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1.
 In order to improve the immunity to diphtheria, the recommended booster dose of diphtheria/tetanus vaccine for adults in Sweden was changed in 1986 from 0.5 ml of tetanus vaccine with a small diphtheria dose to 0.25 ml of a diphtheria/tetanus vaccine containing 7.5 Lf tetanus toxoid and 30 Lf diphtheria toxoid/ml. This change resulted in an increase in the dose of diphtheria toxoid from 0.5 Lf to 7.5 Lf, but a decrease in the recommended booster dose of tetanus toxoid from 3.75 Lf to 1.9 Lf. The aim of the present study was to investigate whether this lower dose of tetanus toxoid was also sufficiently protective for elderly people. Two hundred adults (median age 76 years, range 60–92 years) with no history of tetanus vaccination during the past 10 years volunteered for the study. One hundred two vaccinees were inoculated with 1.9 Lf tetanus toxoid (0.25 ml) and 98 with 3.75 Lf tetanus toxoid (0.5 ml). Paired serum samples were analysed by the toxin-binding inhibition assay. Side effects were few and mild, without significant differences between the groups. Response rates were similar, with the 3.75 Lf dose eliciting a marginally higher antitoxin response. The prevaccination geometric mean titre was the same for both groups: 0.03 IU/ml. Postvaccination geometric mean titres were 1.18 IU/ml for the 3.75 Lf group and 1.93 IU/ml for the 7.5 Lf group, respectively (difference not significant). Forty-seven percent of the vaccinees had a prevaccination titre of ≤0.01 IU/ml. Postvaccination, 85% had a titre >0.01 IU/ml. Booster vaccination with tetanus vaccine containing only 1.9 Lf of tetanus toxoid was thus found to induce an excellent immune response in elderly people, with few side effects resulting.  相似文献   

2.
 The effect of a single booster injection of an adult formulation of a combined diphtheria–tetanus vaccine (Td) on diphtheria-specific immunity was evaluated. The booster injection, containing 2 IU diphtheria toxoid per dose, was given as part of the surgical wound management for adults with open soft tissue injuries. Diphtheria antitoxin concentrations were determined in serum samples from 534 patients (199 women and 335 men, aged 18–70 years) using an enzyme immunoassay and a tissue culture toxin neutralization assay. Seroimmunity against diphtheria toxin was classified at three levels: susceptibility, basic protection, and full protection against the toxic manifestations of the disease. Before vaccination, 27.1% of the subjects were susceptible to diphtheria, 26.5% had basic protection, and 46.4% were fully protected. Six weeks (minimum 25 days, maximum 98 days) after a single booster injection, 89.7% of the subjects achieved full protection against diphtheria, and only 3.9% had antitoxin levels below the protective level. The median increase from the prevaccination to postvaccination antitoxin concentration was found to be 14-fold (4.4–47; quartiles Q25 to Q75). The change in antitoxin levels after revaccination was higher in older age groups (P<0.001), whereas neither sex (P=0.86) nor the country of previous immunization with a different national immunization schedule (P=0.61) had a significant influence on the revaccination effect. Systemic adverse reactions were rare, and local reactions of clinical significance were reported in only 1.9% of subjects.  相似文献   

3.
Recent outbreaks of diphtheria in neighbouring eastern European countries and in the Russian Federation prompted us to evaluate immunity to diphtheria in a sample of 400 healthy individuals (210 male, 190 female) from northern Germany. An age-stratified study population was chosen, including newborns, children, adults and elderly persons over 60 years divided into 8 subgroups of 50 persons each. Diphtheria antitoxin was tested by enzyme immunoassay. The median antitoxin titre was 0.39 IU/ml. There was no difference in the median antitoxin titres of men and women. Inadequate immunity to diphtheria was detected in more than 90 % of the 400 individuals tested, including 4 % who completely lacked immunity (titre<0.01 IU/ml), a further 20 % with minimal protection (titre 0.01–0.1 IU/ml) and the majority of 69 % who showed relative protection for less than one year (titre 0.1–1.0 IU/ml). Only 7 % exhibited lasting protection for more than five years (titre>1.1). Newborns and persons over 50 years of age constituted the least protected groups, with significantly lower median antitoxoid titres than the other age groups (p<0.001). The absence of protective immunity in 7 of the 50 newborns examined (14 %) reflects the inadequate protection of women of reproductive age. Children aged 1 to 10 years were the best immunized and protected group. The results suggest that routine booster immunizations of the majority of the adult population would be advisable in view of the ongoing migration from and the visits to high-risk areas.  相似文献   

