Cost-Effectiveness Threshold for Healthcare: Justification and Quantification.

Every public health expenditure, including the one that saves lives or extends life expectancy of particular persons (target population), bears a cost. Although cost-effectiveness analysis (CEA) is routinely performed in health policy, ethical justification of CEA is rarely discussed. Also, there is neither consensus value nor even consensus method for determining cost-effectiveness threshold (CET) for life-extending measures. In this study, we performed ethical analysis of CEA by policy impact assessment based on connection of health and wealth (poorer people have statistically shorter life expectancies) and concluded that CEA is not only a practical but also an ethical necessity. To quantify CET, we used three independent methods: (1) literature survey of analyzing salaries in risky occupations, (2) utilizing Prospect Theory suggesting that people value their lives in monetary terms twice more than their lifetime earnings, and (3) literature survey of the U.S. current legal practice. To the best of our knowledge, nobody applied method (2) to determine CET. The three methods yielded rather similar results with CET about 1.0 ± 0.4 gross domestic product per capita (GDPpc) per quality-adjusted life-year. Therefore, a sum of not higher than 140% GDPpc is statistically sufficient to "purchase" an additional year of life-or, alternatively, to "rob" one year of life if taken away. Therefore, 140% GDP per capita per quality-adjusted life-year should be considered as the upper limit of prudent and ethically justified expenditure on life extension programs.

A genetic map of melon highly enriched with fruit quality QTLs and EST markers, including sugar and carotenoid metabolism genes.

A genetic map of melon enriched for fruit traits was constructed, using a recombinant inbred (RI) population developed from a cross between representatives of the two subspecies of Cucumis melo L.: PI 414723 (subspecies agrestis) and 'Dulce' (subspecies melo). Phenotyping of 99 RI lines was conducted over three seasons in two locations in Israel and the US. The map includes 668 DNA markers (386 SSRs, 76 SNPs, six INDELs and 200 AFLPs), of which 160 were newly developed from fruit ESTs. These ESTs include candidate genes encoding for enzymes of sugar and carotenoid metabolic pathways that were cloned from melon cDNA or identified through mining of the International Cucurbit Genomics Initiative database (http://www.icugi.org/). The map covers 1,222 cM with an average of 2.672 cM between markers. In addition, a skeleton physical map was initiated and 29 melon BACs harboring fruit ESTs were localized to the 12 linkage groups of the map. Altogether, 44 fruit QTLs were identified: 25 confirming QTLs described using other populations and 19 newly described QTLs. The map includes QTLs for fruit sugar content, particularly sucrose, the major sugar affecting sweetness in melon fruit. Six QTLs interacting in an additive manner account for nearly all the difference in sugar content between the two genotypes. Three QTLs for fruit flesh color and carotenoid content were identified. Interestingly, no clear colocalization of QTLs for either sugar or carotenoid content was observed with over 40 genes encoding for enzymes involved in their metabolism. The RI population described here provides a useful resource for further genomics and metabolomics studies in melon, as well as useful markers for breeding for fruit quality.

Prevalence of HIV-1 infection in urban, semi-urban and rural areas in Arusha region, Tanzania.

OBJECTIVE: To estimate HIV-1 prevalence among the adult population in the Arusha region, northern Tanzania. DESIGN: Cross-sectional study. METHODS: Clusters of 10 households were randomly selected from urban, semi-urban and rural areas in the Arusha region. Informed verbal consent for participation in the interview and HIV-1 test were obtained from the respondents. HIV-1 antibodies were tested using enzyme-linked immunosorbent assay (ELISA) and all ELISA-positive sera were confirmed using Western blot. Approximately 66.0% of the eligible registered adults (aged 15-54 years) participated in the interview, of whom 56.6% provided blood samples for HIV-1 testing. RESULTS: HIV-1 prevalence rates among the study population from the low and high socioeconomic status urban areas, semi-urban area and rural village were 10.7, 5.2, 2.2 and 1.6%, respectively. HIV-1 prevalence was significantly higher among women (6.5%) than men (1.7%), and infection rates were consistently higher among women than men in all areas studied except in the rural village. Divorced and separated individuals had significantly higher HIV-1 prevalence (14.8%) compared with married and cohabiting individuals (4.0%). Significantly more individuals with multiple sexual partners reported regular condom use (19.3%) than those with one sexual partner (6.4%). CONCLUSION: HIV-1 prevalence in the Arusha region was higher among the urban population than among the rural population. Women living in urban areas with low socioeconomic status appeared to be associated with increased risk of HIV-1 infection.

