide variety of prion strains and routes of inoculation, suggesting it may be a common property of prion disease (3, 27, 52, 53, 60).It has been proposed that prion strains compete for a shared “replication site”; however, mechanistic details are not known, and it is unclear whether the blocking strain destroys or occupies the replication sites required for the superinfecting strain (28). The transport to and relative onset of replication of interfering strains in a common population of neurons is an important factor that can determine which strain will emerge (8). In the present study, we sought to determine whether the blocking strain disables transport and spread of the superinfecting strain or whether prion interference is due to competition for a cellular resource.     

The ESCRT-Associated Protein Alix Recruits the Ubiquitin Ligase Nedd4-1 To Facilitate HIV-1 Release through the LYPXnL L Domain Motif

The p6 region of HIV-1 Gag contains two late (L) domains, PTAP and LYPX_nL, that bind Tsg101 and Alix, respectively. Interactions with these two cellular proteins recruit members of the host''s fission machinery (ESCRT) to facilitate HIV-1 release. Other retroviruses gain access to the host ESCRT components by utilizing a PPXY-type L domain that interacts with cellular Nedd4-like ubiquitin ligases. Despite the absence of a PPXY motif in HIV-1 Gag, interaction with the ubiquitin ligase Nedd4-2 was recently shown to stimulate HIV-1 release. We show here that another Nedd4-like ubiquitin ligase, Nedd4-1, corrected release defects resulting from the disruption of PTAP (PTAP⁻), suggesting that HIV-1 Gag also recruits Nedd4-1 to facilitate virus release. Notably, Nedd4-1 remediation of HIV-1 PTAP⁻ budding defects is independent of cellular Tsg101, implying that Nedd4-1''s function in HIV-1 release does not involve ESCRT-I components and is therefore distinct from that of Nedd4-2. Consistent with this finding, deletion of the p6 region decreased Nedd4-1-Gag interaction, and disruption of the LYPX_nL motif eliminated Nedd4-1-mediated restoration of HIV-1 PTAP⁻. This result indicated that both Nedd4-1 interaction with Gag and function in virus release occur through the Alix-binding LYPX_nL motif. Mutations of basic residues located in the NC domain of Gag that are critical for Alix''s facilitation of HIV-1 release, also disrupted release mediated by Nedd4-1, further confirming a Nedd4-1-Alix functional interdependence. In fact we found that Nedd4-1 binds Alix in both immunoprecipitation and yeast-two-hybrid assays. In addition, Nedd4-1 requires its catalytic activity to promote virus release. Remarkably, RNAi knockdown of cellular Nedd4-1 eliminated Alix ubiquitination in the cell and impeded its ability to function in HIV-1 release. Together our data support a model in which Alix recruits Nedd4-1 to facilitate HIV-1 release mediated through the LYPX_nL/Alix budding pathway via a mechanism that involves Alix ubiquitination.Retroviral Gag polyproteins bear short conserved sequences that control virus budding and release. As such, these motifs have been dubbed late or L domains (49). Three types of L domains have thus far been characterized: PT/SAP, LYPX_nL, and PPPY motifs (5, 9, 32). They recruit host proteins known to function in the vacuolar protein sorting (vps) of cargo proteins and the generation of multivesicular bodies (MVB) compartments (2). It is currently accepted that budding of vesicles into MVB involves the sequential recruitment of endosomal sorting complexes required for transport (ESCRT-I, -II, and -III) and the activity of the VPS4 AAA-ATPase (22). These sorting events are believed to be triggered by recognition of ubiquitin molecules conjugated to cargo proteins (20, 24, 41). For retrovirus budding, L domain motifs are the primary signals in Gag that elicit the recruitment of ESCRT components to facilitate viral budding. Consequently, mutations in L domain motifs or dominant-negative interference with the function of ESCRT-III members or the VPS4 ATPase adversely affect virus release. This indicates that Gag interactions with the ESCRT machinery are necessary for virus budding and separation from the cell (7, 10, 15, 16, 21, 28, 44).Two late domains have been identified within the p6 region of human immunodeficiency