4.
This study aimed to evaluate human antibody responses to diphtheria toxin subunits in various age groups. Antibodies against the intact diphtheria toxin and the diphtheria toxin subunits A and B were evaluated in 1319 individuals using a double-antigen ELISA. Although high levels of protection (83.6%, 95% CI 79.2-87.4) were found in children and adolescents, the middle-aged adult population was less protected (28.8%, 95% CI 24.3-33.6). An increase in age was associated with a decrease in the frequency of protected individuals in the 0-39-year age group (p <0.001). Anti-subunit B levels correlated well (p <0.01) with levels of antibodies against the intact toxin. In children aged < or =16 years, the intervals at which the peaks in geometric mean titres of anti-subunit B antibodies were observed were found to correlate with the ages at which booster doses are administered. Overall, males appeared to be more protected than females (OR 1.67, 95% CI 1.34-2.08, p <0.001). A small group of individuals had antibody levels of > or =0.1 IU/mL against the intact toxin, but did not have protective antibody against subunit B. Determination of anti-subunit B antibody levels should help in evaluating the effectiveness of diphtheria boosters and other aspects of diphtheria immunity.  相似文献   

5.
Extraintestinal disease occurs in 5–8% of non-typhoid Salmonella enterica (NTS) infections and is more likely to be associated with hospitalization and death. The study examined the epidemiology of extraintestinal NTS infections in Israel and the possible effects of patients’ age and sex. NTS isolates passively submitted to the National Salmonella Reference Center during 1996–2006 were the source for the study cohort. Poisson regression models were used to assess incidence trends over the study years and to evaluate the effects of patients’ age and sex on the incidence of extraintestinal NTS manifestations. A total of 36,822 stool and 1,415 (3.7%) patient-unique NTS isolates from blood (74.1%), urine (18.3%), and other sources (3.7%) were studied. Serotypes Enteritidis, Virchow, and Typhimurium accounted for 66.3% of the isolates. Analysis showed a highly significant quadratic (U-shaped) relationship between patients’ age and the incidence of extraintestinal isolation (p < 0.001), with increasing risk in the two extremes of age. Differences between the incidence of blood and urine sources were significant in patients <10 and ≥60 years old (relative risk [RR] = 5.88, 95% confidence interval [CI] 3.36–10.30, p < 0.001 and RR = 1.66, 95% CI 1.09–2.53, p = 0.017, respectively). Males ≥60 years of age were more likely than females of the same age to have bacteremia (RR = 1.90, 95% CI 1.39–2.61, p > 0.001) and less likely to have urinary NTS isolation (RR = 0.50, 95% CI 0.28–0.89, p = 0.018). Serotype Virchow had the highest incidence in patients <10 years of age, while serotype Enteritidis had the highest incidence in patients ≥60 years old. The study revealed a complex effect of patients’ age and sex on the epidemiology of extraintestinal NTS manifestations.  相似文献   

6.
 A point prevalence study to document oral yeast carriage was undertaken. Risk factors for the development of oropharyngeal colonization or infection by fluconazole-resistant Candida strains in HIV-infected patients were investigated with a case-control design. Cases included all patients with fluconazole-resistant strains (MIC≥64 μg/ml), and controls were those with susceptible (MIC≤8 μg/ml) or susceptible-dependent-upon-dose (MIC 16–32 μg/ml) strains. One hundred sixty-eight Candida strains were isolated from 153 (88%) patients, 28 (16%) of whom had oropharyngeal candidiasis. Overall, 19 (12%) of the patients harbored at least one resistant organism (MIC≥64 μg/ml). Among patients with resistant strains, tuberculosis (P<0.001), esophageal candidiasis (P=0.001), clinical thrush (P<0.001), and a CD4+ cell count <200/mm3 (P=0.03) were more frequent. These patients had also been treated more commonly with antituberculous drugs (adjusted odds ratio [OR] 6.13; 95% confidence interval [CI] 2.11–17.80), ciprofloxacin (OR 6.0; 95% CI 1.23–29.26), fluconazole (OR 4.59; 95% CI 1.55–13.52), and steroids (OR 4.13; 95% CI 1.11–15.39). Multivariate analysis showed that the determinants for fluconazole resistance were therapy with antituberculous drugs (OR 3.61; 95% CI 1.08–12.07;P=0.03) and one of the following: previous tuberculosis (OR 3.53; 95% CI 1.08–14.57;P=0.03) or fluconazole exposure (OR 3.41; 95% CI 1.10–10.54). Findings from this study indicate that treatment with antituberculous drugs, previous tuberculosis, and fluconazole exposure are the strongest determinants for development of oropharyngeal colonization or infection by fluconazole-resistant Candida strains in HIV-infected patients.  相似文献   