Demographic and AIDS-related characteristics of consenters to a population-based HIV-survey: results from a pilot study in Arusha, Tanzania.

The aim was to compare demographic and AIDS-related characteristics of people who consented to HIV-testing as part of a population survey with those who did not consent to HIV-testing. Subjects, aged 15-54 years, living in ten randomly selected clusters of households in one ward of Arusha town were asked to participate in a structured interview and to provide a blood sample for HIV-testing. Measurements included demographic variables and AIDS-related factors, such as knowledge of AIDS and sexual behaviour, and HIV-testing with Western Blot confirmation. Sixty-two percent of the eligible population (N = 600) participated in the interview, while 38% consented to HIV-testing. Odds ratio analysis techniques were used to compare consenters and non-consenters. More women than men participated in the interview (OR = 4.23), and participating men were younger than non-participating men (29.1 vs 31.9 years). Subjects who had attended secondary school were underrepresented among the HIV- test consenters (OR = 0.40). No other demographic or AIDS-related differences were observed between HIV-test consenters and non-consenters. At least in this pilot, non- consenters did not appear to be at any higher risk for HIV-infection than the consenters. Future population-based HIV-surveys might have to compromise on maximizing participation rate in order to secure informed, non-coerced consent from participants.

PIP: Tanzania is one of the countries in East Africa most severely affected by the HIV/AIDS epidemic. Population-based HIV surveys have been given high priority by the research community in Tanzania because of their ability to provide information on the progression of the epidemic. One major methodological problem with such surveys, however, is the potential for low participation rates which may, in turn, challenge the validity of the data. The authors compared the demographic and AIDS-related characteristics of people who consented to HIV testing as part of a population survey with those who did not consent to such testing. One ward of Arusha was approached in 1991 through the local government and party leaders in which 360 men and 378 women aged 15-54 years were initially registered as eligible to participate in the study. 138 of the individuals had moved, were traveling outside of town for the duration of the study, or had died, and were therefore ineligible to participate in the study. 372 of the remaining 600 individuals consented to participate in a structured interview; 77.8% of the women and 43.9% of men. Only eight people actually refused to be interviewed. 148 others who were not interviewed had work obligations which had them away from home, while information is lacking on reasons for the nonparticipation of 72 subjects. Men who consented to be interviewed were of mean age 29.1 years compared to non-consenters who were of mean age 31.9 years. 227 of the subjects interviewed gave their consent to be tested for HIV-1. Odds ratio analysis techniques were used to compare consenters and non-consenters. In addition to the sex and age differences between the two groups, subjects with secondary or higher education were more likely to refuse HIV testing than subjects with less formal education. No other demographic or AIDS-related differences were observed between HIV test consenters and non-consenters. Non-consenters did not appear to be at any higher risk for HIV infection than consenters. These study results indicate the existence of a potential conflict between achieving a high participation rate and obtaining informed noncoerced consent for participation in population-based HIV surveys. This problem may be increasing as populations become more aware of the HIV/AIDS epidemic and its consequences.

Pathogenesis-related proteins are developmentally regulated in tobacco flowers.