virus type 1 (HIV-1) Gag protein: the PTAP and LYPX_nL motifs. The PTAP motif binds the cellular protein Tsg101 (15, 39, 40, 47), whereas the LYPX_nL motif is the docking site for Alix (44). Tsg101 functions in HIV-1 budding (15) as a member of ESCRT-I (30, 48), a soluble complex required for the generation of MVB. This process is topologically similar to HIV-1 budding and requires the recruitment of ESCRT-III members called the charged-multivesicular body proteins (3, 29, 48) and the activity of the VPS4 AAA-ATPase (4, 48). In addition to binding the LYPX_nL motif, Alix also interacts with the nucleocapsid (NC) domain of HIV-1 Gag (13, 38), thus linking Gag to components of ESCRT-III that are critical for virus release (13).Other retroviruses, including the human T-cell leukemia virus (HTLV) and the Moloney murine leukemia virus (MoMLV), utilize the PPPY-type L domain to efficiently release virus (7, 26, 51). The PPPY motif binds members of the Nedd4-like ubiquitin ligase family (6, 7, 16, 19, 25, 43), whose normal cellular function is to ubiquitinate cargo proteins and target them into the MVB sorting pathway (11, 12, 20). Members of the Nedd4-like ubiquitin ligase family include Nedd4-1, Nedd4-2 (also known as Nedd4L), WWP-1/2, and Itch. They contain three distinct domains: an N-terminal membrane binding C2 domain (12), a central PPPY-interacting WW domain (43), and a C-terminal HECT domain that contains the ubiquitin ligase active site (42). The functional requirement for the binding of Nedd4-like ubiquitin ligases to the PPPY motif in virus budding has been demonstrated (7, 16, 18, 19, 25, 26, 28, 50, 51). Overexpression of dominant-negative mutants of Nedd4-like ligases, ESCRT-III components, or VPS4 cause a potent inhibition of PPPY-dependent virus release (7, 19, 29, 31, 52) and induce assembly and budding defects similar to those observed after perturbation of the PPPY motif (26, 51). These observations demonstrated that Nedd4-like ligases connect Gag encoding PPPY motif to ESCRT-III and VPS4 proteins to facilitate virus release.Whereas the role of Nedd4-like ubiquitin ligases in virus budding has been established, the protein interactions that link them to the cell''s ESCRT-III pathway are still unknown. Evidence for associations of Nedd4-like ligases with ESCRT proteins have been previously reported and include: the binding of Nedd4-like ubiquitin ligases LD1 and Nedd4-1 to ESCRT-I member Tsg101 (6, 31), the colocalization of multiple Nedd4-like ubiquitin ligases with endosomal compartments (1, 28), the requirement of the cell''s ESCRT pathway for Itch mediated L domain independent stimulation of MoMLV release (23), and the ubiquitination of ESCRT-I components with a shorter isoform, Nedd4-2s (8). Therefore, Nedd4-like ubiquitin ligase interactions with members of the cell''s ESCRT pathway may provide retroviral Gag with access to the host budding machinery required for virus release.Although HIV-1 Gag does not carry the PPPY canonical sequence known to interact with Nedd4-like ubiquitin ligases, both Nedd4-1 and Nedd4-2 were shown to restore the release of the HIV-1 PTAP⁻ mutant, albeit Nedd4-1 with less efficiency than Nedd4-2 (8, 46). These findings suggested that HIV-1 might utilize cellular Nedd4-like ubiquitin ligases to increase virus release. We present here evidence demonstrating that Nedd4-1 interacts with Gag and enhances HIV-1 PTAP⁻ virus release. Furthermore, we show that Nedd4-1''s function in HIV-1 release is distinct from that of Nedd4-2 in both its viral and cellular requirements. Notably, we found that Nedd4-1 enhancement of HIV-1 release requires the Alix-binding LYPX_nL L domain motif in the p6 region and basic residues in the NC domain. In addition, Alix''s facilitation of HIV-1 release requires cellular Nedd4-1, since mutations in NC that prevented Alix-mediated HIV-1 release also eliminated release by overexpression of Nedd4-1. This suggested a Nedd4-1-Alix physical and functional interdependence. In agreement with this, we found Nedd4-1 to bind and ubiquitinate Alix in the cell. Taken together, these results support a model in which Alix recruits Nedd4-1 to facilitate late steps of HIV-1 release through the LYPX_nL L domain motif via a mechanism that involves Alix ubiquitination.