7.
A long, prior history of diphtheria is common among middle-aged and elder European adults. The aim of the present study was to determine whether the risk of reduced ventricular function and impaired intraventricular conduction is increased in individuals with a history of diphtheria. A study population of 2,480 subjects (1,222 women) aged 45 years or older who were recruited for the Study of Health in Pomerania were available for the present analyses. Left ventricular function was assessed by echocardiography. Intraventricular conduction blocks were diagnosed using electrocardiograms. Multivariable analyses revealed that individuals with a history of diphtheria had neither an increased odds for reduced fractional shortening (OR 1.21, 95% CI 0.69–2.11; p = 0.51) nor an increased odds for intraventricular conduction blocks (OR 0.90, 95% CI 0.55–1.46; p = 0.67). However, regression models revealed two-way interactions between the exposure variable and hypertension with respect to both endpoints. A history of diphtheria increased the odds for both endpoints in normotensive but not in hypertensive individuals. The findings show that a history of diphtheria several decades previously in a patient is a risk marker for reduced cardiac function and impaired intraventricular conduction in individuals at low risk for these disorders.  相似文献   

8.
Titres of anti-tetanus toxin antibodies ≥0.1 IU/ml were determined using an enzyme linked immunosorbent assay in representative samples of the juvenile and adult population of Catalonia. The prevalence obtained in 1,316 juveniles and 1,296 adults was 99.4 and 68.3%, respectively. In adults, the prevalence in males (76.5%) was higher (P < 0.001) than in females (61.7%), fell with increasing age and was higher in subjects born in Catalonia (72.5%) than in those born outside Catalonia (57.9%) (P < 0.001). These results show that routine vaccination of children is successful. In adults aged ≥45 years, the prevalence is inadequate and efforts should be made to increase vaccination.  相似文献   

9.
Serum samples were obtained from 44 infants vaccinated against diphtheria at the ages of 3, 5 and 12 months with an aluminium-adsorbed diphtheria-tetanus toxoid vaccine containing 15 Lf units of diphtheria toxoid. Toxin-neutralizing antibodies (antitoxin) were measured by the Vero cell assay and IgG, IgM and IgA antibodies against diphtheria toxoid by enzyme-linked immunosorbent assay. A neutralizing antibody titer of 10 corresponded to 0.01 IU/ml, the level considered necessary for short-term protection. Geometric mean neutralizing antibody titers at 3, 5, 6, 12, 13 and 30 months were 28, 21, 173, 61, 1076 and 61. All children had titers of 10 ( 0.01 IU/ml) between 6 and 30 months of age. At 30 months only 48 % had titers of 100 ( 0.1 IU/ml), the level considered necessary for long-term protection. Geometric mean IgG antibody levels were 13, 36, 216, 64, 649 and 57. IgG antibodies significantly correlated with neutralizing titers and predicted neutralizing antibodies above or below 10 and 100 with an accuracy of 96 and 82 %, respectively. IgG antibodies could not, however, be used to predict individual neutralizing antibody titers with great accuracy. IgM antibodies were only detected after the third vaccination. IgA antibodies were not detected in any serum sample from ten infants tested. In conclusion, the Swedish vaccination schedule results in protective antibody levels in infants until at least 30 months of age. The decline of the antibody titers indicates a need for further studies to establish the duration of protection.  相似文献   