The accumulation of pathogenesis-related proteins (PR) in tobacco leaves has been casually related to pathogen and specific physiological stresses. The known enzymatic function of some of these proteins is potentially antimicrobial. By using antibodies specific to three classes of pathogenesis-related proteins, we examined tobacco plants during their normal growth. The pathogenesis-related proteins accumulated during the normal development of the tobacco flower. The PR-1 class of proteins (biological function unknown) is located in sepal tissue. PR-P, Q polypeptides are endochitinases and are present in pedicels, sepals, anthers, and ovaries. A glycoprotein serologically related to the PR-2,N,O class is a (1,3)-beta-glucanase and is present in pistils. Differential appearance during flower development, in situ localization, and post-translational processing of floral pathogenesis-related proteins point to a hitherto unsuspected function these classes of pathogenesis-related proteins play in the normal process of flowering and reproductive physiology.

TAO1, a representative of the molybdenum cofactor containing hydroxylases from tomato.

Aldehyde oxidase and xanthine dehydrogenase are a group of ubiquitous hydroxylases, containing a molybdenum cofactor (MoCo) and two iron-sulfur groups. Plant aldehyde oxidase and xanthine dehydrogenase activities are involved in nitrogen metabolism and hormone biosynthesis, and their corresponding genes have not yet been isolated. Here we describe a new gene from tomato, which shows the characteristics of a MoCo containing hydroxylase. It shares sequence homology with xanthine dehydrogenases and aldehyde oxidases from various organisms, and similarly contains binding sites for two iron-sulfur centers and a molybdenum-binding region. However, it does not contain the xanthine dehydrogenase conserved sequences thought to be involved in NAD binding and in substrate specificity, and is likely to encode an aldehyde oxidase-type activity. This gene was designated tomato aldehyde oxidase 1 (TAO1). TAO1 belongs to a multigene family, whose members are shown to map to clusters on chromosomes 1 and 11. MoCo hydroxylase activity is shown to be recognized by antibodies raised against recombinant TAO1 polypeptides. Immunoblots reveal that TAO1 cross-reacting material is ubiquitously expressed in various organisms, and in plants it is mostly abundant in fruits and rapidly dividing tissues.

Leaf senescence is delayed in tobacco plants expressing the maize homeobox gene knotted1 under the control of a senescence-activated promoter.

Leaf senescence is an active process involving remobilization of nutrients from senescing leaves to other parts of the plant. Whereas senescence is accompanied by a decline in leaf cytokinin content, supplemental cytokinin delays senescence. Plants that overexpress isopentenyl transferase (ipt), a cytokinin-producing gene, or knotted1 (kn1), a homeobox gene, have many phenotypes in common. Many of these phenotypes are characteristic of altered cytokinin physiology. The effect of kn1 on leaf senescence was tested by driving its expression using the promoter of the senescence-associated gene SAG12. SAG:kn1 tobacco plants showed a marked delay in leaf senescence but otherwise developed normally. The delay in senescence was revealed by an increase in chlorophyll content in SAG:kn1 leaves relative to leaves of the control plants and by a decrease in the number of dead leaves. Senescence was also delayed in detached leaves of SAG:kn1 plants. Delayed senescence was accompanied by increased leaf cytokinin content in older leaves expressing kn1. These experiments extend the current understanding of kn1 function and suggest that in addition to mediating meristem maintenance, kn1 is capable of regulating the onset of senescence in leaves.

Mechanisms that control knox gene expression in the Arabidopsis shoot.

Knotted1-like homeobox (knox) genes are expressed in specific patterns within shoot meristems and play an important role in meristem maintenance. Misexpression of the knox genes, KNAT1 or KNAT2, in Arabidopsis produces a variety of phenotypes, including lobed leaves and ectopic stipules and meristems in the sinus, the region between lobes. We sought to determine the mechanisms that control knox gene expression in the shoot by examining recessive mutants that share phenotypic characteristics with 35S::KNAT1 plants. Double mutants of serrate (se) with either asymmetric1 (as1) or asymmetric2 (as2) showed lobed leaves, ectopic stipules in the sinuses and defects in the timely elongation of sepals, petals and stamens, similar to 35S::KNAT1 plants. Ectopic stipules and in rare cases, ectopic meristems, were detected in the sinuses on plants that were mutant for pickle and either as1 or as2. KNAT1 and KNAT2 were misexpressed in the leaves and flowers of single as1 and as2 mutants and in the sinuses of leaves of the different double mutants, but not in se or pickle single mutants. These results suggest that AS1 and AS2 promote leaf differentiation through repression of knox expression in leaves, and that SE and PKL globally restrict the competence to respond to genes that promote morphogenesis.

Correlation of genetic and physical structure in the region surrounding the I2 Fusarium oxysporum resistance locus in tomato.

The dominant gene I2 confers on tomato (Lycopersicon esculentum) resistance against the fungus Fusarium oxysporum f. sp. lycopersici race 2. A restriction fragment length polymorphism (RFLP) marker, TG105, has recently been found to be tightly linked to I2. The potential for cloning this gene by a reverse genetics approach prompted us to describe in both genetic and physical detail the region surrounding the I2 locus on chromosome 11. We have analyzed patterns of segregation of RFLP markers on chromosome 11 and Fusarium resistance in 140 F2 plants from a cross between Fusarium-resistant and susceptible parental lines. Marker TG105 mapped 0.4 centiMorgan (CM) from I2. Physical analysis of TG105 and its flanking RFLP markers, TG26 and TG36, by pulsed field gradient gel electrophoresis (PFGE) yielded a restriction map for this region encompassing at least 620 kb of the tomato genome. TG105 and TG26 hybridized to the same 175 kb MluI-NruI restriction fragment. We have therefore linked two genetically distinct RFLP markers. Based on the 4.1 cM distance between them, we have assigned a mean value of 43 kb for each cM recombination distance in the vicinity of I2. This local ratio between physical and genetic distances is more than 10-fold below the average for the tomato genome. It should therefore be possible to clone I2 by chromosome walking from TG105.

A major stylar matrix polypeptide (sp41) is a member of the pathogenesis-related proteins superclass.

A novel stylar-specific glycosylated protein, sp41, was characterized. Sp41 constitutes greater than 12% of the transmitting tract tissue soluble proteins and is mainly localized in the extracellular matrix. Two cDNA clones corresponding to sp41 mRNA were isolated and sequenced. The decoded sequences are, respectively, 80% and 49% homologous to acidic and basic pathogen-induced (1-3)-beta-glucanases of the leaf. Thus a subfamily of (1-3)-beta-glucanase pathogenesis-related (PR) proteins constitutes one of the major stylar matrix proteins. The accumulation of sp41 transcripts in normally developing and elicitor-treated styles and leaves was followed using an RNase protection assay. During development sp41 transcript accumulation starts well after carpel differentiation. It is first detected in styles at 8 days before anthesis. The maximal level of accumulation is reached during anthesis. Elicitor-treated styles do not accumulate the leaf-type (1-3)-beta-glucanase transcript, although they retain the capacity to synthesize leaf-type pathogenesis-related proteins such as the pathogen-induced acidic chitinase. The developmental regulation of sp41 expression points to a role for them in the normal processes of flowering and reproductive physiology.

Hemoglobin concentration in pregnant women. Experience from Moshi, Tanzania.

BACKGROUND: Anemia in pregnancy is common in Tanzania. Previous information on distribution of hemoglobin concentration in total populations is scarce. METHODS: Standard measurement of hemoglobin concentration in consecutive first visit attenders at the antenatal care clinic in Moshi, 1991-1994, for a total of 1800, divided into three series of 600 each. RESULTS: Hemoglobin concentrations ranged from 41 to 146 g/l, mean 96.9 and s.d. 16.3. For international comparison, 74.5% were below 110 g/l and 7.0% below 70 g/l. The median was 97.0; other percentiles were 10th: 75.0, 90th: 116.0. The distribution did not change with mother's age, but in the years 1991 and 1994 there were more low hemoglobin values than in the intervening years. CONCLUSIONS: Low hemoglobin concentrations are prevalent among pregnant women in Moshi, Tanzania. Seven percent were found to have severe anemia, defined as a hemoglobin concentration below 70 g/l.