10.
Q fever is a vaccine preventable disease; however, despite this, high notification numbers are still recorded annually in Australia. We investigated the seroprevalence of Coxiella burnetii, the Q fever agent, in a Queensland sample population. Notification data (N = 6425) from 1984–2008 were collated, identifying high risk areas of Q fever exposure. Of these 177 were recorded in children. Serum samples were collected from Queensland and screened using both an immunoflourescence assay at 1:10 dilution and a commercially available ELISA kit. Results were collated based on age, geographical location and sex. From 1988 Queensland samples screened, 103 were identified as Q fever IgG-positive, giving a seroprevalence of 5.2% (95% CI 4.3–6.2%). Seroprevalence in the rural/remote population was 5.3% (95% CI 4.6–6.6%), and the metropolitan Brisbane population, which is considered not at risk, was 5.0% (95% CI 3.7–6.7%). Sixty-three seropositive males and 40 females were identified, along with an increase in seropositivity with increasing age. The seropositivity of children was 1.3% (95% CI 0.7–2.3%) from 844 samples. We have shown that both metropolitan and paediatric populations which are considered low risk of Coxiella exposure have surprisingly high seropositivity. These emerging groups require further investigation and consideration for the introduction of preventive measures.  相似文献   

11.
The level of immunity to diphtheria and the effect of vaccination with different doses of diphtheria toxoid was investigated. The 457 study children, 6, 10 and 16 years of age, had as infants received routine primary vaccination with three doses of diphtheria-tetanus-toxoid or diphtheria-tetanus-pertussis vaccine, and the 16 year-olds also had received a booster dose of tetanus with a small dose of diphtheria at the age of ten. Prior to the study booster, 15 % of the 6-year-olds had antitoxin levels against diphtheria <0.01 IU/ml, the given minimum level for protection. Of the 10-year-olds, 48 % had titres <0.01 IU/ml, while the corresponding figure for the 16-year-olds was 24 %. After a booster injection of 0.1, 0.25 or 0.5 ml of diphtheria-tetanus vaccine, more than 97 % of the children showed titre levels 0.1 IU/ml, while levels of 1 IU/ml, indicating titres sufficient for long-term protection, were attained by 23–96 %. Systemic reactions were few and moderate. Local reactions were of little clinical significance. In a group of 5-years-olds given diphtheria-tetanus primary vaccinations over wider intervals, only 1.4 % had antitoxin titres <0.01 IU/ml. The results show a need for serologic monitoring of vaccination programmes.  相似文献   

12.
During the 1990–1998 diphtheria epidemic in the newly independent states of the former Soviet Union, more than 150,000 infections and 5,000 deaths occurred. During this period, more than 10 million trips were made from Finland to Russia or vice versa. This resulted in only 10 cases of diphtheria in Finland. There was no secondary spread to healthcare workers or other close contacts. Three patients had severe respiratory tract diphtheria. All three were middle-aged men who had made a short visit to Russia, during which time they had intimate contact with local women. These findings suggest diphtheria was transmitted mainly by direct saliva contact. All patients with severe diphtheria had a nonprotective level of antitoxin antibodies during the first days of the disease. Only the patient whose antibody titre rose rapidly to a protective level (>1 IU/ml) had an uncomplicated recovery. The other two, one of whom died, had myocarditis and severe polyneuropathy. Electronic Publication  相似文献   

13.
Diphtheria immunity in flanders   总被引:2,自引:0,他引:2  
A serological survey to determine the immunity to diphtheria in the Flemish population was conducted according to the recommendations of the World Health Organization. Immunity to diphtheria was determined on a randomised, stratified sample (1679 serum samples) from an existing serum bank (4058 serum samples) representative of the Flemish population. All age groups between 0 and 100 years were included. A tissue (Vero cell) culture toxin neutralisation assay was used to measure serum diph-theria antitoxin concentrations. The results showed that 43% of the Flemish population was protected against diphtheria (antitoxin titre, 0.1 lU/ml), while 32% was susceptible (antitoxin titre, < 0.01 lU/ml); for 25%, protection was of limited duration (antitoxin titre, 0.01 lU/ml and < 0.1 lU/ml). The proportion of susceptible subjects showed a significant age-related increase, with the highest values in the 35 to 44 and 45 to 54 age groups (57.9% and 55.5%, respectively). These results emphasise the need for booster immunization of adults.  相似文献   