The I2C family from the wilt disease resistance locus I2 belongs to the nucleotide binding, leucine-rich repeat superfamily of plant resistance genes.

Characterization of plant resistance genes is an important step in understanding plant defense mechanisms. Fusarium oxysporum f sp lycopersici is the causal agent of a vascular wilt disease in tomato. Genes conferring resistance to plant vascular diseases have yet to be described molecularly. Members of a new multigene family, complex I2C, were isolated by map-based cloning from the I2 F. o. lycopersici race 2 resistance locus. The genes show structural similarity to the group of recently isolated resistance genes that contain a nucleotide binding motif and leucine-rich repeats. Importantly, the presence of I2C antisense transgenes abrogated race 2 but not race 1 resistance in otherwise normal plants. Expression of the complete sense I2C-1 transgene conferred significant but partial resistance to F. o. lycopersici race 2. All members of the I2C gene family have been mapped genetically and are dispersed on three different chromosomes. Some of the I2C members cosegregate with other tomato resistance loci. Comparison within the leucine-rich repeat region of I2C gene family members shows that they differ from each other mainly by insertions or deletions.

Risk factors for HIV-1 infection among women in the Arusha region of Tanzania.

Risk factors for HIV-1 infection among women were assessed through a population-based cross-sectional study in the Arusha region of northern Tanzania. The study participants were obtained by randomly selecting 10-household clusters from Unga limited, the town of Babati, and the roadside village of Matufa, which are urban, semi-urban, and rural communities, respectively. Informed verbal consent for participation in an interview and in HIV-1 testing was sought from each respondent. Blood samples were collected from each consenting individual for HIV-1 antibody testing using enzyme-linked immunosorbent assay (ELISA), and all positive sera were confirmed using repeated ELISA tests. Information of risk factors was obtained through the interview process using a structured questionnaire. Of the 567 women who gave blood samples, 48 (8.5%) were HIV-1 positive. The HIV-1 seroprevalence rates among women in the urban area, the semi-urban area, and the rural village were 14.4%, 6.9% and 2.3%, respectively. Factors associated with significantly higher HIV-1 seroprevalence were urban residence; history of having traveled out of the Arusha region within Tanzania, as well as having traveled abroad; having multiple sex partners; and having sexual intercourse under the influence of alcohol. Women who reported ever having used condoms had significantly higher probability of being infected with HIV-1 than those who had never used condoms, suggesting that condom use may be a marker of high-risk sexual behavior and that condom use is probably not adhered to in a way that consistently protects against HIV-1 infection. These results suggest the need for health education interventions aimed at increasing appropriate and consistent condom use and reduction of the number of sexual partners.

PIP: A population-based cross-sectional study conducted in northern Tanzania's Arusha region found women to be at even greater risk of human immunodeficiency virus (HIV) infection than men. Three diverse sites--Unga limited (urban), the town of Babati (semi-urban), and the roadside village of Matufa (rural)--were selected. 862 (567 women and 295 men) out of 2216 eligible respondents both completed a questionnaire and provided a blood sample for HIV testing. Overall HIV-1 seroprevalence was significantly higher for women (8.5%) than men (2.0%), with a range from 2.3% among women in the rural village of Matufa to 14.4% among urban women in Unga limited. Marital status, occupation, age at first intercourse, educational status, religion, and travel within the Arusha region were not associated with a significant increase in HIV infection; however, travel out of the region or out of Tanzania was a significant risk factor. Also significant was having two or more sexual partners in the last six months or past five years. Finally, HIV rates were significantly higher among women who used condoms and those who had sexual intercourse under the influence of alcohol. The high HIV seroprevalence rate identified in this study among women may reflect selection bias and other potential risk factors (e.g., previous history of sexually transmitted diseases) that were not assessed. Of particular concern is the likelihood, given condom use as an HIV risk factor, that condoms are being used incorrectly or inconsistently in this population. Since Tanzanian women lack power in sexual relations, HIV/AIDS preventive interventions must target men as well as women.