14.
The objective of this study was to investigate the relationship between depression and screening for breast and cervical cancer. The study sample included Ontario female respondents to the Canadian Community Health Survey Cycle 1.2, Mental Health and Well Being component (2002). Women with Major Depressive Disorder (MDD) were identified based on the World Mental Health Composite International Diagnostic Interview and women with clinically significant depressive symptoms were identified using the Kessler 6-item Distress Scale (K6 ≥ 8). Respondents eligible for screening (N = 4,042 for cervical cancer and N = 1,403 for breast cancer) were linked to Ontario administrative data to prospectively ascertain screening outcomes. Both women with MDD and K6 ≥ 8 were less likely to receive breast cancer screening than their non-depressed counterparts (46.1% vs. 61.5% for MDD, Χ 2 = 5.47, p = 0.02; 49.9% vs. 61.9% for K6, Χ 2 = 6.61, p = 0.01). Adjusted analyses revealed persistence of the association between K6 ≥ 8 and breast cancer screening (adjusted odds ratio (AOR) 0.63, 95% CI 0.40–0.97). Neither MDD nor K6 ≥ 8 were found to be associated with cervical cancer screening in the full sample. A sub-group analysis by age revealed that women over age 40 years with K6 ≥ 8 were less likely to receive cervical cancer screening than their non-depressed counterparts (49.9% vs. 64.5%, X 2 = 6.47, p = 0.01). This association approached statistical significance in adjusted analysis (AOR = 0.65, 95% CI 0.41–1.04). This study’s findings suggest that attention to the uptake of preventive services in women with depressive symptoms is warranted.  相似文献   

15.
In order to determine the prevalence and risk factors for Chlamydia trachomatis infection in adolescent females and young women in central Brazil, 296 subjects attending two public health services were evaluated. The overall prevalence of C. trachomatis infection, as determined using polymerase chain reaction, was 19.6% (95% confidence interval [CI], 15.3–24.7). In multivariate analysis, young age (odds ratio [OR]adjusted 2.32, 95%CI 1.1–4.8, p<0.05) and having 2–3 (ORadjusted 3.41, 95%CI 1.6–6.3, p<0.05) or ≥4 sexual partners in life (ORadjusted 3.10, 95%CI 1.1–6.3, p<0.05) were factors significantly associated with chlamydial infection. In conclusion, the prevalence of C. trachomatis infection was high in the studied population and risk factors were related to age and sexual behavior.  相似文献   

16.
The impacts of acute falciparum malaria on body weight and the host and parasite factors predictive of change in body weight were characterized in 465 prospectively studied children in an endemic area of southwest Nigeria. Pre-treatment weights were significantly lower than the 14 to 28-day post-treatment weights (P = 0.0001). In 187 children, fractional fall in body weight (FFBW) exceeded 4.9%. FFBW correlated negatively with age and body weight (P = 0.014 and 0.0001, respectively), but not with enrolment parasitaemia. In a multiple regression model, an age ≤5 years (AOR = 2.03, 95% CI 1.2–3.2, P = 0.003), a hematocrit ≤29% (AOR = 1.6, 95% CI 1.0–2.3, P = 0.037), and a body weight ≤9.6 kg (AOR = 5.4, 95% CI 1.7–20, P = 0.003) were independent predictors of FFBW ≥5% at presentation. Children who, after initial clearance, had recurrence of their parasitaemia within 28 days had a significantly higher propensity not to gain weight than children who were aparasitaemic after treatment (log-rank statistic 6.76, df = 1, P = 0.009). These results indicate that acute malaria contribute to sub-optimal growth in young children and may have implications for malaria control efforts in sub-Saharan Africa.  相似文献   

17.
 In a prospective study including 137 consecutive catheterised patients in a medical intensive care unit, the following variables were analysed as possible risk factors for catheter-associated bacteriuria, defined as a quantitative culture with ≥105 organisms/ml: age, sex, simplified acute and physiologic score at admission, duration of catheterisation, diabetes mellitus, immunosuppression, neurologic disorders and prior systemic antibiotic exposure during hospitalisation. The frequency of catheter-associated bacteriuria was 30.7%. By multivariate analysis, female sex (odds ratio [OR], 5.1; 95% confidence interval [CI], 1.9–13.5;P=0.001) and a duration of catheterisation  1 11 days (OR, 19.4; 95% CI, 5.5–68.7;P=0.0001) were risk factors for catheter-associated bacteriuria, and prior antibiotic exposure was a protective factor (OR, 0.06; 95% CI, 0.019–0.21;P=0.0001).  相似文献   

18.
All patients with urine culture-confirmed genitourinary tuberculosis (GUTB) diagnosed between 1995 and 2007 at two medical centers in northern Taiwan were included in this retrospective study. Genotypes of 48 preserved Mycobacterium tuberculosis (MTB) isolates from these patients were determined by spoligotyping and double repetitive element PCR (DRE-PCR) analysis. Among the 64 patients, 38 (59.4%) were male with a mean ±SD age of 60.3 ± 16.1 years old. The overall mortality rate was 26.2%. Poor prognostic factors included age over 65 years (HR = 4.03; 95%; CI: 1.27–12.76), cardiovascular disease (HR = 5.96; 95% CI: 1.98–17.92), receiving steroids (HR = 10.16; 95% CI: 2.27–45.47), not being treated (HR 4.81; 95% CI 1.12–20.67). Spoligotyping and DRE-PCR of the 48 MTB isolates revealed that 20 (41.7%) belonged to the Beijing family and 40 (83.3%) had a clustering pattern. Identification of a Beijing family isolate was not correlated with drug resistance or mortality. Clustering strains were likely to be resistant to isoniazid (OR = 4.71; 95% CI: 1.10 to 23.53). In this study of patients with urine culture-confirmed GUTB, age and coexisting diseases were independently associated with an unfavorable outcome. The Beijing family was the dominant genotype of GUTB isolates, but did not correlate with drug resistance or outcome.  相似文献   

19.
The purpose of this paper is to determine the incidence of fungal colonization and infection in non-neutropenic critically ill patients and to identify factors favoring infection by Candida spp. A total of 1,655 consecutive patients (>18 years of age) admitted for ≥7 days to 73 medical-surgical Spanish intensive care units (ICUs) participated in an observational prospective cohort study. Surveillance samples were obtained once a week. One or more fungi were isolated in different samples in 59.2% of patients, 94.2% of which were Candida spp. There were 864 (52.2%) patients with Candida spp. colonization and 92 (5.5%) with proven Candida infection. In the logistic regression analysis risk factors independently associated with Candida spp. infection were sepsis (odds ratio [OR] = 8.29, 95% confidence interval [CI] 5.07–13.6), multifocal colonization (OR = 3.49, 95% CI 1.74–7.00), surgery (OR = 2.04, 95% CI 1.27–3.30), and the use of total parenteral nutrition (OR = 4.37, 95% CI 2.16–8.33). Patients with Candida spp. infection showed significantly higher in-hospital and intra-ICU mortality rates than those colonized or non-colonized non-infected (P < 0.001). Fungal colonization, mainly due to Candida spp., was documented in nearly 60% of non-neutropenic critically ill patients admitted to the ICU for more than 7 days. Proven candidal infection was diagnosed in 5.5% of cases. Risk factors independently associated with Candida spp. infection were sepsis, multifocal colonization, surgery, and the use of total parenteral nutrition.  相似文献   

20.
In Brazil tungiasis is endemic in many resource-poor communities, where various domestic and sylvatic animals act as reservoirs for this zoonosis. To determine the role of animal reservoirs in human tungiasis, a cross-sectional study was performed in a traditional fishing community in northeast Brazil. The human and the animal populations were examined for the presence of embedded sand fleas and the prevalence and the intensity of infestation were correlated. The overall prevalence of tungiasis in humans was 39% (95% CI 34–43%). Of six mammal species present in the village, only cats and dogs were found infested. The prevalence in these animals was 59% (95% CI 50–68%). In households, where infested pet animals were present, a higher percentage of household members had tungiasis (42% [95% CI 30–53%] versus 27% [20–33%], p = 0.02), and the intensity of the infestation was higher (six lesions versus two lesions, p = 0.01). The intensity of infestation in animals correlated with the intensity of infestation in humans (rho = 0.3, p = 0.02). Living in a household with an infested dog or cat led to a 1.6-fold (95% CI 1.1–2.3, p = 0.015) increase in the odds for the presence of tungiasis in household members in the bivariate analysis and remained a significant risk factor in the multivariate regression analysis. The study shows that in this impoverished community tungiasis is highly prevalent in humans and domestic animals. In particular, it underlines the importance to include animals in control operation aiming at the reduction of disease occurrence in the human population.  相似文献   

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